EVIDENCE REPORT

Guidelines for the Screening, Treatment and Monitoring of Lupus Nephritis in Adults

Working Group

UCLABevra H. Hahn, MD (Rheum)

Jennifer M. Grossman, MD (Rheum)Maureen McMahon, MD (Rheum)

W Dean Wallace, MD (Path)Karandeep Singh, MD (Nephrology)

Soo-In Choi, MD (Rheum)Justin Peng, MD (Rheum)

Mazdak Khalighi, MD (Path)Maneesh Gogia, MD (Rheum)John FitzGerald, MD (Rheum)Alan Wilkinson, MD (Renal)

Suzanne Kafaja, MD (Rheum)William J Martin, MD (Rheum)

Christine Lau, MD (Nephrology)Sefali Parikh, MD (Nephrology)

Mohammad Kamgar, MD (Nephrology)Anjay Rastogi, MD (Nephrology)

Weiling Chen, MA (Rheum)Cheryl C Lee, BA (Rheum)Rikke Ogawa (Librarian)

UCLA-HarborGeorge A. Karpouzas, MD (Rheum)

UCLA and Cedars-SinaiDaniel Wallace, MD (Rheum)

OklahomaJoan T. Merrill, MD (Rheum)

UCSFJinoos Yazdany, MD (Rheum)

David Daikh, MD (Rheum)

Special thanks to Rosalind Ramsey-Goldman, MD and Niloo Nobkht, MD

Table of Contents

Abbreviations

1. Introduction

2. Guideline Development Methodsa. Methodology

1. Rationale and Development of a uniform Lupus Nephritis Definition2. Search Strategy3. Study Selection Based on Title and Abstracts4. Selection of Studies Based on Full Text of Articles5. Quality Assessment

b. Data Extraction and Synthesis1. Rating the Strength of Evidence2. RAND/UCLA Appropriateness Method Using the Task Force Panel (TFP)

c. Definition of Key Term

3. Evidence for Screening, Treatment and Monitoring of Lupus Nephritis in Adults

a. Screening Summary - Pathology1. Role of the Renal Biopsy in Lupus Nephritis2. Correlation of Outcome and Biopsy Findings3. Vascular and Tubulointerstitial Disease in Lupus Nephritis

b. Treatment and Monitoring1. Randomized Control Trials2. Cohort Studies

c. End Stage Renal Disease1. When to Consider Transplant2. Graft and Patient Survival3. Immunosuppressive Medications4. Predictors of Outcome After Transplant5. Summary

d. Pregnancy in Lupus Nephritis Patients1. Maternal/Fetal Outcomes of Pregnancy in Women with SLE2. Relationship of Drugs Used to Treat Nephritis and Outcome of Pregnancy

in Lupus Nephritis

4. Biomarkers in SLE Nephritisa. Anti-dsDNA and Complementb. Anti-dsDNAc. Anti-C1Qd. Complement

5. Adjunctive Therapies to Delay Progression of Renal Damage and Development of Co-Morbid Conditions

6. Socio-Economic Costs and Impact of Lupus Nephritisa. Overview of incidence, economic impact and risk factors of lupus nephritisb. Cost of Lupus Nephritisc. Cost Effectiveness Analysis of Specific Treatments

1. IV Cyclophosphamide vs Steroids alone2. Mycophenalate Mofetil vs IV Cyclophosphamide

Tables1. Task Force Panelists2. ISN/RPS 2003 Classification of Lupus Nephritis3. Renal Pathology Scoring System4. Studies of Poor Prognostic Findings based on Renal Biopsy5. RCT Inclusion/Exclusion Criteria and Jadad Scores6. Cohort Studies Inclusion/Exclusion Criteria and Newcastle-Ottawa Scale7. End Stage Renal Disease/Renal Transplantation Articles8 Summary of Commonly Used Medications’ Teratogenic Effects9 Use of Anti-DNA antibodies for prognosis among SLE patients

APPENDICESA. Search StrategyB. Abstraction Tool – Abstracts C. Abstraction Tool – RCT ArticlesD. Abstraction Tool – Cohort ArticlesE. Case Scenarios

REFERENCES

ABBREVIATIONS

ACR American College of RheumatologyANA Anti-nuclear antibodyAnti-dsDNA Anti-double strand Deoxynucleic AcidARA American Rheumatism AssociationAZA AzathioprineCPH Cr CreatinineCR Complete ResponseCrCl Creatinine ClearanceCYC CyclophosphamideD DayG GramHpf High Power FieldISN/RPSKG KilogramIV IntervenousLE Lupus ErythematosusMG MiligramMTX MethotrexatePOPR Partial ResponsePred PrednisoneProt ProteinRBC Red Blood CellserCr Serum CreatinineSLE Systemic Lupus ErythematosusU UrineWBC White Blood CellWHOWk WeekYr Year

1. Introduction

Important clinical advances have been made since the last ACR guidelines on diagnosis and management of SLE were published in 1999 (1). Those advances include a) improved histologic classification of subsets in renal biopsies (2), b) better management strategies to reduce renal damage (3), c) improved instruments to measure disease activity, damage, flare, and response to therapies ACR response criteria 2004 (4-9) and d) introduction of new treatments with evidence for equal or better response rates and less toxicity compared to the “standard” therapies reviewed in the 1999 (1). The promise of biologic therapies is now on the near horizon with very recent reports of successful clinical trials in lupus (e.g. Belimumab (10)) and lupus nephritis (e.g. ALMS (11)). In addition, the methodology underlying guidelines for medical therapy has improved dramatically (see for example the 2008 ACR guidelines for treatment of rheumatoid arthritis (12). Therefore, it is timely for the ACR to issue updated guidelines for screening, treatment and monitoring in people with lupus nephritis.

The purpose of this systematic review generated evidence-based report is to help develop clinical scenarios to be used for guideline development utilizing a collaborative effort with a working group (WG) and core expert panel (CEP) of clinicians and methodologists.

2. Guideline Development Methods

a. Methodology

Rationale and Development of a uniform Lupus Nephritis DefinitionAfter many discussions, the working group defined diagnosis of Lupus Nephritis as one that meets ACR criteria (persistent proteinuria and/or cellular casts) or in the opinion of a trained rheumatologist or nephrologist.

Search StrategyWe conducted a systematic review of randomized controlled trials and large cohort studies for the therapies identified by the CEP that have been used in treatment of Lupus Nephritis. The therapies chosen were selected on the basis of their availability to be used in treatment of lupus nephritis. Therapies currently in development and not yet available on the market were not reviewed. The search strategy is outlined in Appendix A, and briefly, used Medline (through PubMed) by applying MeSH headings and relevant keywords with references through 1/22/2010. The search was updated on August 8, 2010.

Study Selection Based on Titles and AbstractsOur search was limited to human studies, published in English, and having abstracts. We excluded all review articles. The initial literature search identified 10418 potential interest citations. Two reviewers screened each title and abstract for relevance to the specific aims.

The articles were excluded if:Study population not specific for lupus nephritis (e.g. lupus, autoimmune disease)Case series, Review articles, Meta-analysisStudy population consists of all patients less than age 16Study therapy is not currently commercially available

For randomized clinical trial, articles were excluded if total number of lupus nephritis patients in the study were less than 30.

For cohort studies, articles were included using the following criteria:-if treatment has already been studied in randomized clinical trial, the cohort study must

have either higher number of patients and/or longer study duration- if treatment has not been studied in randomized clinical trial but is or will anticipated to

be commercially available (e.g. rituximab, stem cell)

Selection of Studies Based on Full Text of ArticlesAt the screening phase, all articles identified through the searches for lupus nephritis were reviewed independently by two physicians using a structured form (Appendix B). A third reviewer reconciled discordant results and any disagreements between reviewers. For Randomized Clinical Trials and Cohort Studies, the principal investigators reviewed the results and made final acceptance.

Accepted Randomized Clinical Trials, articles were then reviewed and the relevant data abstracted using a standardized data abstraction forms (Appendix C). The full text of all the articles was reviewed and data abstracted by two reviewers. For Cohort Studies, full text of all the articles was reviewed and data abstracted by at least one reviewer with more than 50% of the articles undergoing duplicate independent data abstraction and reconciliation to ensure consistency and accuracy. (Appendix D – cohort study abstraction form). The principle investigator adjudicated discrepant results in both.

Accepted articles in pathology, renal transplant and end stage renal disease articles, pregnancy, biomarker, and socio-economic quality of life were sent to designated reviewers.

Data were entered into an Excel Spreadsheet.

Quality AssessmentThe quality of RCTs was assessed using the Jadad instrument (13). The Jadad scale ranges from 0-5 based on points given for randomization, blinding, and accounting for withdrawals and dropouts. The quality of the cohort Studies was assessed using the New Castle-Ottawa Quality Assessment Scale (14). The New Castle-Ottawa scale ranges from 0 – 9 stars based on points given for selection, comparability and exposure.

b. Data Extraction and Synthesis

Rating the Strength of EvidenceFor each recommendation, the strength of evidence will be assigned using the method from the American College of Cardiology (15) and/or EULAR/ESCIST (16-17) after the Task Force Panel meeting when the recommendations are developed.

RAND/UCLA Appropriateness Method using the Task Force Panel (TFP)The RAND/UCLA methodology (18-20) incorporates elements of the nominal and Delphi methods. The task force panelists received the evidence report and case scenarios (see Appendix E), illustrating the potential key permutations for each guidelines, instructions for grading scenarios and definitions of all variables and agreed upon thresholds and branch points by email. They were asked to use the evidence to rate the appropriateness of the clinical scenarios permutations. Using a 9-point Likert scale to rate each scenario permutation, the first set of ratings occurred before and a second set of ratings after a group meeting. Disagreement was defined when > 1/3 of the panelists rated a scenario in the lowest tertile of theappropriateness (1-2-3) and > 1/3 of the panelist rated the same scenario in the upper tertile (7-8-9). In the absence of disagreement, a median rating in the lowest tertile classified a scenario

permutation as “inappropriate” and a median rating in the upper tertile classified a scenario as appropriate. Those scenario permutations rating in 4-5-6 together with those with disagreement were classified as “uncertain.” Dispersion of the scores provided the degree of agreement

The anonymous ratings of the 1st round of ratings were reviewed with the panelists at each meeting. Through discussion of definitions and scenario, the reasons for the uncertain category were identified and resolution of discrepancies were attempted by modification of the scenarios,clarification of definitions, or acknowledgement of discordance between clinical practice experience and the medical literature.

Please see Table 1 for list of Task Force Panelists.

Definition of Key Term

DEFINITION OF LUPUS NEPHRITIS DIAGNOSISLupus Nephritis is defined as one that meets ACR criteria (persistent proteinuria and/or cellular casts) or in the opinion of a trained rheumatologist or nephrologist.

Evidence for the Screening, Treatment and Monitoring of Lupus Nephritis in Adults.

a. Screening Summary - Pathology

ROLE OF THE RENAL BIOPSY IN LUPUS NEPHRITISThe purpose of the renal biopsy and the significance of its findings in the treatment of lupus nephritis (LN) have been extensively debated despite, or because of, numerous studies evaluating renal biopsy findings in patients with systemic lupus erythematosus. In an effort to better characterize the specific pathologic findings in lupus-related renal disease, the World Health Organization (WHO) developed a classification system for lupus nephritis in 1974. Over the years this system has been modified and recently, in 2003, adapted into a new classification system under the auspices of the International Society of Nephrology and the Renal Pathology Society (2, 21). The lupus classification is based solely on glomerular disease and does not incorporate vascular or tubulointerstitial changes. As with the WHO system, the ISN/RPS classification has six classes: minimal mesangial LN (class I), mesangial LN (class II), focal LN (class III), diffuse LN (class IV), membranous LN (class V), and sclerosing LN (class IV). Classes III and IV are further characterized by the presence of active or chronic lesions and class IV is subdivided into segmental (IV-S) or global (IV-G) glomerular disease (see Table 2). Some studies have since shown improved interobserver reproducibility with this system (22-23).However the clinical significance of each of these classes and subclasses has been a source of investigation and debate. To evaluate acute and chronic changes a semi-quantitative activity and chronicity grading system was published by the National Institute of Health (NIH) and has been used in many studies (24) (see table 2). However, this grading system is not uniformly applied and has been shown to have poor reproducibility by some authors (25). With the wealth of literature from different cohorts of patients from all over the world over the last 30 years, it is not surprising that there are often contradictory findings in similarly structured studies (see Table 3).

The primary role of the renal biopsy is to provide information to guide treatment. Historically, the proliferative lesions (class III and IV LN) have been regarded as clinically more severe and require immunosuppressive therapy (26-28). It has been recognized that these classes have wide variability in activity and chronicity and the exact point at which immunosuppression should be started or increased has been widely investigated. A review of the literature demonstrates a

lack of consensus regarding which lesions respond to therapy and at what point treatment should be initiated. Nevertheless, many studies have shown cellular crescents, glomerular necrosis with karyorrhectic debris, subendothelial deposits, and tubulointerstitial inflammation all correlate with acute renal insufficiency and demonstrate a response to immunosuppressive therapy (29-34).

The corollary to the activity index is the chronicity index. Beyond a certain point, it is futile to attempt aggressive therapy. The point at which renal scarring precludes improvement by treatment has been investigated and should always be an important consideration in the evaluation of the renal biopsy. Sclerosing lupus nephritis (class VI) with 90% or greater glomerular sclerosis has consistently been shown to have poor prognosis or no response to treatment (35). In one study, patients younger than 23 with any form of renal scarring have been found to be at 50% risk for renal failure at 8 years (24). Furthermore, numerous studies have found each chronicity marker, specifically global and/or segmental glomerulosclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis, to be individual risk factors for renal failure and in combination indicate very high risk (29, 36-40). Chronic lesions have poor prognostic implications even in the setting of normal renal function (41).

The specific lesions and threshold of activity that require treatment have been investigated. Studies have shown no or limited response to immunosuppressive treatment in patients with mesangial lupus nephritis (class I and class II). However this should be considered in light of data revealing 50% of patients with class II lupus nephritis have no evidence of renal disease (42). Patients with subepithelial deposits only (class V) have minimal improvement of serum creatinine when treated with immunosuppressive therapy, but may improve proteinuria (43-45).In the setting of combined proliferative LN (class III or IV) and membranous LN (class V), the proliferative process dominates the clinical picture and is a better indicator of response to treatment (46).

There are several findings on the renal biopsy that can strongly suggest lupus as the etiology of the glomerulonephritis. These include “full house” deposition of immunoglobulins and complements (IgG, IgA, IgM, C1q and C3) demonstrated by immunofluorescence microscopy and tubuloreticular structures in endothelial cells seen by electron microscopy (47).Nevertheless, there are no features that are pathognomonic for lupus nephritis and it is recommended in the ISN/RPS classification system to defer the diagnosis of lupus nephritis in the absence of collaborating clinical evidence (21). Of course, the renal biopsy is also an important diagnostic tool to detect non lupus-related renal diseases or, rarely, subclinical lupus nephritis (42).

CORRELATION OF OUTCOME AND BIOPSY FINDINGSThe strongest risk factors for renal failure are primarily chronic changes, especially tubulointerstitial scarring and glomerular sclerosis. In some studies high activity indices especially the presence of cellular crescents, have also correlated with renal failure or death (32, 41, 48-50). However, mild to moderately active proliferative lesions have stronger correlation with acute renal insufficiency than chronic renal failure. This may be a reflection of treatment intervention and not a true picture of the natural disease course. One study found chronic renal insufficiency, as defined by doubling serum creatinine, was predicted by >50% crescents or moderate to severe tubulointerstitial scarring (51) (see Table 4 for composite data indicating poor renal prognosis from multiple studies).

VASCULAR AND TUBULOINTERSTITIAL DISEASE IN LUPUS NEPHRITIS

Vascular lesions are not a component of the lupus nephritis classification systems. However, there are a variety of vascular injuries that may be concurrent with the glomerular disease and may or may not be associated with the underlying lupus. The vascular lesions include nephrosclerosis, uncomplicated immune complex deposits, non-inflammatory necrotizing vasculopathy (lupus vasculopathy), vasculitis and vascular thrombosis (52). Nephrosclerosis is more common in older patients or patients with hypertension. Different studies have found no change or mild reduction in renal survival in the setting of nephrosclerosis and concurrent LN in older patients. Uncomplicated immune complex deposits are due to deposition of circulating lupus-related immune complexes. This finding has not been shown to have clinical significance. Lupus vasculopathy is most commonly seen in active class III and class IV lupus nephritis. Lupus vasculopathy is a poor prognostic finding as demonstrated by one study that found 68.1% renal survival at 5 years in patients with this lesion (53). Concurrent vasculitis is rare and is frequently associated with ANCA antibodies. Vascular thrombosis may indicate thrombotic microangiopathy and in the setting of lupus is often associated with antiphospholipid antibodies. Studies evaluating vasculitis and vascular thromboses in the setting of lupus nephritis have demonstrated increase in glomerular sclerosis and reduced renal survival (31, 53).

Tubulointerstitial inflammation is most commonly present with class III or IV LN and associated with immune complex deposits in 73% of cases (54). This suggests immune complex deposits cause most but not all cases of tubulointerstitial inflammation. The role of tubulointerstitial scarring as an independent risk factor for chronic renal failure has previously been discussed(24, 41).

b. TREATMENT AND MONITORING

Randomized Controlled Trials (RCT)In Randomized Controlled Trials, 31 peer-reviewed articles and 3 abstracts were abstracted based on selection criteria. Treatments inclusion/exclusion criteria are listed in Table 5. Jadadscore was calculated indicating the quality assessment of the article.

Therapies comparison include prednisone PO and IV, cyclosporine, cyclophosphamide PO and IV, azathioprine, plasmapheresis, mycophenolate mofetil, leflunomide, rituximab, belimumab, and tocilizumab. Data abstracted include therapies in which all study participants are on, biopsy data, duration of the study, average lupus and lupus nephritis duration, intervention arms, endpoints, and adverse reactions.

Data are compiled into an excel sheet that includes Intervention and Outcome (I-O) and a separate sheet including Adverse Events (AEs). Yellow highlights indicate statistically significant parameter within treatment arm from baseline to after treatment. Orange highlights indicate statistically significant parameter between treatment arms.

Cohort StudiesIn Cohort studies, 25 peer-reviewed articles were abstracted based on commercially available therapies, large # cohorts or long duration of the study. Newcastle-Ottawa Scale is calculated indicating the quality assessment of the article. Please see Table 6.

Therapies comparison include rituximab, stem cell, anti-malarial, cyclosporine, cytoxan, immunosuppressives, azathioprine, mycophenolate mofetil, leflunomide.

Data are compiled into an excel sheet that includes Intervention and Outcome (I-O) and a separate sheet including Adverse Events (AEs). Yellow highlights indicate statistically

significant parameter within treatment arm from baseline to after treatment. Orange highlights indicate statistically significant parameter between treatment arms.

c. End Stage Renal Disease

When to consider transplantExpert opinion suggests that clinical activity of lupus should be quiescient before transplantation, with quiescence achieved without cytotoxic agents or more than 10 mg of prednisone daily. Clinically active lupus typically improves with the development of chronic kidney disease but may not do so in some patients, particularly African American women. It is the degree of clinical activity, and not the presence or absence of serologic markers of disease activity, that should determine transplant candidacy. Patients who are heavily immunosuppressed during the course of their native kidney disease may be at increased risk for post-transplantation opportunistic infections, lymphoma, and avascular necrosis (55).

When lupus nephritis results in end stage renal disease, dialysis must be given consideration. There is some evidence to suggest that patients who receive peritoneal dialysis have better post-transplant graft outcomes as compared to those receiving hemodialysis (56). However, candidacy for peritoneal dialysis requires the presence of some residual kidney function, and as that is lost hemodialysis is usually required to achieve sufficient clearance.

The timing for transplantation is not an issue for those without donors. However, if there is ready access to a living related kidney donor, preemptive transplantation is generally a good option. One small study found that dialysis greater than 25 months may be associated with worse graft survival in transplant recipients (57), while other studies (58-59) found no association between duration of dialysis and graft outcomes. A study reviewing USRDS data over a several-year period (56) found no difference in recipient mortality in patients receiving hemodialysis prior to transplant versus no dialysis prior to transplant, although there was a trend towards worse graft outcomes in patients not receiving any dialysis (hazard ratio 1.3, p = 0.055).

Graft and patient survivalOnce a decision has been made to proceed with transplant, there is an abundance of data to suggest that kidney transplantation in patients with lupus nephritis is associated with outcomes generally equivalent to transplant recipients with other underlying etiologies (58-66). Living-related kidney transplants appear to be associated with better graft and recipient outcomes as compared to deceased donor kidney transplants (60).

One-, three-, and five-year rates of graft survival reported in the literature range from 68.8-93.6%, 56-84%, and 33-89%, respectively. Weighted mean 1-, 3-, and 5-year graft survival based on number of transplants per study was 85.1%, 60.9%, and 43.9%, respectively. One-,three-, and five-year rates of kidney transplant recipient survival reported in the literature range from 86.5-99.2%, 61-97.2%, and 36-96%, respectively. Weighted mean 1-, 3-, and 5-year patient survival based on number of transplants per study was 93.3%, 70.1%, and 53.5%, respectively.

Though subclinical recurrence of lupus nephritis may be common on routine surveillance biopsies (67), the prevalence of recurrent lupus nephritis was found to be only 2.4% in analysis of multi-year UNOS data (68), with risk factors for recurrence including African American race, female gender, and younger age.

Immunosuppressive medications

The use of calcineurin inhibitors, mycophenolate mofetil/mycophenolic acid, and azathioprine is considered the mainstay of immunosuppressive therapy in all kidney transplant recipients. Therefore, it is not surprising that the use of these drugs has been associated with improved outcomes in kidney transplant recipients with lupus nephritis. Recipients with lupus nephritis who were not treated with a calcineurin inhibitor had an 89% greater risk of graft failure and an 80% greater risk of death. Those who did not receive either mycophenolic acid or azathioprine had a 41% increased risk of graft failure and a 66% increased risk of death (56).

Predictors of outcome after transplantRisk factors for graft failure include multiple pregnancies, multiple blood transfusions, a greater comorbidity index, higher body weight, age, African American race of the donor or recipient, prior history of transplantation, greater PRA levels, lower level of HLA matching, deceased donors, and hemodialysis in pretransplant period. Risk factors for recipient death include higher recipient and donor age, prior transplantations, and higher rate of pretransplant transfusions(56).

SummaryIn summary, kidney transplantation for lupus nephritis should be treated similarly to kidney transplantation for other causes of renal failure. Ideally, lupus should be clinically quiescent at the time of transplant. Peritoneal dialysis should be chosen over hemodialysis as a bridge to transplantation if a living-related kidney donor is not readily available. Graft and patient survival in kidney transplant recipients with lupus nephritis are generally on par with non-lupus-related kidney transplant recipients. The presence of lupus should not influence choice of immunosuppressive medications. Certain factors can be predictive of worse graft and recipientoutcomes. Please see Table 7 for Summary of End Stage Renal Disease/Renal Transplantation Articles.

d. Pregnancy in Lupus Nephritis Patients

Maternal/Fetal outcomes of pregnancy in women with SLE. We identified one systematic review/ meta-analysis that examined pregnancy outcomes in patients with Systemic Lupus Erythematosus and Lupus Nephritis (69). This review yielded 37 studies which fulfilled study entry criteria, including 29 studies that were case series, five case-control studies, and three cohort studies. Twelve studies were prospective, and 25 studies were retrospective. 34 studies had data for active nephritis at the time of conception, whereas 33 reported data from patients with historic nephritis. Overall, the studies included a total of 1842 patients and 2751 pregnancies.

Random-effects analytic methods were used to evaluate pregnancy complication rates. Overall, the induced abortion rate was 5.9%; when these pregnancies were excluded, fetalcomplications included spontaneous abortion (16%), intra-uterine growth restriction (12.7%), stillbirth (3.6%), and neo-natal deaths (2.5%). Among live births, the preterm birth rate was 39.4%. The definitions used to determine these outcomes were not clarified in the manuscript.

The most frequent maternal complications included lupus flare (25.6%), hypertension (16.3%), nephritis (16.1%) (no specification given regarding frequency of new disease vs. recurrence), and pre-eclampsia (7.6%). Severe complications, including eclampsia, stroke, and maternal death were observed in <1% of subjects. Maternal deaths occurred because of opportunistic infections, sepsis, flares of lupus nephritis, and renal impairment.

Random-effects meta-regression analysis was performed to assess the effects of nephritis on pregnancy outcomes. Active nephritis was significantly associated with maternal hypertension and preterm birth, whereas a history of nephritis was significantly associated with hypertension and pre-eclampsia. After controlling for hypertension, the association between active nephritis and preterm birth was still statistically significant.

Nine papers of thrity-seven correlated renal histology with maternal and/or fetal outcomes. Among these studies, there was no statistically significant association seen between histologic subclass and the rate of unsuccessful pregnancy or any pregnancy complication.

Relationship of Drugs Used to Treat Nephritis and Outcome of Pregnancy in Lupus NephritisWe did not identify any randomized controlled studies that examined the use of medications to treat lupus nephritis in pregnancy. We did identify one retrospective case series that correlated outcomes of pregnancy with treatments of lupus (70). In this study, there were no differences in outcome seen between patients treated with prednisolone alone, prednisolone plus azathioprine, and those who received no treatment. 21/23 pregnancies in women taking azathioprine were successful. A summary of data from MICROMEDEX regarding known information about the teratogenic effects of commonly used medications in lupus nephritis is presented in Table 8.

4. BIOMARKERS IN SLE NEPHRITIS

Biomarkers can be defined as a genetic, biological, biochemical or molecular events whose alternations correlate with disease development or manifestations and can be measured in the laboratory (71). Many different types of biomarkers have been, or are being evaluated, including but not limited to genetic tests, RNA microarray profiles, cytokine profiles, autoantibody profiles and flow cytometry assays of B cell subsets. This is an evolving field with numerous promising candidates (reviewed by Mok, CC (72). This evidence report will focus on anti-dsDNA, C3, C4 and anti-C1q as they are easily measured, readily available and frequently evaluated in patients with SLE. Recommendations for the use of biomarkers in SLE will require updating as additional scientific data and clinical feasibility is reported.

Articles for the evidence report came from four sources; recent reviews (72-74), the evidence report for Quality Measures in SLE, kindly provided by Jinoos Yazdani, MD, expert identified articles, and articles from the RCT, CCT and cohort searches as described in the methods section.

Anti-dsDNA and complementThere is no direct evidence from prospective controlled trials that checking SLE specific laboratory tests, such as anti-dsDNA and complements (versus not checking these laboratories) will improve patient outcomes. However, several of these assays are part of the diagnostic criteria for SLE, have been shown to have prognostic significance, and may assist with disease monitoring (discussed under "indirect evidence" below).

With regard to monitoring of anti-dsDNA antibodies and complements, two randomized controlled trials have directly addressed the question of whether SLE flares can be decreased by responding to changing titers of these assays with escalation of immunosuppressive therapy(75-76). Although the morbidity associated with prophylactic escalations of corticosteroids have made enthusiasm for these trials somewhat limited, both trials (discussed below), did demonstrate that flares in a subset of patients can be decreased.

The first study by Dutch investigators (76) performed block randomization of patients with anti-dsDNA antibodies by whether patients experienced a flare in the previous 2 years, and by two immunosuppression maintenance regimens (stable treatment with glucocorticoids and another immunosuppressive or decreasing glucocorticoid dosage versus no immunosuppressive agents). Early treatment with prednisone 30 mg/day when patients in the treatment arm experienced a 25% rise in anti-dsDNA titers reduced the incidence of major and minor flares.

A more recent randomized study by Tseng et al.(75) followed 154 patients monthly for up to 18months. During follow-up, 41 patients were characterized as having serological flares (elevation of both anti-dsDNA level by 25% and the C3a level by 50% over the previous 1-2 monthly visits). Using a double-blind design, half of these patients received 30 mg/day of prednisone or a placebo for two weeks, followed by a taper over the ensuing 2 weeks. A statistically significant reduction in flares in the group receiving prednisone was observed. However, this study also illustrated that the positive predictive value for these biomarkers for clinical flares in SLE was suboptimal, and that many patients would be over-treated if the serological cutoffs used in this study were used.

Anti-dsDNAAnti-dsDNA antibodies have high specificity for SLE and are found in up to 70% of patients at some point in the course of the disease. Several lines of indirect evidence support the utility of checking anti-dsDNA antibodies at baseline (at a minimum) in patients with SLE. These include:

1) Evidence that these antibodies correlate with disease activity

2) Evidence that in a subset of patients, anti-dsDNA antibodies may precede disease exacerbations

3) Evidence that the presence of these antibodies may identify patients with an increased chance of specific severe disease manifestations over time, such as glomerulonephritis.

Each of these is discussed below.

Kavanaugh et al., as part of the American College of Rheumatology Ad Hoc Committee on Immunologic Testing, issued guidelines for the use of the anti-DNA antibody testing in 2002 (77).Using a systematic review of the literature, they calculated sensitivities, specificities, and likelihood ratios for anti-DNA testing in SLE. The results are adapted in Table 9.

As illustrated in Table 9, the positive likelihood ratios of 4.14 (disease activity), 1.7 (renal involvement), and 1.7 (renal activity) show that the presence of anti-DNA can influence the likelihood of important disease parameters. These overall effects are small, but significant. The general conclusion from these data is that anti-DNA antibodies remain an important clinical tool in the management of SLE. However, the specific weighted means are likely prone to error given the immense heterogeneity in studies given different definitions of disease activity and differing patient populations.

The systematic review of the literature performed by Yazdany and colleagues yielded a number of other relevant studies as well:

1) Additional studies demonstrating that anti-dsDNA antibodies correlate with disease activity in SLE were identified (78-86). However, clinical-serological discordance (i.e.

clinical quiescence, but high anti-dsDNA antibodies or vice versa) has also been described in a subset of patients (87-89).

2) Many studies have shown that rising anti-dsDNA antibody titers may predict disease flares in a subset of SLE patients (83, 89-96), particularly renal flares(97-101). However, a few negative studies have also been reported (102-104), and some studies show anti-dsDNA antibody levels actually decrease in the midst of a flare (92-94).

3) A few studies have shown that anti-dsDNA antibodies early in disease increase the chance of the development of certain disease manifestations, such as glomerulonephritis (81, 105-107), and that these antibodies may be associated with poorer renal outcomes (108-110).

Not all studies support the use of routine antiDNA testing. Esdaile and colleagues found the sensitivity for anti-dsDNA detecting a flare as assessed by SLEDAI was 50% and the specificity was less than 75% with positive and negative likelihood ratios near 1.0 (111).

Anti-C1QThe use of anti-C1q as a biomarker in lupus nephritis was recently reviewed by Mok in 2010(72). To summarize, anti-C1q antibodies are present in 20-44% of lupus patients with most studies showing an association of these antibodies with renal disease. A review by Sinico et al noted that anti-C1q correlated with active renal disease with a sensitivity ranging from 44%-100% and a specificity of 70-92% (112).

Two recent prospective studies have been published. In one study of 70 patients with SLE prior to a diagnosis of SLE , 15 developed renal disease all with positive anti-C1q, 93% with anti-dsDNA while 45% without renal disease had anti-C1q and 73% were antiDNA positive (112).The median follow up for patients who had not developed nephritis was 13 years (range 2-17). In this study, anti-C1Q did not correlate with antiDNA.

Moroni and colleagues studied the relationship of antiC1q antibodies in SLE in 228 patients followed for an average of 6 years (113). Elevation of anti-C1q predicted renal flares with a sensitivity of 80.5% and specificity of 71%. This was only marginally better than antiDNA and complement levels. This study suggested that all four tests combined together had a good negative predictive value while antiC1q combined with C3 and C4 yielded the best results for positive predictive value. Anti-C1q was not as informative in patients with membranous GN as 46% of flares occurred in anti-C1q negative patients.

Not all studies support the use of routine antiC1Q testing. Esdaile and colleagues found the sensitivity for anti-C1q detecting a flare as assessed by SLEDAI was 50% and the specificity was less than 75% with positive and negative likelihood ratios near 1.0 (111).

Anti-C1q antibodies are not necessarily specific for SLE as they can be seen in 0-3% in children and up to 18% in elderly individuals (114). They can also be seen with infections.

ComplementThe relationship of complement to SLE is complex and research in this area is ongoing. Despite the limitations of applying this potential biomarker longitudinally to all SLE patients (such as variations in synthesis, genetic deficiencies and varied extravascular distribution) (115-116), evidence supports obtaining baseline values for complements with available assays as a minimal standard of care.

Although not part of the diagnostic criteria for SLE, depressed complement levels may add to the clinical information traditionally used to diagnose the disease. In addition, literature spanning several decades points to the following generalizations:

1) Depressed complements or complement split products roughly correlate with some aspects of disease activity in SLE (85, 115-116), such as renal disease (81, 117-119),

2) Decreasing complements and complement split products can predict flares in some patients (94-96, 99-101, 120-121) and

3) Hypocomplementemia may also be associated with poorer outcomes over time (99, 122).

Not all studies support the use of routine complement testing. Esdaile and colleagues found the sensitivity for C4 detecting a flare as defined by SLEDAI was 50% and the specificity was less than 75% with positive and negative likelihood ratios near 1.0 (111). For C3, the likelihood ratio for a positive test was near 2.0, suggesting that it may be more helpful.

5. ADJUNCTIVE THERAPIES TO DELAY PROGRESSION OF RENAL DAMAGE AND DEVELOPMENT OF CO-MORBID CONDITIONS

Several partly-preventable factors contribute to progressive renal damage, particularly in the setting of proteinuria. These include adaptive hyperfiltration (relatively normal glomeruli increase in size and function in response to damage in other glomeruli, which probably leads to glomerular sclerosis), systemic hypertension, accelerated atherosclerosis, hypovolemia and exposure to nephrotoxic drugs or dyes. Therefore, management of lupus nephritis includes not only the control of SLE but also attention to these other issues, particularly since lupus nephritis tends to flare and/or to persist, making progression to end stage renal disease fairly common over a course of 25 years. The recommendations discussed below are available from the National Kidney Foundation and UpToDate (123-124).

Treatment with an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB) is recommended for any patient with glomerular disease and proteinuria persistent beyond 3 months, and/or patients with glomerular renal disease who are hypertensive. ACE and ARB are more effective in delaying decline of renal function if initiated before serum creatinine levels reach 1.2 mg/dL in women and 1.5 mg/Dl in men. There are two goals of ACE/ARB treatment: a) proteinuria lower than 1000 mg per 24 hours, and b) blood pressure lower than 130/80, with some authorities encouraging an even lower number if proteinuria exceeds 1000 mg per 24 hours. Data are stronger for effectiveness of ACE/ARB therapies in slowing decline of renal function in chronic kidney disease, compared to low protein diets. However, if proteinuria cannot be reduced below 1000 mg/24 hours with ACE/ARB, diet intervention should be considered. A 60% reduction in proteinuria from baseline may be the best achievable outcome. If ACE/ARB are not adequate for control of hypertension, loopdiuretics should be added. ACE/ARB reduce glomerular perfusion; an increase in serum creatinine is common after instituting these agents; an increase of 35% over 2 to 4 months is acceptable if stable. Hyperkalemia is also a potential adverse effect. Both serum Cr and K+ should be assayed at regular intervals after initiation of ACE/ARB therapies.

Other preventable causes of decline in renal function include dehydration for any reason (vomiting, diarrhea, infections, over-diuresis) and administration of potentially nephrotoxic drugs (aminoglycoside antibiotics, NSAIDs, radiographic contrast materials including gadolinium, etc), and these should be avoided when possible.

Metabolic disorders can accompany chronic kidney disease and cause organ damage, such as metabolic acidosis, hyperphosphatemia, hyperparathyroidism, hyperkalemia, and malnutrition

due to anorexia. Guidelines for detection and management of these problems are available (123-124).

Management of hyperlipidemia is also required as a measure to lower cardiovascular disease risk associated both with SLE and with chronic kidney disease CKD. The most common lipid abnormality in CKD is hypertriglyceridemia, which should be treated by diet and appropriate medication. CKD is considered an independent risk factor for coronary heart disease; thus the LDL-cholesterol should be kept below 100 mg/dL (2.6 mmol/L), and some authorities recommend a level less than 70 mg/dL. Statin therapies are usually required to reduce LDL-cholesterol levels. One randomized controlled study shows that patients with SLE who have undergone renal transplantation have significantly fewer cardiovascular events than similar patients on placebo (125).

Anemia of CKD may require treatment; see references (123) and (124).

Planning for renal replacement therapy, discussed in another section, should begin when GFR, falling steadily, reaches a level below 30 mL/min/1.73 M2. Planning for placement of shunts which require months to mature, for identifying and typing potential living donors, etc require time and participation of multiple medical teams. Uremic symptoms are common when GFR falls below 15 mL/min. Uremic symptoms usually requiring immediate dialysis include volume overload that cannot be controlled medically, pericarditis/pleurisy, hypertension that cannot be controlled medically, platelet dysfunction with active bleeding, acute peripheral neuropathy or encephalopathy, and hyperkalemia that cannot be controlled medically.

Prevention of infection and screening for malignancies are additional concerns in managing patients with lupus nephritis receiving chronic immunosuppression. Prospective studies of immunization with influenza or pneumococcal vaccines suggest that they are safe and relatively effective in terms of antibody titers induced (patients on high doses of immunosuppressives are less likely to respond than those on lower doses). Otherwise, systematic prospective studies addressing efficacy and safety of preventing infections and screening for malignancies in SLE patients are not available. A recent USA study (126) showed that administration of influenza/pneumococcal vaccines occurs in approximately 60% of SLE patients, as does routine screening for malignancy (mammograms, cervical smears, colon screening).

6. SOCIO-ECONOMIC COSTS AND IMPACT OF LUPUS NEPHRITISThere have been several studies that address the socio-economic costs of lupus nephritis. Pharmaceutical companies have sponsored many of these studies. However, the studies demonstrate similar findings that the additional cost of lupus nephritis over lupus without nephritis or non-lupus conditions is significant. Additional studies have examined the relative cost-effectiveness of different nephritis treatments with strong evidence supporting cycophosphamide over prednisone mono-therapy for the treatment of severe lupus nephritis (127) and mycophenalate mofetil to be more cost-effective than cyclophosphamide (128).

Overview of incidence, economic impact and risk factors of lupus nephritis

Ward described the incidence of end stage renal disease (ESRD) due to systemic lupus ertythematosus using US Renal Data System, a national population-based registry of all patients receiving renal replacement therapy for ESRD (129). The 2004 incident rate was 4.9per million in 2004. Women had higher rates than did men (7.6 vs. 2.0), African-American

higher than either Hispanic or Caucasian (20.3 vs. 5.8 vs. 3.0). Patients with lower socio-economic status had higher rates than those with high socio-economic status (5.2 vs. 3.8).

Other authors have supported the findings of higher rates of lupus nephritis among African-Americans (130-132). Poverty may account for some of this explanation (131, 133). In a population based ecological study, Ward reported that lower socio-economic areas had higher incidence of endstage renal disease due to SLE (129) suggesting that limited access to care results in poorer SLE renal outcomes. However, Petri attributed the race differences due to other factors including adherence (physician reported) and type of medical insurance (134).Contreras supported the association of poverty and lupus nephritis (132). In an interesting study on race using genetic markers and patient questionnaires from the LUMINA study (135),Fernandez portioned out the contribution of race and socio-economic factors on risk of lupus nephritis. Through logistic modeling, ethnicity explained 7.6% of the variation observed. The ethnicity component could be further broken down into admixture vs. socio-economic status variables.

Ward reported that Lupus patients were as likely to get living related transplants but less likely to get cadaveric renal transplants and more likely to stay on transplant lists longer than other patients with ESRD. Female gender and African-American patients were more prevalent proportions than other causes of renal failure (136).

Cost of Lupus Nephritis

Carls and colleagues described the direct and indirect costs of SLE and SLE nephritis using a large commercial database that contains data on medical and pharmaceutical claims to calculate direct medical costs (2005 US$) and data on employee absenteeism and short-term disability (137). The project was co-authored by the Health and Productivity Divisions, Thomas Healthcare and Bristol-Myers Squibb, UCSF Institute for Health and Productivity and Emory University, Rollins School of Public Health.

Of the 17 million enrollees, 6269 patients with lupus were identified based on at least inpatient or at least 2 outpatient medical claims. Of these SLE patients 592 had nephritis. Lupus nephritis patients’ direct and indirect medical costs totaled $58,389 and $5,806 versus Lupus patients without nephritis $15,447 and $5,714 versus $6,819 and $5,093 (for controls matched to lupus patients without nephritis). Compared to 11 other chronic care conditions, lupus nephritis was associated with the highest medical costs (driven primarily by direct medical costs).

Clarke and colleagues (138) used a cohort of 6 Canadian and US clinics that collected prospective self-reported patient data on health resource utilization and lost work. Patients’ direct and indirect medical expenditures were estimated using patient self reported health utilization and work reported absenteeism. All costs were expressed in terms of 2002 Canadian dollars. Bristol-Myers Squibb supported funding.

Of the 715 patients, 89% had no renal disease. Stratifying patients by the SLICC renal damage count, patients with higher scores had higher direct and indirect medical costs. Patient with no renal disease had median direct and indirect costs of $14K and $46K versus patients whose SLICC renal damage = 3 with costs of $90K and $77K.

Li and colleagues (139) conducted a similar study using Medicaid patients. The study was authored and supported by funding from Bristol-Myers Squibb. Using at least 2 outpatientclaims or at least 1 inpatient claim, 20,125 SLE patients were identified and 2,298 patients with continuous enrollment during the 5-years follow-up. Patients with lupus nephritis had significantly higher direct medical costs ($27,463) than either lupus patients without nephritis

($13,014) or matched controls ($9,258). When nephritis patients were stratified by presence of ESRD, costs for patients with ESRD ($47,660) were significantly higher than costs for patients without ESRD ($18,002). Li also demonstrated that costs increased significantly over the years for lupus patients (particularly for those patients with ESRD).

Pelletier and colleagues used a large US commercial insurance clams dataset to examine cost of lupus nephritis (140). The study was supported and co-authored by Genetech. Of the 15,590 SLE patients identified, 1068 had nephritis. One-third of the patients (30.3%) with nephritis were hospitalized during the year while only 13.6% of the SLE patients without nephritis were hospitalized. Costs across all medical areas of care (e.g. laboratory, outpatient, emergency department, infusions) were higher among patients with nephritis totaling $30,652 vs. $12,029 (in 2008 US$) per patient. Costs directly attributable to SLE were $6,991 and $2,489 respectively.

Cost effectiveness analyses of specific treatments

Intravenous Cyclophosphamide vs. Steroids aloneIn a 1994 NIAMS funded study, McInnes and colleagues reported that cyclophosphamide plussteroids was cost-savings compared to steroids alone, attributable to the significant costs of higher rates of ESRD for patients treated with steroids alone (127). All costs were reported in 1998 dollars. When looking at costs projected over 10 years for a hypothetical cohort of 1130 SLE nephritis patients (annual estimate of incident nephritis), the expected total costs of patients treated with steroids alone would be $65 million (more than 99% of that cost coming from the care for the 50% of patients projected with ESRD). In contrast, the cost of providing care for patients treated with cyclophosphamide was $14 million with only 5% of patients progressing to ESRD. Even though the analysis was over-simplified the magnitude of the cost-savings is clear. (As an example, they have all of the 5% of patients treated with cyclophosphamide progressing to ESRD in year 3.)

Mycophenalate Mofetil vs. Intravenous CyclophosphamideIn a study funded and co-authored by Aspreva, Wilson and colleagues analyzed quality adjusted life-years by treatment type (128). Based on 2.7 g of MMF vs. 750 mg/m2 of cyclophosphamide costs and quality of life were derived for a hypothetical cohort of 10,000 simulated patients. Algorithms were detailed to include crossover patients, expected outcomes, as well as major and some minor adverse infections. The expected cost in 2005 £ for MMF vs. cylophosphamide over 24-weeks was £1,388 vs. £2,994. MMF also had superior quality of life scores with 0.26 QALYs vs. 0.22 QALYs therefore resulting in cost-saving (dominance) of MMF yielding a cost-savings of £41,205 per QALY. The typical willingness to pay for a QALY is £25 -£35 thousand (equivalent to $50 – $70 thousand). Using sensitivity analyses to vary outcomes the confidence interval around the £41,205 per QALY even with poorer outcomes, there was 81% probability that the cost per QALY would be less than the willingness to pay for QALY.

Table 1 – Task Force Panelists

Jo H. M. Berden, MD**Professor of Nephrology

Radboud University Nijmegen Med Ctr

Nijmegen, THE NETHERLANDS

Rosalind Ramsey-Goldman, MD*

Professor of MedicineNorthwestern University

Chicago, ILLINOIS

Chi-Chiu Mok, MD*Chief of Rheumatology

Tuen Mun and Pok Oi HospitalHONG KONG

Jill P. Buyon, MD*Professor of Medicine

NYU / Hospital for Joint DiseasesNew York, NEW YORK

Frederic A. Houssiau, MD, PhD*

Professor and HeadRheumatology

Universite Catholique LouvainBrussels BELGIUM

Liz Shaw-StablerExecutive Director

Center for Lupus Care, Inc.Inglewood, CALIFORNIA

Gabriel Contreras, MD**Associate Professor of Medicine

Div of NephrologyUniversity of MiamiMiami, FLORIDA

David A. Isenberg, MD, FRCP*Professor

Center for Rheumatology Research

University College of London London ENGLAND

Brad Rovin, MD**Professor of MedicineDivision of Nephrology

The Ohio State UniversityColumbus, OHIO

Karen H. Costenbader, MD, MPH*

Assistant Professor of MedicineRheumatology Immunology &

AllergyHarvard Med School / Brigham Boston, MASSACHUSETTS

Kenneth C. Kalunian, MD*Professor of Medicine

Center for Innovative TherapyUCSD School of Medicine

La Jolla, CALIFORNIA

Murray B. Urowitz, MD, FRCPC*

Professor in MedicineThe Toronto Western Hospital

Toronto, CANADA

Mary Ann Dooley, MD*Associate Professor of Medicine

NephrologyUniversity of North Carolina

Chapel Hill, NORTH CAROLINA

Susan Manzi, MD, MPH*Chair, Department of MedicineWest Penn Allegheny Health

SystemPittsburgh, PENNSYLVANIA

David Wofsy, MD*Professor of Rheumatology

Arthritis-ImmunologyVA Medical Center / UCSF

San Francisco, CALIFORNIA

Peng Thim Fan, MD*Rheumatologist, Community

PracticeNorth Hollywood, CALIFORNIA

* = Rheumatology ** = Nephrology *** = Pathology

Table 2.

ISN/RPS 2003 Classification of Lupus Nephritis

Class I Minimal mesangial lupus nephritisClass II Mesangial proliferative lupus nephritisClass III Focal lupus nephritisa

Class III (A) Active lesions: focal proliferative lupus nephritisClass III (A/C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritisClass III (C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis

Class IV Diffuse lupus nephritisbClass IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritisClass IV-G (A) Active lesions: diffuse global proliferative lupus nephritisClass IV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritisClass IV-G (A/C) Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritisClass IV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritisClass IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis

Class V Membranous lupus nephritisClass VI Advanced sclerotic lupus nephritis

Adapted from Weening et al. (21)

Table 3.

Renal Pathology Scoring System

Activity Index Chronicity IndexGlomerular Abnormallties

1. Cellular proliferation 1. Glomerular sclerosis2. Fibrinoid necrosis, karyorrhexis 2. Fibrous crescents3. Cellular crescents4. Hyaline thrombi, wire loops5. Leukocyte infiltration

Tubulointerstitial Abnormalities1. Mononuclear-cell infiltration 1. Interstitial fibrosis

2. Tubular atrophy

All parameters are scored from 1-3 in terms of severity.Fibrinoid necrosis and cellular crescents are weighted by factorof 2. Maximum score of activity index is 24, of chronicity index is 12

Adapted from Austin et al. (24)

Table 4. Studies of Poor Prognostic Findings based on Renal Biopsy

Study Poor prognostic findings N YearAustin et al. (24) 50% renal failure at 8 years in high risk group (CI

1+ in pts age 8-23 or CI 5+ in pts 24-61) 102 1983

Austin et al. (36) 25% of class IV developed renal failure at 10 years follow up. Chronicity markers are individual risk factors for renal failure and very high risk factor in combination.

102 1984

Austin et al. (51) >50% crescents or moderate/severe interstitial fibrosis at high risk for doubling creatinine

64 1995

Banfi et al (53) Renal vascular lesions (Lupus vasculopathy, vasculitis, thrombosis, nephrosclerosis) 5 & 10year survival of 74.3% and 58% in pts with RVL vs 92% and 83.3% in pts without RVL

285 1991

Blanco et al. (48) Vascular hyalinosis, glomerular sclerosis, fibrous crescents and CI >3

85 1994

Contreras et al (141) chronicity index >/= 2 213 2005Esdaile et al (142) Tubulointerstitial fibrosis/atrophy 87 1989Esdaile et al. (33) Class IV LN Marked subendothelial immune

deposits87 1991

Faurschou et al (35) Class III, Class VI lupus nephritis 100 2010Hill et al. (143) Presence of tubular macrophages,

karyorrhexis/fibrinoid necrosis, cellular crescents71 2001

Kojo et al. (39) Cellular crescents, fibrous crescents, segmental sclerosis

99 2009

Magil et al (144) Presence of karyorrhexis 45 1988Makino et al. (30) Karyorrhexis associated with response to high

dose steroids60 1993

Miranda et al. (31) Glomerular thrombosis strongly associated with crescents, glomerular necrosis and increased AI

108 1994

Moroni et al (145) CI > 2 93 2007Mosca et al. (26) AI 9+, CI 4+ 81 1997Nossent et al (38) AI 12+, CI 4+ 116 1990Parichatikanond et al (37)

>25% sclerotic glomeruli, >25% tubular atrophy, >25% interstitital mononuclear, infiltrate

81 1997

Yokoyama et al. (23) Class IV(S &G), ESRF in patients with IV(S or G) vs I, II, III, V (40.9% vs 2.6%)

60 2004

AI = activity index, CI = chronicity index, RVL = renal vascular lesion, LN = lupus nephritis

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pers

ensi

tivity

to a

stu

dy d

rug,

or a

ser

um

crea

tinin

e gr

eate

r tha

n 4.

0mg%

(cre

atin

ine

clea

ranc

e <2

0ml/m

in)

4

Car

ette

et a

l, N

IH, U

SA

,19

83(1

48)

Dia

gnos

is o

f SLE

by

ARA

pre

limin

ary

crite

ria,

posi

tive

lupu

s er

ythe

mat

osus

cel

l tes

t, an

d ki

dney

di

seas

e un

acco

unte

d fo

r by

othe

r pat

holo

gic

proc

esse

s w

ith a

t lea

st o

ne o

f the

follo

win

g: r

ed

cell

cast

s in

a fr

esh

cent

rifug

ed u

rine

sedi

men

t; ce

llula

r cas

ts a

nd e

ither

hem

atur

ia (t

en

eryt

hroc

ytes

per

hig

h po

wer

fiel

d) o

r pyu

ria (t

en

leuk

ocyt

es p

er h

igh

pow

er fi

eld)

in th

e ab

senc

e of

in

fect

ion;

pro

tein

uria

of a

t lea

st 1

g/d

or t

he

com

bina

tion

of h

igh

seru

m D

NA

bin

ding

act

ivity

, lo

w s

erum

com

plem

ent a

nd re

nal b

iops

y re

sults

co

nsis

tent

with

lupu

s gl

omer

ulon

ephr

itis

A m

ajor

infe

ctio

n w

ithin

the

prec

edin

g 2

wee

ks,

preg

nanc

y, im

mun

osup

pres

sive

ther

apy

with

in 2

m

onth

s, s

ever

e liv

er d

isea

se, a

his

tory

of

hype

rsen

sitiv

ity to

a s

tudy

dru

g, o

r a s

erum

cr

eatin

ine

grea

ter t

han

4.0m

g% (c

reat

inin

e cl

eara

nce

<20m

l/min

)

1

Aus

tin e

t al,

Dia

gnos

is o

f SLE

as

defin

ed b

y A

RA

, clin

ical

or

Cre

atin

ine

clea

ranc

e co

nsis

tent

ly le

ss th

an 2

0ml

1

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Pred

niso

ne (P

red)

vs

Aza

thio

prin

e (A

ZA) v

s C

yclo

phos

pham

ide

(CYC

)A

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eN

IH, U

SA

,19

86(1

49)

hist

olog

ic e

vide

nce

of a

ctiv

e lu

pus

glom

erul

onep

hriti

s, a

nd in

form

ed c

onse

nt to

all

aspe

cts

of th

e st

udy.

per m

inut

e, m

ajor

infe

ctio

n w

ithin

2 w

eek

s of

stu

dy

entry

, pre

gnan

cy, a

leuk

ocyt

e co

unt o

f les

s th

an

2000

per

cub

ic m

illim

eter

, cyt

otox

ic-d

rug

ther

apy

with

in e

ight

wee

ks, a

nd s

ensi

tivity

to th

e st

udy

drug

Ste

inbe

rg a

nd

Ste

inbe

rg,

NIH

, US

A,

1991

(150

)

Dia

gnos

is o

f sys

tem

ic lu

pus

eryt

hem

atos

us a

nd

clin

ical

/his

tolo

gic

evid

ence

of a

ctiv

e lu

pus

glom

erul

onep

hriti

s.

Cre

atin

ine

clea

ranc

e co

nsis

tent

ly <

20m

l/min

ute,

pr

esen

ce o

f a m

ajor

infe

ctio

n w

ithin

the

prev

ious

2

wee

ks, p

regn

ancy

, whi

te b

lood

cel

l cou

nt

<200

0/m

m3,

trea

tmen

t with

a c

ytot

oxic

dru

g w

ithin

th

e pr

evio

us 8

wee

ks, o

r kno

wn

sens

itivi

ty to

any

st

udy

drug

.

2

Gro

otsc

holte

n et

al,

Net

herla

nds

Nep

hrol

ogy,

20

06(1

51)

The

pres

ence

of >

=4 A

CR

crit

eria

for S

LE, a

ge 1

8 to

60

year

s, c

reat

inin

e cl

eara

nce

(Coc

kcro

ft-G

ault)

>2

5ml/m

in, a

nd b

iops

y-pr

oven

pro

lifer

ativ

e LN

. Fo

r pa

tient

s al

read

y kn

own

to h

ave

prol

ifera

tive

LN, t

hela

st re

nal b

iops

y ha

d to

be

perfo

rmed

less

than

one

ye

ar b

efor

e. P

atie

nts

with

WH

O-c

lass

IV o

r Vd

LN

wer

e el

igib

le w

hen

they

had

sig

ns o

f act

ive

neph

ritis

or a

det

erio

ratio

n of

rena

l fun

ctio

n.

Pat

ient

s w

ith W

HO

-cla

ss II

I or V

c LN

had

to m

eet

both

crit

eria

.

Pat

ient

s w

ith m

embr

anou

s LN

WH

O-c

lass

Va

or V

b w

ere

excl

uded

.. D

eclin

e in

rena

l fun

ctio

n (m

ore

than

30%

incr

ease

in s

erum

cre

atin

ine)

dur

ing

treat

men

t with

cyt

otox

ic im

mun

osup

pres

sive

age

nts

in th

e m

onth

bef

ore

incl

usio

n. A

ctiv

e in

fect

ion.

M

alig

nanc

y <5

yea

rs b

efor

e ra

ndom

izat

ion.

P

regn

ancy

or r

efus

al to

use

relia

ble

cont

race

ptiv

es

durin

g th

e fir

st 2

.5 y

ears

of t

reat

men

t. C

hron

ic

activ

e or

per

sist

ing

hepa

titis

or c

irrho

sis

of th

e liv

er,

activ

e pe

ptic

ulc

er, l

euko

cyto

peni

a (<

3.0x

10 9

/l) o

r th

rom

bocy

tope

nia

(<10

0 x

10 9

/l), w

ith s

uppr

esse

d bo

ne m

arro

w (a

s sh

own

in a

bon

e m

arro

w

aspi

rate

). K

now

n al

lerg

y fo

r aza

thio

prin

e or

cy

clop

hosp

ham

ide.

2

Pred

niso

ne (P

red)

vs

Cyc

loph

osph

amid

e (C

YC) I

VA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Bou

mpa

s et

al

, NIH

, US

A19

92(1

52)

Pat

ient

s ha

d 4

or m

ore

crite

ria fo

r SLE

and

sev

ere

lupu

s ne

phrit

is d

efin

ed b

y a

neph

ritic

urin

e se

dim

ent a

nd im

paire

d re

nal f

unct

ion

with

a

crea

tinin

e cl

eara

nce

betw

een

25 a

nd 8

0 m

l per

m

in.

If cr

eatin

ine

clea

ranc

e w

as h

ighe

r tha

n 80

ml

per m

in, t

he c

andi

date

had

to h

ave

very

act

ive

rena

l his

tolo

gy w

ith c

resc

ents

or n

ecro

sis

in m

ore

Pre

gnan

cy o

r had

rece

ived

cyt

otox

ic d

rug

ther

apy

for m

ore

than

10

wee

ks a

t any

tim

e, a

ctiv

e in

fect

ions

, ins

ulin

-dep

ende

nt d

iabe

tes,

or p

revi

ous

mal

igna

ncy.

2

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Pred

niso

ne (P

red)

vs

Aza

thio

prin

e (A

ZA) v

s C

yclo

phos

pham

ide

(CYC

)A

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eth

an 2

5% o

f glo

mer

uli.

Ren

al b

iops

ies

wer

e ev

alua

ted

by li

ght a

nd e

lect

ron

mic

rosc

opy.

Gou

rley

et a

l, N

IH, U

SA

,19

96(1

53)

Pat

ient

s ha

d to

hav

e bo

th g

lom

erul

onep

hriti

s an

d a

diag

nosi

s of

sys

tem

ic lu

pus

eryt

hem

atos

us.

Glo

mer

ulon

ephr

itis

was

def

ined

as

a se

dim

ent o

n tw

o or

mor

e ur

ianl

yses

that

sho

wed

eith

er 1

0 or

m

ore

eryt

hroc

ytes

per

hig

h-po

wer

fiel

d or

er

ythr

ocyt

e or

leuk

ocyt

e ca

sts

(with

out e

vide

nce

of

infe

ctio

n) o

r bot

h, p

lus

hist

olog

ic e

vide

nce

of a

ctiv

e pr

olife

rativ

e lu

pus

glom

erul

onep

hriti

s on

a re

nal

biop

sy s

peci

men

obt

aine

d w

ithin

3 m

onth

s of

stu

dy

entry

(pro

vide

d th

at a

bio

psy

coul

d be

don

e sa

fely

).

Rec

eipt

of c

ytot

oxic

dru

g tre

atm

ent f

or m

ore

than

2

wee

ks d

urin

g th

e 6

wee

ks b

efor

e st

udy

entry

or

rece

ipt o

f cyl

opho

spha

mid

e th

erap

y fo

r mor

e th

an

10 w

eeks

at a

ny ti

me;

rece

ipt o

f pul

se th

erap

y w

ith

corti

cost

eroi

ds d

urin

g th

e 6

wee

ks b

efor

e st

udy

entry

; nee

d (a

t the

tim

eof

stu

dy e

ntry

_ fo

r ora

l co

rtico

ster

oids

in d

osag

es g

reat

er th

an 0

.5m

g of

a

pred

niso

ne e

quiv

alen

t per

kilo

gram

of b

ody

wei

ght

per d

ay to

con

trol e

xtra

rena

l dis

ease

; act

ive

or

chro

nic

infe

ctio

n; p

regn

ancy

; the

pre

senc

e of

onl

y on

e ki

dney

; ins

ulin

-dep

ende

ntdi

abet

es m

ellit

us;

and

alle

rgy

to m

ethy

pred

niso

lone

or

cylo

phos

pham

ide.

2

Pred

niso

ne (P

red)

vs

Cyc

loph

osph

amid

e (C

YC) P

OA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Don

adio

et

al, M

ayo,

U

SA

,19

76(1

54)

Clin

ical

dia

gnos

is o

f SLE

and

fulfi

lled

4 or

mor

e of

th

e cr

iteria

for t

he c

lass

ifica

tion

of S

LE a

s de

velo

ped

by th

e A

RA

Com

mitt

ee o

n D

iagn

ostic

an

d Th

erap

eutic

Crit

eria

. Se

rolo

gic

conf

irmat

ion

of

the

dise

ase

was

als

o re

quire

d, b

ased

on

findi

ng o

f a

posi

tive

LE-c

ell p

repa

ratio

n an

d an

AN

A in

a ti

ter

>= 1

:32

–or

if a

pos

itive

LE

-cel

l pre

para

tion

was

no

t obt

aine

d, o

n fin

ding

two

doub

tful p

ositi

ve (f

or

exam

ple,

rose

ttes

of n

eutro

phils

or n

ucle

olys

is) a

nd

an A

NA

titer

>=

1:32

. In

add

ition

, wor

king

crit

eria

defin

ing

prog

ress

ive

lupu

s gl

omer

ulon

ephr

itis

on

the

basi

s of

rena

l ins

uffic

ienc

y ba

sed

eith

er o

n re

duce

d in

itial

cre

atin

ine

clea

ranc

e to

less

than

80

ml/m

in p

er 1

.73m

2 or

on

a 25

% re

duct

ion

in

crea

tinin

e cl

eara

nce

as c

ompa

red

to in

itial

Cyc

loph

osph

amid

e ha

d be

en u

sed

in th

e pa

st o

r if

othe

r im

mun

osup

pres

sive

dru

gs h

ad b

een

used

w

ithin

6 m

onth

s of

ent

ry in

to th

e st

udy.

2

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Pred

niso

ne (P

red)

vs

Cyc

loph

osph

amid

e (C

YC) P

OA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

ecl

eara

nce

over

am

axim

um p

erio

d of

3 m

onth

s, a

nd

on a

rena

l mor

phol

ogic

dia

gnos

is o

f act

ive

glom

erul

onep

hriti

s. A

rbitr

arily

est

ablis

hed

a 25

%

chan

ge in

cre

atin

ine

clea

ranc

e as

indi

ctin

g an

im

porta

nt c

hang

e in

rena

l fun

ctio

n so

as

to ta

ke in

to

cons

ider

atio

n th

e bi

olog

ic v

aria

bilit

y of

cre

atin

ine

excr

etio

n th

at in

fluen

ces

crea

tinin

e cl

eara

nce.

P

atie

nts

prev

ious

ly u

ntre

ated

or t

reat

ed w

ith

adre

noco

rtico

ids

wer

e co

nsid

ered

to b

e el

igib

le fo

r th

e st

udy

Dan

adio

et

al, M

ayo

Clin

ic, U

SA

19

78(1

55)

Clin

ical

dia

gnos

is o

f sys

tem

ic lu

pus

eryt

hem

atos

us

and

have

fulfi

lled

4 or

mor

e of

the

crite

ria u

sed

for

the

clas

sific

atio

n of

the

dise

ase.

A p

ositi

ve L

E-c

ell

prep

arat

ion

or ro

sette

s of

neu

troph

ils o

r nu

cleo

lysi

s, a

pos

itive

AN

A >

= 1:

32 o

r sin

ce m

id-

1973

, ele

vate

d le

vels

of a

nti-n

DN

A, c

reat

inin

e cl

eara

nce

less

than

80m

l/min

/1.7

3m2

or a

re

duct

ion

of 2

5% in

cre

atin

ine

clea

ranc

e as

co

mpa

red

with

the

initi

al c

lear

ance

ove

r a m

axim

al

perio

d of

3 m

onth

s, a

nd a

dequ

ate

rena

l bio

psy

show

ing

diffu

se p

rolif

erat

ive

glom

erul

onep

hriti

s.

Pat

ient

s pr

evio

usly

unt

reat

ed o

r tre

ated

with

ste

roid

ag

ents

wer

e el

igib

le.

Cyc

loph

osph

amid

e ha

d be

en u

sed

in th

e pa

st o

r if

othe

r im

mun

osup

pres

sive

dru

gs h

ad b

een

used

w

ithin

6 m

onth

s of

ent

ry in

to th

e st

udy.

2

Pred

niso

ne (P

red)

+ C

yclo

phos

pham

ide

(CYC

) vs

plas

map

here

sis

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

Jada

d Sc

ore

Cla

rk e

t al,

C

anad

a an

d Ja

mai

ca,

1983

(156

)

4 of

the

AR

A c

riter

ia fo

r the

dia

gnos

is o

f SLE

and

ha

d at

leas

t one

epi

sode

of A

NA

pos

itivi

ty, e

leva

ted

DN

A b

indi

ng a

nd c

ompl

emen

t dep

ress

ion.

All

had

rena

l bio

psy

with

the

diag

nosi

s of

diff

use

prol

ifera

tive

glom

erul

onep

hriti

s.

Cre

atin

ine

cler

aran

ce w

as le

ss th

an 3

mg/

100m

l.1

Poh

l et a

l,Lu

pus

Dia

gnos

is o

f SLE

con

firm

ed b

y at

leas

t 4 o

f the

A

RA

dia

gnos

tic c

riter

ia w

ith s

ome

mod

ifica

tions

; by

Ser

um c

reat

inin

e co

ncen

tratio

n of

mor

e th

an 5

33

mic

rom

ol/L

(6.0

mg/

dL);

prev

ious

pla

smap

here

sis

2

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Pred

niso

ne (P

red)

+ C

yclo

phos

pham

ide

(CYC

) vs

plas

map

here

sis

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

Jada

d Sc

ore

Nep

hriti

s C

olla

bora

tive

Stu

dy G

roup

, N

IH, U

SA

,19

91(1

57)

curre

nt re

nal b

iops

y ev

iden

ce o

f sev

ere

lupu

s gl

omer

ulon

ephr

itis

(WH

O C

lass

III o

r IV

with

mor

e th

an 5

0% o

f glo

mer

uli i

nvol

ved

or c

lass

V w

ith

supe

rimpo

sed

diffu

se o

r sev

ere

segm

enta

l pr

olife

ratio

n)

for a

ny re

ason

; a h

isto

ry o

f ste

roid

psy

chos

is;

curre

nt p

regn

ancy

; a h

isto

ry o

f neo

plas

m w

ithin

the

prev

ious

5 y

ears

; a n

eutro

phil

coun

t of l

ess

than

1500

/mm

3; o

r age

of l

ess

than

16

year

s.

Lew

is e

t al,

Lupu

s N

ephr

itis

Col

labo

rativ

e G

roup

, US

A,

1992

(158

)

16 y

ears

of a

ge o

r old

er; d

iagn

osis

of S

LE a

s de

fined

by

AR

A a

nd a

qua

lifyi

ng re

nal b

iops

y.P

regn

ancy

, ser

um c

reat

inin

e co

ncen

tratio

n ab

ove

530

mic

rom

ol p

er li

ter (

6mg/

dL),

prev

ious

trea

tmen

t w

ith p

lasm

aphe

resi

s, a

his

tory

of p

rimar

y m

yoca

rdia

l dis

ease

, a h

isto

ry o

f can

cer w

ithin

the

past

5 y

ears

, pre

dnis

one-

asso

ciat

ed p

sych

osis

, pe

ptic

ulc

er d

isas

e, a

nd a

ctiv

e liv

er d

isea

se.

3

Cyc

loph

osph

amid

e (C

YC) I

V vs

Cyc

loph

osph

amid

e (C

YC) P

OA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Mok

et a

l, H

ong

Kon

g,

2001

(159

)

Fulfi

lled

at l

east

4 o

f the

AC

R c

riter

ia fo

r the

cl

assi

ficat

ion

of S

LE a

nd h

ad D

PGN

(WH

O C

lass

IV

a or

IVb)

dia

gnos

ed a

nd tr

eate

d in

two

larg

e re

gion

al h

ospi

tals

in H

ong

Kon

g (Q

ueen

Mar

y an

d Te

n M

un H

ospi

tals

) bet

wee

n 19

95 a

nd 1

998

wer

e in

clud

ed in

this

stu

dy.

Ref

used

CYC

trea

tmen

t or i

n w

hom

rena

l bio

psy

show

ed s

igni

fican

t scl

eros

is o

r chr

onic

cha

nges

but

w

ithou

t act

ivity

wer

e ex

clud

ed.

0

Hig

h-D

ose

Cyc

loph

osph

amid

e (C

YC) I

V vs

Low

Dos

e C

yclo

phos

pham

ide

(CYC

) IV

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

Jada

d Sc

ore

Hou

ssia

u et

al

, Eur

o-Lu

pus

Nep

hriti

s Tr

ial,

2002

(160

)

Dia

gnos

is o

f SLE

acc

ordi

ng to

the

AC

R c

riter

ia,

age

>= 1

4 ye

ars,

bio

psy

prov

en p

rolif

erat

ive

lupu

s gl

omer

ulon

ephr

itis

(WH

O C

lass

II, I

V, V

c, o

r Vd)

, an

d pr

otei

nuria

>= 5

00m

g in

24

hour

s.

Pat

ient

s w

ho h

ad ta

ken

CYC

or A

ZA d

urin

g th

e pr

evio

us y

ear o

r had

take

n >=

15m

g/da

y pr

edni

sone

(o

r equ

ival

ent)

durin

g th

e pr

evio

us m

onth

wer

e ex

clud

ed (e

xcep

t for

a c

ours

e of

glu

coco

rtico

ids

for

a m

axim

um o

f 10

days

bef

ore

the

refe

rral).

Oth

er

excl

usio

n cr

iteria

wer

e re

nal t

hrom

botic

m

icro

angi

opat

hy, p

reex

istin

g ch

roni

c re

nal f

ailu

re,

preg

nanc

y, p

revi

ous

mal

igna

ncy

(exc

ept s

kin

and

cerv

ical

intra

epith

elia

l neo

plas

is),

diab

etes

mel

litus

,

2

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Hig

h-D

ose

Cyc

loph

osph

amid

e (C

YC) I

V vs

Low

Dos

e C

yclo

phos

pham

ide

(CYC

) IV

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

Jada

d Sc

ore

prev

ious

ly d

ocum

ente

d se

vere

toxi

city

to

imm

unos

uppr

essi

ve d

rugs

, and

ant

icip

ated

poo

r co

mpl

ianc

e w

ith th

e pr

otoc

ol.

Myc

ophe

nola

te M

ofet

il (M

MF)

+ T

acro

limus

vs

Cyc

loph

osph

amid

e (C

YC) I

VA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Bao

et a

l, N

anjin

g,20

08(1

61)

Elig

ible

pat

ient

s w

ere

eith

er g

ende

r and

bet

wee

n 12

and

60

yr o

f age

; pro

vide

d w

ritte

n in

form

ed

cons

ent;

diag

nosi

s of

SLE

acc

ordi

ng fo

r AC

R

(199

7); s

how

ed a

n SL

E d

isea

se a

ctiv

ity in

dex

>=12

; had

a d

iagn

osis

of C

lass

V+I

V LN

acc

ordi

ng

to IS

N/R

PS 2

003

clas

sific

atio

n of

LN

, with

a

path

olog

ic c

hron

ic in

dex

(CI)

<4 p

rove

d by

ligh

t, im

mun

oflu

ores

cenc

e, a

nd e

lect

ron

mic

rosc

opy

with

in 3

wk

befo

re e

nrol

lmen

t; an

d ex

hibi

ted

over

t pr

otei

nuria

(>=1

.5g

of p

rote

in in

a 2

4-h

urin

e sp

ecim

en) w

ith o

r with

out a

ctiv

e ur

inar

y se

dim

ent

(any

of u

rine

sedi

men

t RB

C c

ount

>10

x 1

0 4/

ml o

r w

hite

blo

od c

ells

> 5

per

hig

h-po

wer

fiel

d or

red

cell

cast

s in

the

abse

nce

of in

fect

ion

or o

ther

cau

ses.

Ser

um c

reat

inin

e >

3.0m

g/dl

(265

.2 m

icro

lmol

/L) o

r es

timat

ed C

reat

inin

e cl

eara

nce

<30m

l/min

per

1.

73m

2 on

repe

ated

test

ing;

live

r fun

ctio

n w

ith A

LT,

AS

ST, o

r bilir

ubin

gre

ater

than

twic

e th

e up

per l

imit

of th

e re

fere

nce

rang

e; a

bnor

mal

glu

cose

m

etab

olis

m, d

efin

ed a

s a

fast

ing

(i.e.

, no

calo

ric

inta

ke fo

r at l

east

8 h

) pla

sem

a gl

ucos

e le

vel >

6.1

m

mol

/L a

nd/o

r a 2

-h p

lasm

a gl

ucos

e le

vel >

7.8

m

mol

/L; k

now

n hy

pers

ensi

tivity

or c

ontra

indi

catio

n to

any

com

pone

nts

of th

ese

regi

men

s; u

se o

f CTX

, M

MF,

or t

acro

limus

with

in th

e pa

st 1

2 w

k;

preg

nanc

y or

lact

atio

n; li

fe-th

reat

enin

g co

mpl

icat

ions

suc

h as

cer

ebra

l lup

us; o

r oth

er

seve

re c

oexi

stin

g co

nditi

ons

prec

ludi

ng

imm

unos

uppr

essi

ve th

erap

y or

con

ditio

ns re

quiri

ng

intra

veno

us a

ntib

iotic

ther

apy.

2

Myc

ophe

nola

te M

ofet

il (M

MF)

vs

Cyc

loph

osph

amid

e (C

YC) I

VA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Hu

et a

l, N

anjin

g,

2002

(162

)

Pat

ient

s ha

s SL

E d

iagn

osis

acc

ordi

ng to

AR

A

crite

ria; u

rinal

ysis

sho

wed

act

ive

urin

e se

dim

ents

,pr

otei

nuria

>2g

/d; r

enal

bio

psy

revi

ewed

lupu

s ne

phrit

is W

HO

IV w

ithin

3 m

onth

s pr

ior t

o th

e st

udy

Sev

ere

com

plic

atio

n su

ch a

s in

fect

ion,

leuc

open

ia,

hear

t fai

lure

or m

alfu

nctio

n of

the

cent

ral n

erve

sy

stem

or l

iver

-1

Ong

et a

l, M

alay

sia,

2005

(163

)

SLE

fulfi

lling

AR

A c

riter

ia w

ith W

HO

Cla

ss II

I or I

V

lupu

s ne

phrit

is, a

ged

16 y

ears

or o

lder

Ser

um c

reat

inin

e m

ore

than

200

mic

rom

ol/L

, whi

te

bloo

d ce

ll co

unt <

3.5

x 1

0 9

L, e

vide

nce

of m

ajor

in

fect

ion,

his

tory

of c

ance

r, al

coho

l or s

ubst

ance

2

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Myc

ophe

nola

te M

ofet

il (M

MF)

vs

Cyc

loph

osph

amid

e (C

YC) I

VA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eab

use,

act

ive

pept

ic u

lcer

dis

ease

, pre

gnan

t or

lact

atin

g w

omen

, kno

wn

alle

rgy

to M

MF

or

cycl

opho

spha

mid

e an

d us

e of

stu

dy d

rugs

in th

e pr

eced

ing

6 m

onth

s.

Gin

zler

et a

l,U

SA

,20

05(1

64)

SLE

mee

ting

4 cl

assi

ficat

ion

crite

ria o

f the

AC

R;

rena

l bio

psy

docu

men

ting

lupu

s ne

phrit

is a

ccor

ding

to

the

clas

sific

atio

n of

WH

O II

I, IV

, or V

; clin

ical

ac

tivity

as

defin

ed b

y on

e or

mor

e of

the

follo

win

g:

inci

denc

e de

crea

se in

rena

l fun

ctio

n (s

erum

cr

eatin

ine,

>1m

g/dL

(88.

4 m

icro

mol

/L),

prot

einu

ria

(def

ined

as

mor

e th

an 5

00m

g of

pro

tein

in a

24-

hur

ine

spec

imen

), m

icro

scop

ic h

emat

uria

(def

ined

as

>5

red

cells

per

hig

h po

wer

-fiel

d) o

r the

pr

esen

ce o

f cel

lula

r cas

ts, i

ncre

asin

g pr

otei

nuria

w

ith ri

sing

leve

ls o

f ser

um c

reat

inin

e, a

ctiv

e ur

ine

sedi

men

t (he

mat

uria

or c

ellu

ar c

asts

), or

ser

olog

ic

abno

rmal

ity (a

nti-D

NA

ant

ibod

ies

or

hypo

com

plem

ente

mia

). T

hose

with

Cla

ss II

I or V

lu

pus

neph

ritis

wer

e re

quire

d to

hav

e a

seru

m

crea

tinin

e le

vel g

reat

er th

an 1

mg/

dL o

r pro

tein

uria

gr

eate

r tha

n 2g

in a

24-

h ur

ine

spec

imen

.

Cre

atin

ine

clea

ranc

e of

less

than

30m

l /m

in, s

erum

cr

eatin

ine

on re

peat

ed te

stin

g gr

eate

r tha

n 3m

g/dL

(2

65.2

mic

rolm

ol /L

), se

vere

coe

xist

ing

cond

ition

s pr

eclu

ding

imm

unos

uppr

essi

ve th

erap

y or

co

nditi

ons

requ

iring

intra

veno

us a

ntib

iotic

ther

apy,

pr

ior t

reat

men

t with

myc

ophe

nola

te m

ofet

il,

treat

men

t with

intra

veno

us c

yclo

phos

pham

ide

with

in th

e pa

st 1

2 m

onth

s, m

onoc

lona

l ant

ibod

y th

erap

y w

ithin

the

past

30

days

, or p

regn

ancy

or

lact

atio

n.

2

Wan

g et

al,

Nan

jing,

2007

(165

)

AR

A c

riter

ia o

f SLE

, 18-

50 y

rs o

f age

; urin

e pr

otei

n >=

1g/

24h

with

act

ive

urin

e se

dim

ent;

seru

m

crea

tinin

e <3

mg/

dL (2

65m

icro

lmol

/L) o

r cre

atin

ine

clea

ranc

e >=

30m

L/m

in, b

iops

y pr

oven

ISN

/RP

S

Cla

ss IV

with

exc

eptio

n of

sup

erim

pose

d m

embr

anou

s ch

ange

s an

d N

NV

lesi

on s

how

n in

ar

terio

les

and

inte

rlobu

lar a

rterie

s an

d th

e pr

opor

tion

of g

lom

erul

ar s

cler

osis

<50

% a

nd

chro

nic

inde

x <4

.

Ser

um c

reat

inin

e >=

3 m

g/dL

or c

reat

inin

e cl

eara

nce

<30m

L/m

in; p

ropo

rtion

of g

lom

erul

ar

scle

rosi

s >=

50%

, chr

onic

ity in

dex

>=4

with

sev

eral

re

nal t

ubul

e-in

ters

titia

l fib

rosi

s; p

rimar

y or

se

cond

ary

imm

unod

efic

ienc

y, e

spec

ially

leuk

ocyt

e co

unt o

f <=2

x 1

9 9

L; a

ny c

linic

ally

sig

nific

ant

infe

ctio

n, p

regn

ancy

or l

acta

tion,

act

ive

type

B o

r C

hepa

titis

, tub

ercu

losi

s an

d th

e re

ceip

t of C

TX,

MM

F, o

r oth

er c

ytot

oxic

dru

gs w

ithin

the

past

3

mon

ths

3

App

el e

t al,

ALM

S,

2009

(166

)

Age

d 12

to 7

5 yr

s, d

iagn

osis

of S

LE, L

N (a

ctiv

e or

ac

tive/

chro

nic)

con

form

ed b

y ki

dney

bio

psy

with

in

6 m

o be

fore

rand

omiz

atio

n as

ISN

/RP

S 2

003

Trea

tmen

t with

MM

F or

IVC

with

in th

e pr

evio

us

year

, con

tinuo

us d

ialy

sis

for ?

2 w

k be

fore

ra

ndom

izat

ion

or a

ntic

ipat

ed d

urin

g lo

nger

than

8

3

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Myc

ophe

nola

te M

ofet

il (M

MF)

vs

Cyc

loph

osph

amid

e (C

YC) I

VA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eC

lass

III,

IV-S

or I

V-G

, V, I

II+V

, or I

V+V

. Pa

tient

s w

ith c

lass

III o

r V L

N m

ust h

ave

had

prot

einu

ria (a

t le

ast 2

g/d)

whi

ch w

as c

onsi

dere

d cl

inic

ally

si

gnifi

cant

leve

l of p

rote

inur

ia, a

nd m

ight

indi

cate

a

rece

nt d

eter

iora

tion

in re

nal f

unct

ion.

wk,

pan

crea

titis

, gas

troni

ntes

tinal

hem

orrh

age

with

in 6

mo

or a

ctiv

e pe

ptic

ulc

er w

ithin

3 m

o,

seve

re v

iral i

nfec

tion,

sev

ere

card

iova

scul

ar

dise

ase,

bon

e m

arro

w in

suffi

cien

cy w

ith c

ytop

enia

s no

t attr

ibut

able

to S

LE, o

r cur

rent

infe

ctio

n re

quiri

ng in

trave

nous

ant

ibio

tics.

Pul

se

intra

veno

us c

ortic

oste

roid

s w

ere

proh

ibite

d w

ithin

2

wk

befo

re fi

rst r

ando

miz

atio

n an

d th

roug

hout

the

stud

y.

Isen

berg

et a

l, S

ub A

naly

sis

of A

LMS

trial

,20

10(1

67)

Age

d 12

to 7

5 yr

s, d

iagn

osis

of S

LE, L

N (a

ctiv

e or

ac

tive/

chro

nic)

con

form

ed b

y ki

dney

bio

psy

with

in

6 m

o be

fore

rand

omiz

atio

n as

ISN

/RP

S 2

003

Cla

ss II

I, IV

-S o

r IV

-G, V

, III+

V, o

r IV

+V.

Patie

nts

with

cla

ss II

I or V

LN

mus

t hav

e ha

d pr

otei

nuria

(at

leas

t 2g/

d) w

hich

was

con

side

red

clin

ical

ly

sign

ifica

nt le

vel o

f pro

tein

uria

, and

mig

ht in

dica

te a

re

cent

det

erio

ratio

n in

rena

l fun

ctio

n.

Trea

tmen

t with

MM

F or

IVC

with

in th

e pr

evio

us

year

, con

tinuo

us d

ialy

sis

for ?

2 w

k be

fore

ra

ndom

izat

ion

or a

ntic

ipat

ed d

urin

g lo

nger

than

8

wk,

pan

crea

titis

, gas

troni

ntes

tinal

hem

orrh

age

with

in6

mo

or a

ctiv

e pe

ptic

ulc

er w

ithin

3 m

o,

seve

re v

iral i

nfec

tion,

sev

ere

card

iova

scul

ar

dise

ase,

bon

e m

arro

w in

suffi

cien

cy w

ith c

ytop

enia

s no

t attr

ibut

able

to S

LE, o

r cur

rent

infe

ctio

n re

quiri

ng in

trave

nous

ant

ibio

tics.

Pul

se

intra

veno

us c

ortic

oste

roid

s w

ere

proh

ibite

d w

ithin

2

wk

befo

re fi

rst r

ando

miz

atio

n an

d th

roug

hout

the

stud

y.

Rad

hakr

ishn

an

et a

l, A

LMS

+

Gin

zler

et a

l, 20

10

(NO

TE

CO

MB

INE

D 2

st

udie

s)(4

3)

Pur

e C

lass

V L

N in

clud

ed in

this

ana

lysi

s on

ly.

ALM

S-A

ged

12 to

75

yrs,

dia

gnos

is o

f SLE

, LN

(a

ctiv

e or

act

ive/

chro

nic)

con

form

ed b

y ki

dney

bi

opsy

with

in 6

mo

befo

re ra

ndom

izat

ion

as

ISN

/RP

S 2

003

Cla

ss II

I, IV

-S o

r IV

-G, V

, III+

V, o

r IV

+V.

Patie

nts

with

cla

ss II

I or V

LN

mus

t hav

e ha

d pr

otei

nuria

(at l

east

2g/

d) w

hich

was

co

nsid

ered

clin

ical

ly s

igni

fican

t lev

el o

f pro

tein

uria

, an

d m

ight

indi

cate

a re

cent

det

erio

ratio

n in

rena

l fu

nctio

n.G

INZL

ER

-S

LE m

eetin

g 4

clas

sific

atio

n cr

iteria

of

the

AC

R; r

enal

bio

psy

docu

men

ting

lupu

s ne

phrit

is

ALM

S -

Trea

tmen

t with

MM

F or

IVC

with

in th

e pr

evio

us y

ear,

cont

inuo

us d

ialy

sis

for ?

2 w

k be

fore

ra

ndom

izat

ion

or a

ntic

ipat

ed d

urin

g lo

nger

than

8

wk,

pan

crea

titis

, gas

troni

ntes

tinal

hem

orrh

age

with

in 6

mo

or a

ctiv

e pe

ptic

ulc

er w

ithin

3 m

o,

seve

re v

iral i

nfec

tion,

sev

ere

card

iova

scul

ar

dise

ase,

bon

e m

arro

w in

suffi

cien

cy w

ith c

ytop

enia

s no

t attr

ibut

able

to S

LE, o

r cur

rent

infe

ctio

n re

quiri

ng in

trave

nous

ant

ibio

tics.

Pul

se

intra

veno

us c

ortic

oste

roid

s w

ere

proh

ibite

d w

ithin

2

wk

befo

re fi

rst r

ando

miz

atio

n an

d th

roug

hout

the

stud

y.G

INZL

ER

-C

reat

inin

e cl

eara

nce

of le

ss th

an 3

0ml

2

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Myc

ophe

nola

te M

ofet

il (M

MF)

vs

Cyc

loph

osph

amid

e (C

YC) I

VA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eac

cord

ing

to th

e cl

assi

ficat

ion

of W

HO

III,

IV, o

r V;

clin

ical

act

ivity

as

defin

ed b

y on

e or

mor

e of

the

follo

win

g: in

cide

nce

decr

ease

in re

nal f

unct

ion

(ser

um c

reat

inin

e, >

1mg/

dL (8

8.4

mic

rom

ol/L

), pr

otei

nuria

(def

ined

as

mor

e th

an 5

00m

g of

pro

tein

in

a 2

4-h

urin

e sp

ecim

en),

mic

rosc

opic

hem

atur

ia

(def

ined

as

>5 re

d ce

lls p

er h

igh

pow

er-fi

eld)

or t

he

pres

ence

of c

ellu

lar c

asts

, inc

reas

ing

prot

einu

ria

with

risi

ng le

vels

of s

erum

cre

atin

ine,

act

ive

urin

e se

dim

ent (

hem

atur

ia o

r cel

luar

cas

ts),

or s

erol

ogic

ab

norm

ality

(ant

i-DN

A a

ntib

odie

s or

hy

poco

mpl

emen

tem

ia).

Tho

se w

ith C

lass

III o

r V

lupu

s ne

phrit

is w

ere

requ

ired

to h

ave

a se

rum

cr

eatin

ine

leve

l gre

ater

than

1m

g/dL

or p

rote

inur

ia

grea

ter t

han

2g in

a 2

4-h

urin

e sp

ecim

en.

/min

, ser

um c

reat

inin

e on

repe

ated

test

ing

grea

ter

than

3m

g/dL

(265

.2 m

icro

lmol

/L),

seve

re

coex

istin

g co

nditi

ons

prec

ludi

ng

imm

unos

uppr

essi

ve th

erap

y or

con

ditio

ns re

quiri

ng

intra

veno

us a

ntib

iotic

ther

apy,

prio

r tre

atm

ent w

ith

myc

ophe

nola

te m

ofet

il, tr

eatm

ent w

ith in

trave

nous

cy

clop

hosp

ham

ide

with

in th

e pa

st 1

2 m

onth

s,

mon

oclo

nal a

ntib

ody

ther

apy

with

in th

e pa

st 3

0 da

ys, o

r pre

gnan

cy o

r lac

tatio

n.

El

Sha

fey

et

al, E

gypt

,20

10(1

68)

SLE

mee

ting

4 cl

assi

ficat

ion

crite

ria o

f the

AC

R

with

new

ly d

iagn

osed

act

ive

prol

ifera

tive

clas

s III

or

IV lu

pus

neph

ritis

and

age

d 15

yea

rs o

r old

er w

ere

enro

lled

in th

e st

udy.

Est

imat

ed g

lom

erul

ar fi

ltrat

ion

rate

(eG

FR) o

f les

s th

an 3

0ml p

er m

inut

e, s

erum

cer

eatin

ine

on

repe

ated

test

ing

mor

e th

an 2

00 m

icro

mol

/L, w

hite

bl

ood

cell

(WBC

) cou

nt o

f les

s th

an 3

.5 x

19

9/l,

evid

ence

of m

ajor

infe

ctio

n, h

isto

ry o

f can

cer,

alco

hol o

r sub

stan

ce a

buse

, act

ive

pept

ic u

lcer

di

seas

e, p

regn

ant o

r lac

tatin

g w

omen

, kno

wn

alle

rgy

to M

MF

or c

yclo

phos

pham

ide,

and

the

use

of s

tudy

dru

gs in

the

prec

edin

g 6

mon

ths.

2

MM

F +

AZA

vs

CYC

PO

+ A

ZAA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Cha

n et

al,

Hon

g K

ong,

20

00(1

69)

SLE

acc

ordi

ng to

AR

A in

clud

ing

rena

l-bio

psy

evid

ence

of d

iffus

e pr

olife

rativ

e lu

pus

neph

ritis

(W

HO

IV),

urin

ary

prot

ein

excr

etio

n of

1g

or m

ore

per 2

4 ho

urs,

ser

um a

lbum

in c

once

ntra

tion

of

Ser

um c

reat

inin

e co

ncen

tratio

n hi

gher

than

3.

4mg/

dL (3

00 m

icro

mol

per

lite

r); li

fe-th

reat

enin

g co

mpl

icat

ions

suc

h as

cer

ebra

l lup

us o

r sev

ere

infe

ctio

n, h

isto

ry o

f poo

r com

plia

nce

with

dru

g

2

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

MM

F +

AZA

vs

CYC

PO

+ A

ZAA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e3.

5g/d

L or

less

. re

gim

ens,

wom

en w

ho w

ere

preg

nant

or u

nwill

ing

to u

se c

ontra

cept

ion.

Pat

ient

s w

ho h

ad re

ceiv

ed

cycl

opho

spha

mid

e w

ithin

the

prev

ious

6 m

onth

s or

w

ho h

ad ta

ken

oral

pre

dnis

olon

e at

ado

se o

f 0.

8mg/

kg o

f bod

y w

eigh

t per

day

or m

ore

for m

ore

than

2 w

eeks

.

Cha

n et

al,

Hon

g K

ong,

20

05(1

70)

SLE

def

ined

by

1982

AR

A c

riter

ia, r

enal

bio

psy

show

ing

diffu

se p

rolif

erat

ive

lupu

s ne

phrit

is (W

HO

C

lass

IV) w

hich

cor

resp

onde

d to

200

3 IS

N/R

PS

cl

ass

IV-S

or I

V-G

, urin

ary

prot

ein

exre

tion

of 1

g/24

ho

urs

or a

bove

, and

ser

um a

lbum

in c

once

ntra

tion

<35g

/L.

Ser

um c

reat

inin

e co

ncen

tratio

n >4

.52

mg/

dL

(400

mic

rom

ol/L

), lif

e-th

reat

enin

g co

mpl

icat

ions

su

ch a

s ce

rebr

al lu

pus

or s

ever

e in

fect

ion,

poo

r dr

ug c

ompl

ianc

e, tr

eatm

ent w

ith C

TX o

r MM

F w

ithin

6 m

o be

fore

bas

elin

e, o

r tre

atm

ent w

ith

pred

niso

lone

at d

ose

>0.4

mg/

kg p

er d

ora

lly fo

r >2

wk

befo

re b

asel

ine.

3

MM

F vs

AZA

vs

CYC

IVA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Con

trera

s et

al

,U

SA

,20

04(1

71)

SLE

acc

ordi

ng to

AR

A w

ho h

ad u

nder

gone

a

kidn

ey b

iops

y. 1

8 ye

ars

of a

ge o

r old

er.

His

tolo

gic

diag

nosi

s of

pro

lifer

ativ

e lu

pus

neph

ritis

(WH

O

Cla

ss II

I, IV

, or V

b)

Cre

atin

ine

clea

ranc

e th

at w

as c

onsi

sten

tly le

ss

than

20m

l/min

, any

clin

ical

ly s

igni

fican

t inf

ectio

n,

preg

nanc

y, re

ceip

t ofm

ore

than

7 d

oses

of

intra

veno

us c

yclo

phos

pham

ide,

or t

he re

ceip

t of

azat

hiop

rine

for l

onge

r tha

n 8

wee

ks.

2

MM

F vs

AZA

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

Jada

dSc

ore

Hou

ssia

u et

al

, M

AIN

TAIN

N

ephr

itis

Tria

l, 20

10(d

iffer

ent

coho

rt fro

m

ELN

T)(1

72)

Age

>=1

4 ye

ars,

SLE

acc

ordi

ng to

AC

R

clas

sific

atio

n cr

iteria

, 24h

pro

tein

uria

>=

500m

g,

biop

sy –

prov

en W

HO

Cla

ss II

I, IV

, Vc

or V

d lu

pus

glom

erul

onep

hriti

s (b

iops

y pe

rform

ed le

ss th

an 1

m

onth

bef

ore

entry

to p

roto

col),

con

trace

ptio

n (o

r se

xual

abs

tinen

ce)

Non

-lupu

s re

late

d re

nal d

isea

se (s

uch

as

mic

roth

rom

botic

dis

ease

ass

ocia

ted

with

an

tipho

spho

lipid

syn

drom

e),tr

eatm

ent w

ith

gluc

ocor

ticoi

ds (G

Cs)

(>15

mg

equi

vale

nt

pred

niso

lone

/day

) in

the

last

mon

th b

efor

e en

try

into

t he

stud

y (e

xcep

t a v

ery

shor

t-cou

rse

high

-do

se o

ral G

C tr

eatm

ent b

efor

e re

ferra

l), tr

eatm

ent

with

CY,

AZA

, MM

F, o

r cyc

losp

orin

e A

in th

e

3

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

MM

F vs

AZA

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

Jada

dSc

ore

prev

ious

yea

r, pr

e-ex

istin

g ch

roni

c re

nal f

ailu

re

(def

ined

as

a se

rum

cre

atin

ine

valu

e ab

ove

the

uppe

r nor

mal

val

ue fo

r the

loca

l lab

orat

ory)

due

to

a pr

evio

us e

piso

de o

f LN

or o

ther

cau

se,

preg

nanc

y, b

reas

t fee

ding

, pre

viou

s m

alig

nanc

y (e

xcep

t for

ski

n an

d ce

rvic

al in

traep

ithel

ial

neop

lasi

as),

diab

etes

mel

litus

, pre

viou

sly

docu

men

ted

seve

re to

xici

ty o

f im

mun

osup

pres

sant

s, a

ntic

ipat

ed n

on-c

ompl

ianc

e w

ith th

e pr

otoc

ol.

Abs

tract

A

LMS

M

aint

enan

ce

(Wof

sy e

t al,

2010

)

0

Leflu

nom

ide

vs C

YC IV

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

Jada

dSc

ore

Wan

g et

al,

Leflu

nom

id

Lupu

s N

ephr

itis

Stu

dy G

roup

,C

hina

,20

08(1

73)

SLE

acc

ordi

ng to

199

7 A

CR

crit

eria

; SLE

DA

I >=

8;

clin

ical

ly e

vide

nt re

nal d

isea

se a

nd b

iops

y-do

cum

ente

d di

ffuse

pro

lifer

ativ

e or

foca

l pr

olife

rativ

e lu

pus

neph

ritis

(IS

N/R

PS

200

3 Ty

pe IV

A

or A

/C a

nd T

ype

III A

or A

/C) w

ith o

r with

out

coin

cide

nt m

embr

anou

s ne

phro

path

y an

d pa

thol

ogic

al a

ctiv

ity in

dex

(AI)

>=4.

Rec

eive

d cy

clop

hosp

ham

ide

with

in th

e pr

evio

us 3

m

onth

s. C

ereb

ral l

upus

, sev

ere

infe

ctio

n, li

ver

dise

ase,

pre

gnan

cy, a

nd a

ntic

ipat

ed p

oor

com

plia

nce

with

the

prot

ocol

.

0

Ritu

xim

abA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eA

BST

RA

CT

-Fur

ie e

t al,

LUN

AR

,20

09

Pts

with

Cla

ss II

I/IV

LN

and

urin

e pr

otei

n to

cr

eatin

ine

ratio

>1

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Bel

imum

abA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eA

BST

RA

CT

-Man

zi e

t al,

BLI

SS

2010

Ser

opos

itive

(AN

A >

=1:3

0 an

d/or

ant

i-dsD

NA

>=3

0 IU

/mL)

SLE

with

SEL

ENA

SLE

DAI

>=6

on

stab

le

stan

dard

-of –

care

ther

apy

ofr >

=30d

wer

e en

rolle

d

No

activ

e LN

Toci

lizum

abA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

e

Illei

, et a

l,U

SA

,20

10(1

74)

Age

>18

yea

rs w

ho fu

lfille

d A

CR

cla

ssifi

catio

n cr

iteria

for S

LE, m

oder

atel

y ac

tive

lupu

s de

fined

by

1 of

the

2 se

ts o

f crit

eria

. C

riter

ia s

et 1

–pr

esen

ce

of c

hron

ic g

lom

erul

onep

hriti

s w

ith a

n in

adeq

uate

re

spon

se to

at l

east

6 m

onth

s of

ade

quat

e im

mun

osup

pres

sive

ther

apy

(with

eith

er

met

hylp

redn

isol

one

puls

e do

ses,

cy

lcop

hosp

ham

ide,

aza

thio

prin

e, c

yclo

spor

ine,

m

ycop

heno

late

mof

etil,

hig

h-do

se d

ialy

co

rtico

ster

oids

, met

hotre

xate

, or i

ntra

veno

us

imm

unog

lobu

lin, p

lus

the

follo

win

g 4

feat

ures

: les

s th

an a

30%

inc

reas

e in

ser

um c

reat

inin

e le

vels

as

com

pare

d w

ith th

e lo

wes

t lev

el a

chiv

ed d

urin

g tre

atm

ent;

prot

einu

ria a

t lev

els

<=1.

5 tim

es th

e va

lue

at b

asel

ine

(bef

ore

treat

men

t); <

= 2+

cel

lula

r ca

sts

in th

e ur

inar

y se

dim

ents

; and

ext

rare

nal

dise

ase

activ

ity n

ot e

xcee

ding

a s

core

of 1

0 on

the

nonr

enal

com

pone

nts

of th

e SE

LEN

A ve

rsio

n of

S

LED

AI.

Cre

iteria

set

2 c

onsi

sted

of m

oder

atel

y ac

tive

extra

rena

l lup

us, d

efin

ed a

s ex

trare

nal

SE

LEN

A-S

LED

AI s

core

in th

e ra

nge

of 3

-10.

S

ELE

NA

-SLE

DA

I sco

re m

ust h

ave

been

sta

ble

for

Pre

gnan

cy, a

ny th

erap

y w

ith h

uman

, mur

ine

antib

odie

s, o

r any

exp

erim

enta

l the

rapy

with

in 3

m

onth

s, th

erap

y w

ith c

yclo

phos

pham

ide,

pul

se

met

hylp

redn

isol

one

or IV

IG w

ithin

4 w

eeks

, or

azat

hiop

rine,

myc

ophe

nola

te m

ofet

il, c

yclo

spor

ine,

or

met

hotre

xate

with

in 2

wee

ks o

f the

firs

t dos

e of

st

udy

med

icat

ion.

Ser

um c

reat

inin

e le

vel >

3.0

mg/

dl, w

hite

blo

od c

ell c

ount

<35

00/m

icro

L,

abso

lute

neu

troph

il co

unt <

300

0 m

icro

lL, a

bsol

ute

lym

phoc

yte

coun

t <=

500/

mic

rolL

, hem

oglo

bin

valu

e <8

.0 g

m/d

l, pl

atel

et c

ount

<50

000/

mic

rolL

, A

ST o

r ALT

leve

ls >

1.5

times

the

uppe

r lim

its o

f no

rmal

, or >

1000

Eps

tein

-Bar

r viru

s ge

nom

e eq

uiva

lent

s/10

6 p

reip

hera

l blo

od m

onon

ucle

ar

cells

.

0

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

RA

ND

OM

IZE

D C

LIN

ICA

L T

RIA

LS

Toci

lizum

abA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaJa

dad

Scor

eat

leas

t 2 w

eeks

prio

r to

scre

enin

g. R

equi

red

pres

ence

of a

t lea

st 1

ser

olog

ical

mar

ker o

f au

toan

tibod

y pr

oduc

tion

or s

yste

mic

infla

mm

atio

n,

ther

efor

e 1

or m

ore

of th

e fo

llow

ing

4 fe

atur

es h

ad

to b

e pr

esen

t: se

rum

ant

i-dsD

NA

ant

ibod

y le

vel >

= 30

IU, a

n Ig

G a

ntic

ardi

olip

in a

ntib

ody

leve

l >=2

0 ig

G

phos

phol

ipid

uni

ts/m

l, a

C-re

activ

e pr

otei

n le

vel

(CR

P) >

0.8

mg/

dl, o

r an

eryt

hroc

yte

sedi

men

tatio

n ra

te (E

SR

) >25

mm

/h in

men

and

>42

mm

/h in

w

omen

. S

tabl

e do

se o

f Pre

dnis

one

<=0.

3 m

g/kg

/d

for a

t lea

st 2

wee

ks b

efor

e th

e fir

st d

ose

of s

tudy

m

edic

atio

n. E

ffect

ive

form

f co

ntra

cept

ion.

Ple

ase

see

encl

osed

exc

el s

heet

for R

ando

miz

ed C

ontro

lled

Tria

l (R

CT)

–In

terv

entio

n-O

utco

me

(I-O

) and

Adv

erse

Eve

nt (A

E)

data

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

CO

HO

RT

ST

UD

IES

Tabl

e 6.

Coh

ort S

tudi

es In

clus

ion/

Excl

usio

n C

riter

ia a

nd N

ewca

stle

-Otta

wa

Scal

eR

ituxi

mab

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

eC

atap

ano

et

al, U

K a

nd

Italy

, 201

0(1

75)

Dat

a ex

tract

ed fr

om 2

ele

ctro

nic

data

base

s an

d pa

tient

s’ n

ote

in V

ascu

litis

an

d Lu

pus

Clin

ic a

t Add

enbr

ooke

’s H

ospi

tal,

Cam

brid

ge, U

K. F

ulfil

l at l

east

4A

CR

dia

gnos

tic c

riter

ia.

Pat

ient

s re

ceiv

ing

ritux

imab

for r

efra

ctor

y or

rela

psin

g S

LE.

3

Terri

er e

t al,

Fran

ce, 2

010

(176

)

Dat

a co

llect

ed p

rosp

ectiv

ely

from

82

cent

ers

in th

e A

IR re

gist

ry.

SLE

cl

assi

fied

acco

rdin

g to

AC

R 1

982

revi

sed

crite

ria.

6

Jons

dotti

r et

al, E

urop

e,

2010

(177

)

SLE

and

act

ive

LN.

Pool

ed d

ata

from

2 c

ohor

ts, W

HO

Cla

ss V

and

WH

O

Cla

ss II

I or I

V.

1

Stem

Cel

lA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaN

ewca

stle

O

ttaw

a Sc

ale

Jayn

e et

al,

UK

, 200

4(1

78)

Ret

rosp

ectiv

e da

ta fr

om th

e Eu

rope

an G

roup

for B

lood

and

M

arro

w T

rans

plan

tatio

n an

d Eu

rope

an L

eagu

e ag

ains

t R

heum

atis

m R

egis

try.

4

Bur

t et a

l, U

SA

, 20

06(1

79)

At l

east

4 o

f 11

AC

R C

riter

ia fo

r SLE

and

requ

ired

mor

e th

an

20m

g/d

of p

redn

ison

e or

its

equi

vale

nt d

espi

te u

se o

f cy

clop

hosp

ham

ide.

WH

O C

lass

III o

r IV

glo

mer

ulon

ephr

itis,

in

volv

emen

t of l

the

lung

, inv

olve

men

t of t

he c

entra

l ner

vous

sy

stem

, vas

culit

is, m

yosi

tis, t

rans

fusi

on-d

epen

dent

aut

oim

mun

e cy

tope

nias

, sev

ere

sero

sitii

s, u

lcer

ativ

e m

ucoc

utan

eous

dis

ease

, or

ant

ipho

spho

lipid

syn

drom

e (d

efin

ied

by S

appo

ro c

riter

ia).

N

ephr

itis

requ

ired

failu

re o

f 6 o

r mor

e m

onth

ly p

ulse

of

cylc

opho

spha

mid

e. N

onre

nal v

isce

ral o

rgan

invo

lvem

ent

requ

ired

failu

re o

f at l

east

3 m

onth

s of

cyc

loph

osph

amid

e.

4

Lian

g et

al,

Nan

jing,

S

LE re

fract

ory

to s

tand

ard

ther

apie

s. A

ll pa

tient

s ha

d at

leas

t 4

of 1

1 A

CR

crit

eria

for S

LE.

Elig

ibili

ty c

riter

ia in

clud

e on

e of

the

1

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

Stem

Cel

lA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaN

ewca

stle

O

ttaw

a Sc

ale

2010

(180

)fo

llow

ing

feat

ures

: pr

ogre

ssiv

e an

d ac

tive

dise

ase

with

SEL

EN

A

SLE

DA

I sco

re >

=8 d

espi

te c

ontin

uous

trea

tmen

t with

IV p

ulse

C

YC w

ith a

tot

al d

osag

e of

400

-800

mg

ever

y m

onth

for a

t lea

st

6 m

onth

s or

ora

l MM

F 10

00-2

000

mg/

d fo

r at l

east

3 m

onth

s an

d co

ntin

ued

daily

dos

age

of m

ore

than

20m

g of

pre

dnis

one

or it

s eq

uiva

lent

; ref

ract

ory

imm

une-

med

iate

d th

rom

bocy

tope

nia;

re

fract

or L

N d

efin

ed e

ither

as

prot

einu

ria >

=100

0mg/

24 h

, se

rcum

cre

atin

ine

>=1.

5mg/

dL o

r dec

reas

ed C

reat

inin

e cl

eara

nce

with

out e

nd-s

tage

rena

l fai

lure

in p

atie

nts

with

WH

O

Cla

ss IV

/V g

lom

erul

onep

hriti

s de

spite

6 m

onth

s of

CYC

or M

MF.

Sun

et a

l, N

anjin

g C

hina

, 201

0(1

81)

All

patie

nts

met

at l

east

4 o

f the

11

AC

R c

riter

ia fo

r SLE

. S

LED

AI s

ocre

>=8

, lac

k of

resp

onse

to tr

eatm

ent w

ith m

onth

ly

IV C

YC 5

00-1

000

mg/

m2

for >

= 6

mon

ths

or la

ck o

f res

pons

e to

tre

atm

ent w

ith o

ral M

MF

(200

0 m

g/da

y) fo

r >=3

mon

ths,

and

co

ntin

ued

daily

dos

es o

f >20

mg

of p

redn

ison

e or

its

equi

vale

nt.

Als

o if

they

had

refra

ctor

y im

mun

e-m

edia

ted

trans

fusi

on-

depe

nden

t thr

ombo

cyto

peni

a or

refra

ctor

y lu

pus

neph

ritis

de

fined

as

eith

er p

rote

inur

ia >

= 10

00m

g/24

h o

r ser

um

crea

tinin

e >=

1.5

mg/

dL o

r dec

reas

ed c

reat

inin

e cl

eara

nce

with

out e

nd-s

tage

rena

l fai

lure

in p

atie

nts

with

WH

OC

IV/V

gl

omer

ulon

ephr

itis

desp

ite 6

mon

ths

treat

men

t of C

YC o

r 3

mon

ths

of tr

eatm

ent w

ith M

MF.

Unc

ontro

lled

infe

ctio

n, m

ean

pulm

onar

y ar

tery

pre

ssur

e >

50m

m

Hg,

failu

re o

f one

of t

he v

ital o

rgan

s,

wer

e pr

egna

nt o

r lac

tatin

g.

3

Ant

imal

aria

lA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaN

ewca

stle

O

ttaw

a Sc

ale

Sis

o et

al,

Spa

in, 2

008

(182

)

Sin

gle

cent

er.

Fulfi

lled

1997

revi

sed

crite

ria fo

r SLE

cl

assi

ficat

ion.

Bio

psy

prov

en L

N.

Ren

al b

iops

ies

revi

ewed

by

2 pa

thol

ogis

ts a

nd c

ateg

oriz

ed a

ccor

ding

to IS

N/R

PS

in 2

004.

5

Pon

s-E

stel

et

al,

USA

an

d P

uerto

R

ico,

200

9

Long

itudi

nal o

bser

vatio

nal c

ohor

t. P

atie

nts

wer

e >=

16

year

s of

ag

e an

d ha

d di

seas

e du

ratio

n of

<=

5 ye

ars.

Eac

h pa

tient

had

a

base

line

or e

nrol

lmen

t vis

it (T

0) fo

llow

ed b

y a

6 m

onth

vis

it (T

0.5)

and

sub

sequ

ently

yea

rly v

isit.

Tim

e of

dia

gnos

is (T

D)

4

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

Ant

imal

aria

lA

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaN

ewca

stle

O

ttaw

a Sc

ale

LUM

INA

st

udy

(183

)w

as d

efin

ed a

s th

e tim

e w

hen

each

pat

ient

met

4 A

CR

crit

eria

.

Cyc

losp

orin

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

eR

ihov

a et

al,

Cze

ch

Rep

ublic

, 20

07(1

84)

Ret

rosp

ectiv

e ch

arge

revi

ew.

Pat

ient

mee

t the

198

2 A

CR

cr

iteria

for t

he d

iagn

osis

of S

LE a

nd h

ave

an a

ctiv

e LN

ver

ified

an

d cl

assi

fied

by a

rena

l bio

psy,

trea

ted

with

CsA

.

2

Cyc

loph

osph

amid

e (C

YC)

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

e

Doo

ley

et a

l, U

SA

, 199

6(1

85)

Ren

al b

iops

y di

agno

sis

of S

LE-D

PG

N fr

om w

ithin

the

Glo

mer

ular

Dis

ease

Col

labo

rativ

e N

etw

ork

(GD

CN

) wer

e el

igib

le

for i

nclu

sion

in th

is s

tudy

. P

atie

nt fu

lfille

d 4

or m

ore

crite

ria fr

om

the

1982

AC

R re

vise

d cr

iteria

for c

lass

ifica

tion

of S

LE.

Doc

umen

tatio

n of

trea

tmen

t or i

nten

tion

to tr

eat w

ith C

YC IV

was

re

quire

d fo

r stu

dy e

ntry

.

0

Ioan

nidi

s et

al

, US

A a

nd

Gre

ece,

20

00(1

86)

All

patie

nts

with

bio

psy-

docu

men

ted

diag

nosi

s of

pro

lifer

ativ

e lu

pus

neph

ritis

(WH

O ty

pe II

I or I

V) t

reat

ed w

ith IV

C.

1

Mok

et a

l, H

ong

Kon

g,

Chi

na, 2

004

(187

)

SLE

pat

ient

s w

ith b

iops

y pr

oven

DP

GN

initi

ally

trea

ted

with

re

gim

ens

that

incl

uded

CYC

and

cor

ticos

tero

ids

betw

een

year

s 19

88 a

nd 2

001.

All

fulfi

lled

at le

ast 4

of t

he A

CR

crit

eria

for S

LE

clas

sific

atio

n.

3

de C

astro

et

al, B

razi

l, 20

07(1

88)

SLE

cla

ssifi

catio

n by

AC

R c

lass

ifica

tion

crite

ria, t

reat

ed a

nd

follo

wed

from

Jul

y 19

88 to

Dec

embe

r 200

3.H

isto

logi

cal c

lass

II o

r V a

ccor

ding

to

1995

WH

O c

lass

ifica

tion.

6

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

Cyc

loph

osph

amid

e (C

YC)

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

e

Mok

et a

l, H

ong

Kon

g C

hina

, 200

6(1

89)

Ren

al b

iops

y pr

oven

diff

use

prol

ifera

tive

lupu

s gl

omer

ulon

ephr

itis

(199

5 W

HO

Cla

ss IV

) tre

ated

in H

ong

Kon

g id

entif

ied

by c

linic

al re

gist

ries

or re

nal b

iops

y da

taba

ses.

All

patie

nts

fulfi

lled

at le

ast 4

AC

R c

riter

ia fo

r SLE

cla

ssifi

catio

ns

and

wer

e in

itial

ly tr

eate

d w

ith c

ortic

oste

roid

s an

d C

YC.

3

Pet

ri et

al,

US

A, 2

010

(190

)

Pro

spec

tive

rand

omiz

ed tr

ial w

ith 1

:1 ra

ndom

izat

ion.

SLE

pa

tient

s m

et >

= 4

of re

vise

d A

CR

crit

eria

for S

LE w

ith m

oder

ate

to s

ever

e ac

tivity

in a

n or

gan

as d

efin

ed a

s B

ILA

G A

or a

hig

h sc

ore

for t

hat o

rgan

on

the

SLA

M o

r hos

pita

lizat

ion

for

invo

lvem

ent o

f tha

t org

an.

Lack

of r

espo

nse

or e

xpec

ted

lack

of

resp

onse

to m

oder

ate-

to h

igh-

dose

cor

ticos

tero

ids,

to th

e eq

uiva

lent

deg

ree

of im

mun

osup

pres

sion

, or t

o ap

prop

riate

ot

her t

reat

men

t. C

ombi

natio

n th

erap

y of

bot

h hy

drox

ycho

rolo

guin

e an

d qu

inac

rine

as w

ell a

s im

mun

osup

pres

sion

had

to h

ave

faile

d fo

r SLE

pat

ient

s w

ith

cuta

neou

s lu

pus.

Mus

culo

skel

etal

lupu

s fro

m th

e ca

tego

ry o

f elig

ible

org

an in

volv

emen

t.4

Imm

unos

uppr

essi

ves

vs C

yclo

phos

pham

ide

(CYC

)A

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaN

ewca

stle

O

ttaw

a Sc

ale

Uro

witz

et a

l, To

ront

o,

Can

ada,

20

07(1

91)

SLE

>=

4 A

CR

crit

eria

or 3

AC

R c

riter

ia p

lus

a ty

pica

l hi

stol

ogic

al le

sion

of S

LE o

n re

nal o

r ski

n bi

opsy

. P

atie

nts

with

ac

tive

rena

l dis

ease

trea

ted

with

imm

unos

uppr

essi

ve/c

ytot

oxic

m

edic

atio

ns in

the

year

afte

r dia

gnos

is o

f act

ive

rena

l dis

ease

w

ere

sele

cted

from

clin

ic d

atab

ase.

Act

ive

rena

l dis

ease

de

fined

as

pres

ence

of 2

con

secu

tive

visi

ts o

f one

of:

red

bloo

d ce

ll ca

sts

or h

emeg

ranu

lar c

asts

, hem

atur

ia o

r pyr

uia

in th

e ab

senc

e of

oth

er c

ause

s, o

r pro

tein

uria

(>50

0mg/

24h

or >

= 3+

on

dip

stic

k) o

r an

abno

rmal

kid

ney

biop

sy s

how

ing

activ

e lu

pus

neph

ritis

.

3

Cyc

loph

osph

amid

e (C

YC) v

s A

zath

iopr

ine

(AZA

)

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

e

Dec

ker e

t al,

NIH

, 197

5(1

92)

Dia

gnos

is o

f SLE

by

ARA

crit

eria

incl

udin

g a

posi

tive

eryt

hem

atos

us c

ell t

est;

kidn

ey d

isea

se w

ith e

ither

ery

thro

cyte

ca

sts,

cel

luar

cas

ts, a

nd e

ither

hem

atur

ia (2

0 er

ythr

ocyt

es/h

pf)

or h

igh

anti-

DN

A a

ntib

odie

s, lo

w c

ompl

emen

t, an

d a

posi

tive

rena

l bio

psy,

and

diff

use

glom

erul

onep

hriti

s w

ith a

t lea

st a

po

rtion

of a

ll gl

omer

uli i

nvol

ved.

Ser

um c

reat

inin

e of

gre

ater

than

4m

g/10

0ml o

r cre

atin

ine

clea

ranc

e of

le

ss th

an 2

0ml/m

in

3

Cyc

loph

osph

amid

e (C

YC) +

Aza

thio

prin

e (A

ZA)

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

e

Cha

n et

al,

Hon

g K

ong,

C

hina

, 200

5(1

70)

Pro

spec

tive

coho

rt. D

iagn

osis

of W

HO

Cla

ss IV

lupu

s ne

phrit

is

conf

irmed

by

rena

l bio

psy,

bas

elin

e ur

inar

y pr

otei

n ex

cret

ion

exce

edin

g 1g

/24h

, bas

elin

e se

rum

alb

umin

bel

ow 3

5g/L

, tre

atm

ent w

ith s

eque

ntia

l im

mun

osup

pres

sion

. P

atie

nts

with

su

perim

pose

d m

embr

anou

s ch

ange

s w

ere

incl

uded

pro

vide

d th

at th

ere

wer

e co

ncom

itant

diff

use

prol

ifera

tive

feat

ures

.

Ser

um c

reat

inin

e ex

ceed

ing

400m

icro

mol

/L, t

reat

men

t with

cy

clop

hosp

ham

ide

or m

ycop

heno

late

m

ofet

il w

ithin

6 m

onth

s, o

r pr

edni

solo

ne d

ose

exce

edin

g 0.

4mg/

kg/d

for m

ore

than

2 w

eeks

prio

r to

bas

elin

e/

3

Hig

h do

se c

yclo

phos

pham

ide

(CYC

) vs

Low

dos

e cy

clop

hosp

ham

ide

follo

wed

by

Aza

thio

prin

e (A

ZA)

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

e

Hou

ssia

u et

al

, Eur

ope,

E

LNT,

200

4S

uban

alys

is(1

93)

SLE

pat

ient

s ac

cord

ing

to A

CR

crit

eria

, age

14

year

s or

old

er

with

bio

psy

prov

en p

rolif

erat

ive

lupu

s gl

omer

ulon

ephr

itis

(WH

O

Cla

ss II

I, IV

, Vc,

or V

d) a

nd p

rote

inur

ia >

= 50

0mg/

24 h

.

Pat

ient

s w

ho h

ad ta

ken

CYC

or A

ZA

durin

g th

e pr

evio

us y

ear o

r had

take

n >=

15m

g/da

y pr

edni

sone

(or e

quiv

alen

t) du

ring

the

prev

ious

mon

th w

ere

excl

uded

(exc

ept f

or a

cou

rse

of

gluc

ocor

ticoi

ds fo

r a m

axim

um o

f 10

days

bef

ore

the

refe

rral).

Oth

er

excl

usio

n cr

iteria

wer

e re

nal t

hrom

botic

m

icro

angi

opat

hy, p

reex

istin

g ch

roni

c re

nal f

ailu

re, p

regn

ancy

, pre

viou

s m

alig

nanc

y (e

xcep

t ski

n an

d ce

rvic

al

3

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

Hig

h do

se c

yclo

phos

pham

ide

(CYC

) vs

Low

dos

e cy

clop

hosp

ham

ide

follo

wed

by

Aza

thio

prin

e (A

ZA)

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

ein

traep

ithel

ial n

eopl

asis

), di

abet

es

mel

litus

, pre

viou

sly

docu

men

ted

seve

re

toxi

city

to im

mun

osup

pres

sive

dru

gs,

and

antic

ipat

ed p

oor c

ompl

ianc

e w

ith

the

prot

ocol

.

Myc

ophe

nola

te M

ofet

il (M

MF)

A

rtic

leIn

clus

ion

Crit

eria

Excl

usio

n C

riter

iaN

ewca

stle

O

ttaw

a Sc

ale

Tang

et a

l, N

anjin

g C

hinc

a, 2

008

(194

)

Sin

gle

cent

er, r

etro

spec

tive.

Pat

ient

s fu

lfille

d 19

97 S

LE

diag

nosi

s cr

iterio

n of

AR

A, p

rese

ntat

ion

of c

linic

al re

nal l

esio

n,

cres

cent

form

atio

n m

ore

than

50%

and

hav

ing

unde

rtake

n M

MF

or C

TX th

erap

y du

ring

thei

r ind

uctio

n pe

riod.

5

Riv

era

et a

l, 20

09(1

95)

Sin

gle

cent

er re

trosp

ectiv

e ch

art r

evie

w o

f SLE

pat

ient

s w

ith

biop

sy IS

N/R

PS

crit

eria

Cla

ss II

, III,

IV,V

, and

VI.

Pat

ient

s m

ust b

e fo

llow

ed fo

r at l

east

6 m

onth

s.

3

Cor

tez-

Her

nand

ez

et a

l, S

pain

, 20

10(1

96)

SLE

acc

ordi

ng to

AC

R c

riter

ia, c

lass

III/I

V/V

LN

trea

ted

with

M

MF.

3

Aza

thio

prin

e (A

ZA)

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

eM

ok e

t al,

Hon

g K

ong,

C

hina

, 200

4(1

97)

Ope

n la

bel -

Ren

al b

iops

y-pr

oven

pur

e m

embr

anou

s lu

pus

glom

erul

onep

hriti

s (W

HO

Va

and

Vb)

.W

HO

Cla

ssifi

catio

n V

c an

d V

d.3

Leflu

nom

ide

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

Art

icle

Incl

usio

n C

riter

iaEx

clus

ion

Crit

eria

New

cast

le

Otta

wa

Scal

e

Zhan

g et

al,

Har

bin

Chi

na, 2

009

(198

)

Fulfi

lled

1997

AC

R c

lass

ifica

tion

crite

ria fo

r SLE

adm

itted

as

inpa

tient

s un

derg

oing

kid

ney

biop

sy.

Sev

ere

insu

ffici

ency

of o

rgan

s be

side

s ki

dney

, inc

ludi

ng h

eart

failu

re, l

iver

fa

ilure

, sev

ere

psyc

hosi

s, le

ukoc

yte

and

plat

elet

cou

nt le

ss th

an 3

x 1

0 9/

L an

d 50

x 1

0 9

resp

ectiv

ely,

pre

gnan

t w

omen

, lac

tatin

g w

omen

, chi

ldre

n of

le

ss th

an 1

6 ag

e.

3

Ple

ase

see

encl

osed

exc

el s

heet

for C

ohor

t Tria

l –In

terv

entio

n-O

utco

me

(I-O

) and

Adv

erse

Eve

nt (A

E) d

ata

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

Has

hem

i V, N

adja

fi I,

Azz

orde

gan

F,

Gha

hram

ani N

, Br

oum

and

B. S

haria

ti H

ospi

tal,

Tehr

an

Uni

vers

ity o

f Med

ical

Sc

ienc

es, I

ran.

Tr

ansp

lant

Pro

c.

1999

D

ec;3

1(8)

:314

2-3.

Ren

al

trans

plan

tatio

n in

sy

stem

ic lu

pus

eryt

hem

atos

us: a

m

ultic

ente

r stu

dy

with

37

patie

nts

in

Iran.

Look

ed a

t 37

pts

with

LN

and

ESR

D w

ho

had

unde

rgon

ere

nal t

rans

plan

tatio

n. P

ost-

trans

plan

t med

s =

CsA

, aza

, and

pre

d,

exce

pt in

1 c

ase

aza+

pred

.

Gra

ft su

rviv

al a

t 1 y

r = 8

5.6%

, 3 y

r = 7

3%. N

o co

rrela

tion

w/

gend

er, a

ge a

t tra

nspl

ant,

and

dono

r sou

rce.

Cau

ses

of g

raft

loss

: chr

onic

gra

ft re

ject

ion

11/3

7, a

cute

reje

ctio

n 2/

37,

recu

rren

ce o

f LN

1/3

7. P

atie

nt s

urvi

val a

t 1 y

r 94.

4%, a

t 3 y

rs

91.7

%. 2

/37

died

of M

I, 1/

37 d

ied

of p

neum

ococ

cal

infe

ctio

n/se

psis

, 1/3

7 di

ed o

f opi

um to

xici

ty.

War

d M

M.

Pal

o A

lto

Hea

lth C

are

Sys

tem

, Pa

lo A

lto, C

A K

idne

y In

t. 20

00

May

;57(

5):2

136-

43.

Out

com

es o

f ren

al

trans

plan

tatio

n am

ong

patie

nts

with

en

d-st

age

rena

l di

seas

e ca

used

by

lupu

s ne

phrit

is.

Gra

ft fa

ilure

and

pat

ient

mor

talit

y af

ter t

he

first

cad

aver

ic re

nal t

rans

plan

tatio

n w

ere

com

pare

d be

twee

n 77

2 ad

ults

with

ES

RD

ca

used

by lu

pus

neph

ritis

and

32,

644

adul

ts

with

ESR

D c

ause

d by

oth

er c

ause

s w

ho

rece

ived

a tr

ansp

lant

bet

wee

n 19

87 a

nd

1994

and

wer

e in

clud

ed in

the

Uni

ted

Sta

tes

Ren

al D

ata

Sys

tem

. The

med

ian

follo

w-u

p tim

es w

ere

4.9

and

5.0

year

s in

the

two

grou

ps, r

espe

ctiv

ely.

Mul

tivar

iate

Cox

re

gres

sion

mod

els

wer

e us

ed to

adj

ust t

he

risks

of g

raft

failu

re a

nd m

orta

lity

for g

roup

di

ffere

nces

in re

cipi

ent a

nd d

onor

ch

arac

teris

tics.

Sim

ilar c

ompa

rison

s w

ere

perfo

rmed

bet

wee

n 39

0 ad

ults

with

ES

RD

ca

used

by

lupu

s ne

phrit

is a

nd 1

0,51

2 ad

ults

w

ith E

SRD

cau

sed

by o

ther

cau

ses

afte

r fir

st li

ving

-rel

ated

rena

l tra

nspl

anta

tion.

RES

ULT

S: In

an

unad

just

ed a

naly

sis,

the

risk

of g

raft

failu

re a

fter

first

cad

aver

ic tr

ansp

lant

was

slig

htly

but

sig

nific

antly

gre

ater

am

ong

patie

nts

with

ESR

D c

ause

d by

lupu

s ne

phrit

is th

an

amon

g th

ose

with

ESR

D c

ause

d by

oth

er c

ause

s [h

azar

d ra

tio

(HR

), 1.

13; 9

5% C

I, 1.

01 to

1. 2

6, P

= 0

.04]

. How

ever

, afte

r ad

just

men

t for

pot

entia

l con

foun

ding

fact

ors,

the

risk

of g

raft

failu

re w

as n

ot in

crea

sed

in p

atie

nts

with

ESR

D c

ause

d by

lupu

s ne

phrit

is (H

R, 1

.08;

95%

CI,

0.94

to 1

.23,

P =

0.2

8). M

orta

lity

afte

r the

firs

t cad

aver

ic tr

ansp

lant

atio

n di

d no

t diff

er b

etw

een

grou

ps. T

he a

djus

ted

risks

of g

raft

failu

re (H

R, 1

.06;

95%

CI,

0.84

to 1

.32,

P =

0.6

2) a

nd p

atie

nt m

orta

lity

(HR

= 0

. 69;

95%

CI,

0.45

to 1

.05,

P =

0.0

9) a

fter t

he fi

rst l

ivin

g-re

late

d re

nal t

rans

plan

t w

ere

also

not

sig

nific

antly

hig

her a

mon

g pa

tient

s w

ith E

SRD

ca

used

by

lupu

s ne

phrit

is. C

ON

CLU

SIO

NS:

Gra

ft an

d pa

tient

su

rviv

al a

fter f

irst c

adav

eric

and

firs

tliv

ing-

rela

ted

rena

l tra

nspl

ants

are

sim

ilar i

n pa

tient

s w

ith E

SRD

cau

sed

by lu

pus

neph

ritis

and

pat

ient

s w

ith E

SRD

from

oth

er c

ause

s.

Gor

al S

, Yna

res

C,

Shap

pell

SB,

Sny

der

S, F

eure

r ID

, Ka

zanc

iogl

u R

, Fog

o AB

, Hel

derm

an J

H.

Uni

vers

ity o

f Pe

nnsy

lvan

ia S

choo

l of

Med

icin

e

Tran

spla

ntat

ion.

200

3 M

ar 1

5;75

(5):6

51-6

.

Rec

urre

nt lu

pus

neph

ritis

in re

nal

trans

plan

t rec

ipie

nts

revi

site

d: it

is n

ot

rare

.

The

reco

rds

of 5

4 re

nal t

rans

plan

t rec

ipie

nts

with

SLE

wer

e re

view

ed. T

hirty

-one

pat

ient

s un

derw

ent b

iops

y be

caus

e of

wor

seni

ng

rena

l fun

ctio

n an

d pr

otei

nuria

. All

biop

sy

spec

imen

s w

ere

eval

uate

d by

ligh

t m

icro

scop

y, im

mun

oflu

ores

cenc

e (IF

), an

d el

ectro

n m

icro

scop

y (E

M).

RES

ULT

S: A

mon

g th

e 50

pat

ient

s w

ith a

t lea

st 3

mon

ths

of

follo

w-u

p, R

LN w

as p

rese

nt in

15

(52%

of p

atie

nts

who

un

derw

ent b

iops

y, 3

0% o

f tot

al p

atie

nts)

: mes

angi

al lu

pus

neph

ritis

(LN

) (cl

ass

II) in

eig

ht, f

ocal

pro

lifer

ativ

e LN

(cla

ss II

I) in

fo

ur, a

nd m

embr

anou

s LN

(cla

ss V

b) in

thre

e pa

tient

s. O

ne

patie

nt h

ad g

raft

loss

bec

ause

of R

LN (c

lass

II) a

t 10.

5 ye

ars.

Th

e du

ratio

n of

dia

lysi

s be

fore

tran

spla

ntat

ion

was

not

diff

eren

t be

twee

n pa

tient

s w

ith R

LN c

ompa

red

to p

atie

nts

with

out R

LN

(P=0

.40)

. Ove

rall

patie

nt s

urvi

val (

n=50

) was

96%

at 1

yea

r and

82

% a

t 5 y

ears

, and

gra

ft su

rviv

al w

as 8

7% a

t1 y

ear a

nd 6

0% a

t 5

year

s. G

raft

surv

ival

was

wor

se in

pat

ient

s w

ho u

nder

wen

t bi

opsy

com

pare

d w

ith p

atie

nts

who

nev

er u

nder

wen

t bio

psy

(P<0

.01)

. CO

NC

LUSI

ON

S: R

LN is

mor

e co

mm

on th

an

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

prev

ious

ly re

porte

d, b

ut in

our

ser

ies,

gra

ft lo

ss b

ecau

se o

f RLN

w

as ra

re. A

ggre

ssiv

e us

e of

allo

graf

t bio

psie

s an

d m

orph

olog

ic

eval

uatio

n w

ith IF

and

EM

are

impo

rtant

fact

ors

in th

e di

agno

sis

of R

LN. T

he im

pact

of n

ew im

mun

osup

pres

sive

age

nts

on th

e in

cide

nce

of R

LN re

mai

ns to

be

seen

.

Dee

gens

JK,

Artz

M

A, H

oits

ma

AJ,

Wet

zels

JF.

U

nive

rsity

Med

ical

C

ente

r of N

ijmeg

en,

The

Net

herla

nds.

Tr

ansp

l Int

. 200

3 Ju

n;16

(6):4

11-8

. Ep

ub 2

003

Mar

19.

Out

com

e of

rena

l tra

nspl

anta

tion

in

patie

nts

with

sy

stem

ic lu

pus

eryt

hem

atos

us.

We

stud

ied

the

outc

ome

of re

nal

trans

plan

tatio

n in

pat

ient

s w

ith S

LE w

ho

unde

rwen

t tra

nspl

anta

tions

in o

ur c

ente

r be

twee

n 19

68 a

nd 2

001.

Pat

ient

and

gra

ft su

rviv

al w

ere

com

pare

d w

ith a

mat

ched

co

ntro

l gro

up. W

e sp

ecifi

cally

look

ed fo

r any

ev

iden

ce o

f rec

urre

nt d

isea

se. T

here

wer

e 23

pat

ient

s (tw

o m

ale,

21

fem

ale)

with

a

mea

n +/

-SD

age

of 3

4+/-1

2 ye

ars

at

trans

plan

tatio

n.

One

pat

ient

dev

elop

ed re

nal f

ailu

re w

ith s

erol

ogic

al e

vide

nce

of

SLE

activ

ity a

t 61

mon

ths

afte

r tra

nspl

anta

tion.

In th

e ab

senc

e of

ur

ine

abno

rmal

ities

we

favo

red

the

diag

nosi

s of

reje

ctio

n,

alth

ough

recu

rren

ce o

f lup

us n

ephr

itis

coul

d no

t for

mal

ly b

e ex

clud

ed. T

his

was

the

only

cas

e of

a p

ossi

ble

recu

rren

ce o

f lu

pus

neph

ritis

. Tw

o ot

her p

atie

nts

deve

lope

d ex

tra-r

enal

m

anife

stat

ions

of S

LE a

t 6 a

nd 1

7 m

onth

s af

ter t

rans

plan

tatio

n.

Patie

nt a

nd g

raft

surv

ival

rate

s at

5 y

ears

afte

r tra

nspl

anta

tion

wer

e 86

% a

nd 6

8%, r

espe

ctiv

ely.

Sur

viva

l rat

es w

ere

not

sign

ifica

ntly

diff

eren

t fro

m th

ose

of a

mat

ched

con

trol g

roup

, 95%

an

d 78

%, r

espe

ctiv

ely.

Rec

urre

nce

of S

LE a

fter t

rans

plan

tatio

n is

ra

re. T

he re

sults

of r

enal

tran

spla

ntat

ion

in p

atie

nts

with

SLE

do

not d

iffer

sig

nific

antly

from

a m

atch

ed c

ontro

l gro

up. R

enal

tra

nspl

anta

tion

is a

goo

d al

tern

ativ

e fo

r ren

al re

plac

emen

t th

erap

y in

pat

ient

s w

ith lu

pus

neph

ritis

.M

oron

i G, T

anta

rdin

i F,

Gal

lelli

B, Q

uagl

ini

S, B

anfi

G, P

oli F

, M

onta

gnin

o G

, M

eron

i P, M

essa

P,

Pont

icel

li C

. C

entro

Tr

asfu

sion

ale

e di

Im

mun

olog

ia d

ei

Trap

iant

i IR

CC

S,

Osp

edal

e M

aggi

ore

Mila

no, I

taly

Am

J

Kidn

ey D

is. 2

005

May

;45(

5):9

03-1

1.

The

long

-term

pr

ogno

sis

of re

nal

trans

plan

tatio

n in

pa

tient

s w

ith lu

pus

neph

ritis

.

Betw

een

June

198

2 an

d 20

04, a

tota

l of 3

3 ad

ults

with

lupu

s ne

phrit

is re

ceiv

ed 3

5 ki

dney

allo

graf

ts. O

utco

mes

of t

hese

gra

fts

and

thos

e of

70

cont

rols

mat

ched

for a

ge,

sex,

and

don

or s

ourc

e w

ho u

nder

wen

t tra

nspl

anta

tion

durin

gth

e sa

me

perio

d w

ere

com

pare

d.

RES

ULT

S: M

ean

follo

w-u

p af

ter r

enal

tran

spla

ntat

ion

was

91

+/-

59 m

onth

s fo

r pat

ient

s w

ith lu

pus

and

90 +

/-64

mon

ths

for

cont

rols

. Act

uaria

l 15-

year

pat

ient

(80%

ver

sus

83%

) and

dea

th-

cens

ored

gra

ft su

rviv

al ra

tes

(69%

ver

sus

67%

) wer

e no

t si

gnifi

cant

ly d

iffer

ent b

etw

een

patie

nts

with

lupu

s an

d co

ntro

ls.

Ris

ks fo

r acu

te a

nd c

hron

ic re

ject

ion,

arte

rial h

yper

tens

ion,

and

in

fect

ion

wer

e no

t diff

eren

t bet

wee

n th

e 2

grou

ps. M

ean

seru

m

crea

tinin

e le

vels

als

o w

ere

sim

ilar i

n th

e 2

grou

ps a

t the

last

fo

llow

-up

visi

t. In

trava

scul

ar th

rom

botic

eve

nts

occu

rred

in 9

pa

tient

s w

ith S

LE (2

6%) a

nd 6

con

trols

(8.6

%; P

= 0

.038

). In

the

SLE

grou

p, 6

of 7

ant

ipho

spho

lipid

(aPL

) ant

ibod

y-po

sitiv

e ve

rsus

3 o

f 17

aPL

antib

ody-

nega

tive

patie

nts

expe

rienc

ed

thro

mbo

tic e

vent

s ( P

= 0

.015

). R

ecur

renc

e of

lupu

s ne

phrit

is

was

doc

umen

ted

in 3

rena

l gra

fts (8

.6%

), bu

t no

graf

t was

lost

be

caus

e of

recu

rren

t lup

us n

ephr

itis.

CO

NC

LUSI

ON

: Lon

g-te

rm

patie

nt a

nd g

raft

surv

ival

pro

babi

litie

s w

ere

sim

ilar i

n pa

tient

s

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

with

SLE

and

mat

ched

con

trols

. The

risk

for t

hrom

botic

co

mpl

icat

ions

was

gre

ater

in p

atie

nts

with

SLE

, par

ticul

arly

aPL

-po

sitiv

e pa

tient

s. N

ephr

itis

recu

rred

in le

ss th

an 1

0% o

f pat

ient

s w

ith S

LE a

nd d

id n

ot in

fluen

ce g

raft

surv

ival

.

Bunn

apra

dist

S,

Chu

ng P

, Pen

g A,

H

ong

A, C

hung

P,

Lee

B, F

ukam

i S,

Take

mot

o SK

, Sin

gh

AK. T

rans

plan

tatio

n.

2006

Sep

15

;82(

5):6

12-8

.

Out

com

es o

f ren

al

trans

plan

tatio

n fo

r re

cipi

ents

with

lupu

s ne

phrit

is: a

naly

sis

of

the

Org

an

Proc

urem

ent a

nd

Tran

spla

ntat

ion

Net

wor

k da

taba

se.

Her

e, w

e co

mpa

red

patie

nt a

nd g

raft

outc

omes

in lu

pus

and

non-

lupu

s re

cipi

ents

tra

nspl

ante

d be

twee

n 19

96 to

200

0 us

ing

the

Uni

ted

Net

wor

k of

Org

an S

harin

g/O

rgan

Pr

ocur

emen

t Tra

nspl

ant N

etw

ork

data

base

. W

e ev

alua

ted

the

impa

ct o

f rec

ipie

nt a

nd

dono

r dem

ogra

phic

fact

ors,

tim

e on

dia

lysi

s an

d th

e in

itial

imm

unos

uppr

essi

on re

gim

en

on re

ject

ion

rate

s an

d tra

nspl

ant o

utco

mes

.

Uni

varia

te a

naly

sis

show

ed s

imila

r gra

ft bu

t bet

ter p

atie

nt

surv

ival

rate

s fo

r prim

ary

lupu

s an

d no

n-lu

pus

trans

plan

t re

cipi

ents

(5-y

ear p

atie

nt s

urvi

val r

ates

for l

upus

coh

ort 8

5.2%

for

dece

ased

don

or tr

ansp

lant

s an

d 92

.1%

for l

ivin

g do

nor

trans

plan

ts a

s op

pose

d to

82.

1% a

nd 8

9.8%

resp

ectiv

ely

for t

he

non-

lupu

s co

hort;

P=0

.05

and

0.03

) but

sim

ilar p

atie

nt s

urvi

val

rate

s fo

r dec

ease

d do

nor r

etra

nspl

ant p

atie

nts.

Afte

r con

trolli

ng

for c

onfo

undi

ng fa

ctor

s, n

o di

ffere

nces

in p

atie

nt o

r gra

ft su

rviv

al

wer

e se

en b

etw

een

the

two

grou

ps. N

o di

ffere

nce

in a

cute

re

ject

ion

rate

s w

ere

obse

rved

in d

ecea

sed

dono

r tra

nspl

ants

, but

th

ere

was

a s

mal

l but

sig

nific

ant i

ncre

ase

in th

e ris

k of

acu

te

reje

ctio

n in

livi

ng d

onor

lupu

s tra

nspl

ant r

ecip

ient

s (h

azar

d ra

tio=1

.19,

P=0

.05)

. Ris

k of

gra

ft fa

ilure

was

low

er fo

r dec

ease

d do

nor r

ecip

ient

s re

ceiv

ing

MM

F (fi

ve-y

ear g

raft

loss

rate

=29.

6%

for M

MF

vs. 4

0.2%

for t

hose

not

rece

ivin

g M

MF,

P<0

.000

1), b

ut

no d

iffer

ence

s w

ere

seen

am

ong

livin

g do

nor r

ecip

ient

s.

Out

com

es w

ere

sim

ilar r

egar

dles

s of

type

of c

alci

neur

in in

hibi

tor,

indu

ctio

n th

erap

y, a

nd ti

me

on d

ialy

sis.

We

conc

lude

that

lupu

s tra

nspl

ant r

ecip

ient

s ha

ve o

utco

mes

gen

eral

ly e

quiv

alen

t to

non-

lupu

s tra

nspl

ant r

ecip

ient

s.C

hela

mch

arla

M,

Java

id B

, Bai

rd B

C,

Gol

dfar

b-R

umya

ntze

v AS

. U

nive

rsity

of U

tah

Hea

lth S

cien

ces

Cen

ter

Nep

hrol

Dia

l Tr

ansp

lant

. 200

7 D

ec;2

2(12

):362

3-30

. Ep

ub 2

007

Jul 1

9.

The

outc

ome

of

rena

ltra

nspl

anta

tion

amon

g sy

stem

ic

lupu

s er

ythe

mat

osus

pa

tient

s.

We

cond

ucte

d th

e re

trosp

ectiv

e an

alys

is

usin

g da

ta fr

om U

SR

DS

and

UN

OS

da

taba

ses.

Pat

ient

s w

ere

divi

ded

into

five

gr

oups

bas

ed o

n th

e ca

use

of e

nd-s

tage

re

nal d

isea

se (E

SRD

): di

abet

es m

ellit

us

(DM

), SL

E, g

lom

erul

onep

hriti

s, h

yper

tens

ion

and

othe

r cau

ses.

Bet

wee

n 19

90 a

nd 1

999,

28

86 re

nal t

rans

plan

tatio

n re

cipi

ents

with

ES

RD

due

to S

LE w

ere

iden

tifie

d fro

m a

to

tal o

f 92

844

patie

nts.

RES

ULT

S: T

he m

ean

follo

w-u

p pe

riod

of th

is s

tudy

was

4.7

+/-

2.4

year

s. W

hile

una

djus

ted

anal

ysis

usi

ng K

apla

n-M

eier

cur

ves

dem

onst

rate

d an

ass

ocia

tion

betw

een

SLE

and

impr

oved

al

logr

aft s

urvi

val c

ompa

red

with

DM

, in

mul

tivar

iate

ana

lysi

s th

e SL

E gr

oup

had

wor

se a

llogr

aft [

haza

rd ra

tio (H

R) 1

.09,

P <

0.0

5]

and

reci

pien

t (H

R 1

.19,

P <

0.0

5) s

urvi

val c

ompa

red

with

the

DM

gr

oup.

Sub

grou

p an

alys

is b

ased

on

the

type

of d

onor

sho

wed

th

at S

LE p

atie

nts

who

rece

ived

dec

ease

d do

nor a

llogr

aft h

ad

wor

se a

llogr

aft a

nd re

cipi

ent s

urvi

val (

HR

1.1

4, P

= 0

.002

and

H

R 1

.30,

P =

0.0

01, r

espe

ctiv

ely)

com

pare

d w

ith n

on-S

LE

dece

ased

don

or a

llogr

aft r

ecip

ient

s. A

mon

g liv

ing

allo

graf

t

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

reci

pien

ts, t

here

wer

e no

sig

nific

ant d

iffer

ence

s in

eith

er a

llogr

aft

or re

cipi

ent s

urvi

val c

ompa

red

with

non

-SLE

reci

pien

ts.

CO

NC

LUSI

ON

S: S

LE a

s a

caus

e of

ES

RD

in re

nal t

rans

plan

t re

cipi

ents

is a

ssoc

iate

d w

ith w

orse

allo

graf

t and

reci

pien

t sur

viva

l co

mpa

red

with

DM

; thi

s as

soci

atio

n is

true

for t

he e

ntire

po

pula

tion

and

for t

he re

cipi

ents

of d

ecea

sed

dono

r (bu

t not

liv

ing

dono

r) tr

ansp

lant

. Dec

ease

d do

nor a

llogr

aft r

ecip

ient

s ha

ve

wor

se o

utco

mes

com

pare

d w

ith li

ving

allo

graf

t rec

ipie

nts.

Tang

H,

Che

lam

char

la M

, Ba

ird B

C, S

hiha

b FS

, Ko

ford

JK,

Gol

dfar

b-R

umya

ntze

v AS

. U

nive

rsity

of U

tah

Scho

ol o

f Med

icin

e

Clin

Tra

nspl

ant.

2008

M

ay-J

un;2

2(3)

:263

-72

.

Fact

ors

affe

ctin

g ki

dney

-tran

spla

nt

outc

ome

in

reci

pien

ts w

ith lu

pus

neph

ritis

.

Usi

ng th

e da

ta fr

om th

e U

nite

d St

ates

Ren

al

Dat

a S

yste

m o

f pat

ient

s tra

nspl

ante

d be

twee

n Ja

nuar

y 1,

199

5 th

roug

h D

ecem

ber 3

1, 2

002

(and

follo

wed

thro

ugh

Dec

embe

r 31,

200

3) (n

= 2

882)

, we

perfo

rmed

a re

trosp

ectiv

e an

alys

is o

f fac

tors

as

soci

ated

with

long

-term

dea

th-c

enso

red

graf

t sur

viva

l and

reci

pien

t sur

viva

l.

RES

ULT

S: T

he n

umbe

r of p

retra

nspl

ant p

regn

anci

es

incr

emen

tally

incr

ease

d th

e ris

k of

gra

ft fa

ilure

[haz

ard

ratio

(HR

) 1.

54, p

< 0

.05]

in th

e en

tire

subg

roup

of f

emal

es a

nd in

the

subg

roup

of r

ecip

ient

s ag

ed 2

5-35

yr.

Rec

ipie

nt a

nd d

onor

age

ha

d an

ass

ocia

tion

with

bot

h th

e ris

k of

gra

ft fa

ilure

(HR

0.9

6, p

<

0.00

1; H

R 1

.01,

p <

0.0

05) a

nd re

cipi

ent d

eath

(HR

1.0

4, p

<

0.00

1; H

R 1

.01,

p<

0.05

). G

reat

er g

raft-

failu

re ri

sk a

ccom

pani

ed

incr

ease

d re

cipi

ent w

eigh

t (H

R 1

.01,

p <

0.0

01);

Afric

an

Amer

ican

s co

mpa

red

with

whi

tes

(HR

1.5

5, p

< 0

.001

); gr

eate

r C

harls

on c

omor

bidi

ty in

dex

(HR

1.1

7, p

< 0

.05)

; and

gre

ater

pa

nel r

eact

ive

antib

ody

(PR

A)le

vels

(HR

1.0

6, p

< 0

.001

). Pr

etra

nspl

ant p

erito

neal

dia

lysi

s as

the

pred

omin

ant m

odal

ity

had

an a

ssoc

iatio

n w

ith d

ecre

ased

risk

of g

raft

failu

re (H

R 0

.49,

p

< 0.

001)

, whi

le p

rior t

rans

plan

tatio

n w

as a

ssoc

iate

d w

ith

grea

ter r

isk

of g

raft

failu

re a

nd re

cipi

ent d

eath

(HR

2.2

9, p

<

0.00

1; H

R 3

.59,

p <

0.0

01, r

espe

ctiv

ely)

com

pare

d w

ith

hem

odia

lysi

s (H

D).

The

num

ber o

f mat

ched

hum

an le

ukoc

yte

antig

ens

(HLA

) ant

igen

s an

d liv

ing

dono

rs (H

R 0

.92,

p <

0.0

5;

HR

0.6

4, p

< 0

.001

, res

pect

ivel

y) w

as a

ssoc

iate

d w

ith d

ecre

ased

ris

k of

gra

ft fa

ilure

. Inc

reas

ed ri

sk o

f gra

ft fa

ilure

and

reci

pien

t de

ath

was

ass

ocia

ted

with

non

use

of c

alci

neur

in in

hibi

tors

(HR

1.

89, p

< 0

.005

; HR

1.8

0, p

< 0

.005

) and

myc

ophe

nolic

aci

d (M

PA) (

incl

udin

g m

ycop

heno

late

mof

etil

and

MP

A) o

r az

athi

oprin

e (H

R 1

.41,

p <

0.0

5; H

R 1

.66,

p <

0.0

1). U

sing

bot

h cy

clos

porin

e an

d ta

crol

imus

was

ass

ocia

ted

with

incr

ease

d ris

k of

gra

ft fa

ilure

(HR

2.0

9, p

< 0

.05)

. Usi

ng M

PA

is a

ssoc

iate

d w

ith

grea

ter r

isk

of re

cipi

ent d

eath

com

pare

d w

ith a

zath

iopr

ine

(HR

1.

47,p

< 0

.05)

. CO

NC

LUS

ION

: In

rena

l tra

nspl

ant r

ecip

ient

s w

ith

lupu

s ne

phrit

is, m

ultip

le p

regn

anci

es, m

ultip

le b

lood

tran

sfus

ions

, gr

eate

r com

orbi

dity

inde

x, h

ighe

r bod

y w

eigh

t, ag

e an

d Af

rican

Am

eric

an ra

ce o

f the

don

or o

r rec

ipie

nt, p

rior h

isto

ry o

f

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

trans

plan

tatio

n, g

reat

er P

RA

leve

ls, l

ower

leve

l of H

LA m

atch

ing,

de

ceas

ed d

onor

s, a

nd H

D in

pre

trans

plan

t per

iod

have

an

asso

ciat

ion

with

incr

ease

d ris

k of

gra

ft fa

ilure

. Sim

ilarly

, hig

her

reci

pien

t and

don

or a

ge, p

rior t

rans

plan

tatio

ns, a

nd h

ighe

r rat

e of

pr

etra

nspl

ant t

rans

fusi

ons

are

asso

ciat

ed w

ith g

reat

er ri

sk o

f re

cipi

ent m

orta

lity.

Usi

ng n

eith

er c

yclo

spor

ine

nor t

acro

limus

or

usin

g bo

th (c

ompa

red

with

tacr

olim

us) a

nd n

eith

er M

PA

nor

azat

hiop

rine

(com

pare

d w

ith a

zath

iopr

ine)

was

ass

ocia

ted

with

in

crea

sed

risk

of g

raft

failu

re a

nd re

cipi

ent d

eath

. Usi

ng M

PA is

as

soci

ated

with

gre

ater

risk

of r

ecip

ient

dea

th c

ompa

red

with

az

athi

oprin

e. T

estin

g th

ese

resu

lts in

a p

rosp

ectiv

e st

udy

mig

ht

prov

ide

impo

rtant

info

rmat

ion

for c

linic

al p

ract

ice.

War

d M

M.

NIH

/NIA

MS

/IRP

J

Rhe

umat

ol. 2

009

Jan;

36(1

):63-

7.

Cha

nges

in th

e in

cide

nce

of

ends

tage

rena

l di

seas

e du

e to

lupu

s ne

phrit

is in

the

Uni

ted

Stat

es, 1

996-

2004

.

Patie

nts

age

15 y

ears

or o

lder

with

inci

dent

ES

RD

due

to lu

pus

neph

ritis

in 1

996-

2004

an

d liv

ing

in o

ne o

f the

50 U

nite

d St

ates

or

the

Dis

trict

of C

olum

bia

wer

e id

entif

ied

usin

g th

e U

S R

enal

Dat

a S

yste

m, a

nat

iona

l po

pula

tion-

base

d re

gist

ry o

f all

patie

nts

rece

ivin

g re

nal r

epla

cem

ent t

hera

py fo

r ES

RD

. Inc

iden

ce ra

tes

wer

e co

mpu

ted

for

each

cal

enda

r yea

r, us

ing

popu

latio

n es

timat

es o

f the

US

cens

us a

s de

nom

inat

ors.

RES

ULT

S: O

ver t

he 9

-yea

r stu

dy p

erio

d, 9

199

new

cas

es o

f ES

RD

due

to lu

pus

neph

ritis

wer

e ob

serv

ed. I

ncid

ence

rate

s,

adju

sted

to th

e ag

e, s

ex, a

nd ra

ce c

ompo

sitio

n of

the

US

popu

latio

n in

200

0, w

ere

4.4

per m

illio

n in

199

6 an

d 4.

9 pe

r m

illion

in 2

004.

Com

pare

d to

the

pool

ed in

cide

nce

rate

in 1

996-

1998

, the

rela

tive

risk

of E

SRD

due

to lu

pus

neph

ritis

in 1

999-

2000

was

0.9

9 (9

5% C

I 0.9

3-1.

06),

in 2

001-

2002

was

0.9

9 (9

5%

CI 0

.92-

1.06

), an

d in

200

3-20

04 w

as 0

.96

(95%

CI 0

.89-

1.02

). Fi

ndin

gs w

ere

sim

ilar i

n an

alys

es s

tratif

ied

by s

ex, a

ge g

roup

, ra

ce, a

nd s

ocio

econ

omic

sta

tus.

CO

NC

LUS

ION

: The

re w

as n

o de

crea

se in

the

inci

denc

e of

ESR

D d

ue to

lupu

s ne

phrit

is

betw

een

1996

and

200

4. T

his

may

refle

ct th

e lim

its o

f ef

fect

iven

ess

of c

urre

nt tr

eatm

ents

, or l

imita

tions

in a

cces

s, u

se,

or a

dher

ence

to tr

eatm

ent.

Burg

os P

I, Pe

rkin

s EL

, Pon

s-Es

tel G

J,

Kend

rick

SA, L

iu J

M,

Kend

rick

WT,

Coo

k W

J, J

ulia

n B

A,

Alar

cón

GS,

Kew

CE

2n

d. U

nive

rsity

of

Alab

ama

at

Birm

ingh

am A

rthrit

is

Rhe

um. 2

009

Sep;

60(9

):275

7-66

.

Ris

k fa

ctor

s an

d im

pact

of r

ecur

rent

lu

pus

neph

ritis

in

patie

nts

with

sy

stem

ic lu

pus

eryt

hem

atos

us

unde

rgoi

ng re

nal

trans

plan

tatio

n: d

ata

from

a s

ingl

e U

S in

stitu

tion.

The

arch

ival

reco

rds

of a

ll ki

dney

tran

spla

nt

reci

pien

ts w

ith a

prio

r dia

gnos

is o

f SLE

(a

ccor

ding

to th

e Am

eric

an C

olle

ge o

f R

heum

atol

ogy

crite

ria) f

rom

Jun

e 19

77 to

Ju

ne 2

007

wer

e re

view

ed. P

atie

nts

who

had

di

ed o

r los

t the

allo

graf

t with

in 9

0 da

ys o

f en

graf

tmen

t wer

e ex

clud

ed. T

ime-

to-e

vent

da

ta w

ere

exam

ined

by

univ

aria

ble

and

mul

tivar

iabl

e C

ox p

ropo

rtion

al h

azar

ds

regr

essi

on a

naly

ses.

RES

ULT

S: T

wo

hund

red

twen

ty o

f nea

rly 7

,000

rena

l tra

nspl

anta

tions

wer

e pe

rform

ed in

202

SLE

pat

ient

s du

ring

the

30-y

ear i

nter

val.

Of t

he 1

77 p

atie

nts

who

met

the

crite

ria fo

r st

udy

entry

, the

maj

ority

wer

e w

omen

(80%

) and

Afri

can

Amer

ican

(65%

), th

e m

ean

age

was

35.

6 ye

ars,

and

the

mea

n di

seas

e du

ratio

n w

as 1

1.2

year

s. R

ecur

rent

lupu

s ne

phrit

is w

as

note

d in

20

patie

nts

(11%

), al

logr

aft l

oss

in 6

9 pa

tient

s (3

9%),

and

deat

h in

36 p

atie

nts

(20%

). Af

rican

Am

eric

an e

thni

city

was

fo

und

to b

e as

soci

ated

with

a s

horte

r tim

e-to

-eve

nt fo

r rec

urre

nt

lupu

s ne

phrit

is (h

azar

d ra

tio [H

R] 4

.63,

95%

con

fiden

ce in

terv

al

[95%

CI]

1.29

-16.

65) a

nd d

eath

(HR

2.4

7, 9

5% C

I 0.9

1-6.

71),

alth

ough

, with

the

latte

r, th

e as

soci

atio

n w

as n

ot s

tatis

tical

ly

sign

ifica

nt. R

ecur

rent

lupu

s ne

phrit

is a

nd c

hron

ic re

ject

ion

of th

e ki

dney

tran

spla

nt w

ere

foun

d to

be

risk

fact

ors

for a

llogr

aft l

oss

(HR

2.4

8, 9

5% C

I 1.0

9-5.

60 a

nd H

R 2

.72,

95%

CI 1

.55-

4.78

, re

spec

tivel

y). I

n pa

tient

s w

ith re

curr

ent l

upus

nep

hriti

s, th

e le

sion

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

in th

e en

graf

ted

kidn

ey w

as p

redo

min

antly

mes

angi

al, c

ompa

red

with

a p

redo

min

ance

of p

rolif

erat

ive

or m

embr

anou

s le

sion

s in

th

e na

tive

kidn

eys.

CO

NC

LUSI

ON

: Afri

can

Amer

ican

eth

nici

ty

was

inde

pend

ently

ass

ocia

ted

with

recu

rren

t lup

us n

ephr

itis.

Al

logr

aft l

oss

was

ass

ocia

ted

with

chr

onic

tran

spla

nt re

ject

ion

and

recu

rren

ce o

f lup

us n

ephr

itis.

Rec

urre

nt lu

pus

neph

ritis

is

infre

quen

t and

rela

tivel

y be

nign

, with

out i

nflu

ence

on

a pa

tient

's

surv

ival

.

Lian

g C

C, H

uang

CC

, W

ang

IK, C

hang

CT,

C

hen

KH

, Wen

g C

H,

Lin

JL, H

ung

CC

, Ya

ng C

W, Y

en T

H.

Chi

na M

edic

al

Uni

vers

ity H

ospi

tal,

Taic

hung

, Tai

wan

Th

er A

pher

Dia

l. 20

10 F

eb;1

4(1)

:35-

42.

Impa

ct o

f ren

al

surv

ival

on

the

cour

se a

nd o

utco

me

of s

yste

mic

lupu

s er

ythe

mat

osus

pa

tient

s tre

ated

with

ch

roni

c pe

riton

eal

dial

ysis

.

This

long

itudi

nal s

tudy

inve

stig

ated

whe

ther

re

nal s

urvi

val c

an a

ffect

the

cour

se a

nd

outc

ome

of s

yste

mic

lupu

s er

ythe

mat

osus

(S

LE) p

atie

nts

treat

ed w

ith c

hron

ic

perit

onea

l dia

lysi

s (P

D).

Thirt

y-fiv

e SL

E pa

tient

s, o

ut o

f 111

5 en

d-st

age

rena

l di

seas

e (E

SR

D) p

atie

nts

treat

ed w

ith

chro

nic

PD

, wer

e se

en b

etw

een

1990

and

20

07 a

t the

Cha

ng G

ung

Mem

oria

l Hos

pita

l. Pa

tient

s w

ere

follo

wed

up

for a

mea

n of

38

.8 +

/-22

.9 m

onth

s.

Ther

e w

ere

no s

igni

fican

t diff

eren

ces

betw

een

patie

nts

with

sho

rt re

nal s

urvi

val (

<3 y

ears

) and

long

rena

l sur

viva

l (>3

yea

rs) f

or th

e va

rious

dem

ogra

phic

var

iabl

es s

uch

as a

ge, s

ex, P

D d

urat

ion,

im

mun

osup

pres

sive

dru

g ad

min

istra

tion,

or e

xcha

nge

syst

em (P

>

0.05

). In

tere

stin

gly,

bef

ore

PD, p

atie

nts

with

sho

rt re

nal

surv

ival

had

low

er s

erum

com

plem

ent l

evel

s th

an p

atie

nts

with

lo

ng re

nal s

urvi

val (

C3,

40.

2 +/

-14.

4 vs

76.

3 +/

-18.

5 m

g/dL

, P <

0.

001;

and

C4,

14.

8 +/

-4.7

vs

22.4

+/-

8.1

mg/

dL, P

< 0

.05)

. H

owev

er, t

he d

iffer

ence

s in

com

plem

ent l

evel

s be

twee

n th

e gr

oups

dis

appe

ared

afte

r PD

(C3,

76.

5 +/

-27.

3 vs

84.

2 +/

-27.

8 m

g/dL

; and

C4,

26.

7 +/

-11.

3 vs

22.

6 +/

-10.

8 m

g/dL

, bot

h P

> 0.

05).

Patie

nts

with

sho

rt re

nal s

urvi

val w

ere

mor

e lik

ely

to h

ave

a hi

gh p

erito

neal

sol

ute

trans

porte

r rat

e (P

STR

) tha

n th

eir l

ong

rena

l sur

viva

l cou

nter

parts

(chi

(2)-

test

, P =

0.0

2, a

nd A

UR

OC

=

0.74

4 an

d P

= 0

.040

); ho

wev

er, t

here

wer

e no

sig

nific

ant

diffe

renc

es fo

r oth

er v

aria

bles

suc

h as

car

diot

hora

cic

ratio

(CTR

), Kt

/V, r

esid

ual r

enal

func

tion,

exi

t site

infe

ctio

n, a

nd p

erito

nitis

(P

> 0.

05).

Fina

lly, K

apla

n-M

eier

ana

lysi

s re

veal

ed th

at th

e tw

o gr

oups

did

not

diff

er in

pat

ient

and

tech

nica

l sur

viva

l (P

> 0.

05).

Ther

efor

e it

was

con

clud

ed th

at re

nal s

urvi

val m

ight

be

asso

ciat

ed w

ith P

STR

, but

not

with

pat

ient

and

tech

nica

l sur

viva

l in

SLE

pat

ient

s tre

ated

with

PD

.

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

Nor

by G

E, S

trøm

EH

, M

idtv

edt K

, Har

tman

n A,

Gilb

oe IM

, Le

ives

tad

T,

Ste

nstrø

m J

, Hol

daas

H

. O

slo

Uni

vers

ity

Hos

pita

l, N

orw

ay.

A

nn R

heum

Dis

. 20

10

Aug;

69(8

):148

4-7.

Ep

ub 2

010

May

24.

Rec

urre

nt lu

pus

neph

ritis

afte

r kid

ney

trans

plan

tatio

n: a

su

rvei

llanc

e bi

opsy

st

udy.

All p

atie

nts

with

SLE

that

had

und

ergo

ne

trans

plan

t with

a fu

nctio

ning

gra

ft w

ere

aske

d in

200

8 to

par

ticip

ate

in a

cro

ss-

sect

iona

l stu

dy. T

he s

tudy

incl

uded

a

stan

dard

ised

clin

ical

exam

inat

ion,

labo

rato

ry

test

s an

d a

biop

sy o

f the

tran

spla

nted

ki

dney

.

RES

ULT

S: A

tota

l of 4

1 (9

3%) o

f a c

ohor

t of 4

4 pa

tient

s w

ith

SLE

with

rena

l tra

nspl

ants

par

ticip

ated

. Of t

he b

iops

ies,

3 w

ere

indi

catio

n bi

opsi

es a

nd 3

8 w

ere

surv

eilla

nce

biop

sies

. In

all,

22

patie

nts

(54%

) had

bio

psy-

prov

en re

curr

ence

of L

N. T

he m

ajor

ity

of th

e ca

ses

wer

e su

bclin

ical

and

cha

ract

eris

ed a

s cl

ass

I/cla

ss II

LN

. Pro

tein

uria

(mg

prot

ein/

mm

ol c

reat

inin

e) w

as s

igni

fican

tly

incr

ease

d in

pat

ient

s w

ith re

curr

ence

, 70.

6 (1

04.9

) mg/

mm

ol

vers

us 1

1.9

(6.7

) mg/

mm

ol in

pat

ient

s w

ithou

t rec

urre

nce

(p=0

.038

). Lu

pus

antic

oagu

lant

was

foun

d m

ore

frequ

ently

in th

e pa

tient

s w

ith re

curr

ence

, nin

e ve

rsus

two

patie

nts

(p=0

.033

). R

ecur

renc

e of

LN

was

ass

ocia

ted

with

rece

ivin

g a

kidn

ey fr

om a

liv

ing

dono

r (p=

0.04

9). I

n al

l, 83

% (3

4 of

41)

had

chr

onic

allo

graf

t ne

phro

path

y in

the

trans

plan

ted

kidn

eys

with

no

diffe

renc

e be

twee

n pa

tient

s w

ith re

curr

ence

or w

ithou

t. C

ON

CLU

SIO

NS:

Su

bclin

ical

recu

rren

ce o

f LN

is c

omm

on in

pat

ient

s w

ith re

nal

trans

plan

tsw

ith S

LE. T

he m

ajor

ity o

f the

pat

ient

s ha

ve c

hron

ic

allo

graf

t nep

hrop

athy

.Bu

mga

rdne

r GL,

M

auer

SM

, Pay

ne W

, D

unn

DL,

Sut

herla

nd

DE

, Fry

d D

S, A

sche

r N

L, S

imm

ons

RL,

N

ajar

ian

JS.

Uni

vers

ity o

f M

inne

sota

, M

inne

apol

is

Tran

spla

ntat

ion.

198

8 N

ov;4

6(5)

:703

-9.

Sing

le-c

ente

r 1-1

5-ye

ar re

sults

of r

enal

tra

nspl

anta

tion

in

patie

nts

with

sy

stem

ic lu

pus

eryt

hem

atos

us.

How

ever

, sin

ce th

e lo

ng-te

rm o

utco

me

afte

r tra

nspl

anta

tion

in th

is g

roup

of p

atie

nts

is

not w

ell e

stab

lishe

d, w

e ha

ve e

xam

ined

the

long

-term

out

com

e in

SLE

pat

ient

s w

ho

unde

rwen

t ren

al tr

ansp

lant

atio

n at

the

Uni

vers

ity o

f Min

neso

ta. T

hirty

-two

SLE

pa

tient

s re

ceiv

ing

33 tr

ansp

lant

s be

twee

n D

ecem

ber 1

969

and

Dec

embe

r 198

7 w

ere

stud

ied

retro

spec

tivel

y an

d co

mpa

red

with

co

ntro

ls m

atch

ed fo

r age

, sex

, don

orso

urce

, HLA

mat

ch, d

ate

of tr

ansp

lant

, and

di

abet

ic s

tatu

s.

A to

tal o

f 69%

(22/

32) o

f pat

ient

s un

derw

ent l

ess

than

1 y

ear o

f di

alys

is p

rior t

o tra

nspl

anta

tion,

and

50%

(16/

32) e

xper

ienc

ed

biop

sy-p

rove

d ac

ute

reje

ctio

n, w

hich

was

reve

rsib

le in

67%

(1

1/16

).Ac

tuar

ial g

raft

func

tion

and

patie

nt s

urvi

val r

ate

in S

LE

patie

nts

wer

e no

t sig

nific

antly

diff

eren

t fro

m th

ose

in th

e m

atch

ed

cont

rol g

roup

. Dur

atio

n of

prio

r dia

lysi

s di

d no

t affe

ct o

utco

me.

Su

rviv

ing

graf

ts h

ave

exce

llent

func

tion

as m

easu

red

by s

erum

cr

eatin

ine

(1.3

+/-

0.4

mg/

dl, m

eans

+/-

SD).

Cau

ses

of d

eath

w

ere

seps

is (5

) and

myo

card

ial i

nfar

ctio

n (1

). O

ne p

atie

nt lo

st th

e gr

aft f

rom

reje

ctio

n af

ter w

ithdr

awal

of i

mm

unos

uppr

essi

on

beca

use

of a

mal

igna

ncy

one

mon

th p

osttr

ansp

lant

. Thr

ee

patie

nts

lost

gra

ft fu

nctio

n du

e to

chr

onic

reje

ctio

n. T

o da

te n

o pa

tient

s ha

ve h

ad e

vide

nce

of re

curr

ent S

LE n

ephr

itis.

Pollo

ck C

A, Ib

els

LS.

Roy

al N

orth

Sho

re

Hos

pita

l, N

SW.

Aus

t N

Z J

Med

. 198

7 Ju

n;17

(3):3

21-5

.

Dia

lysi

s an

d tra

nspl

anta

tion

in

patie

nts

with

rena

lfa

ilure

due

to

syst

emic

lupu

s er

ythe

mat

osus

. The

A

ustra

lian

and

New

Ze

alan

d ex

perie

nce.

Betw

een

1977

and

198

5, 5

726

patie

nts

in

Aust

ralia

and

New

Zea

land

ent

ered

end

st

age

rena

l fai

lure

pro

gram

mes

. Of t

hese

, 63

pat

ient

s ha

d re

nal f

ailu

re d

ue to

sys

tem

ic

lupu

s er

ythe

mat

osus

(a p

reva

lenc

e of

1.1

%

of p

atie

nts

ente

ring

rena

l rep

lace

men

t pr

ogra

mm

es).

Whe

n co

mpa

red

with

pat

ient

s w

ith o

ther

form

s of

gl

omer

ulon

ephr

itis,

ther

e w

as a

fem

ale

prep

onde

ranc

e an

d a

youn

ger a

ge d

istri

butio

n in

pat

ient

s w

ith re

nal f

ailu

redu

e to

lupu

s ne

phrit

is. I

nteg

rate

d pa

tient

, dia

lysi

s, a

nd tr

ansp

lant

sur

viva

l dat

a sh

owed

that

resu

lts in

pat

ient

s w

ith re

nal f

ailu

re d

ue to

lupu

s ne

phrit

is w

ere

com

para

ble

with

thos

e in

pat

ient

s w

ith o

ther

form

s of

glo

mer

ulon

ephr

itis

or in

pat

ient

s w

ith re

nal f

ailu

re d

ue to

any

ca

use.

Age

at e

ntry

sig

nific

antly

affe

cted

sur

viva

l, w

ith s

igni

fican

t di

ffere

nces

bei

ng fo

und

in th

ose

patie

nts

unde

r as

oppo

sed

to

over

50

year

s of

age

. Cau

ses

of d

eath

in p

atie

nts

with

lupu

s ne

phrit

is w

ere

sim

ilar t

o th

ose

in p

atie

nts

with

rena

l fai

lure

due

to

othe

r cau

ses.

It is

con

clud

ed th

at d

ialy

sis

and

trans

plan

tatio

n ar

e

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

acce

ptab

le fo

rms

of tr

eatm

ent f

or p

atie

nts

with

end

sta

ge re

nal

failu

re d

ue to

sys

tem

ic lu

pus

eryt

hem

atos

us.

Loch

head

KM

, Pirs

ch

JD, D

'Ale

ssan

dro

AM, K

nech

tle S

J,

Kala

yogl

u M

, So

lling

er H

W, B

elze

r FO

. U

nive

rsity

of

Wis

cons

in H

ospi

tal

and

Clin

ics

Kid

ney

Int.

1996

Fe

b;49

(2):5

12-7

.

Ris

k fa

ctor

s fo

r ren

al

allo

graf

t los

s in

pa

tient

s w

ith

syst

emic

lupu

s er

ythe

mat

osus

.

This

stu

dy is

a re

trosp

ectiv

e ev

alua

tion

ofea

ch o

f the

se in

depe

nden

t ris

k fa

ctor

s in

80

rena

l tra

nspl

ants

for E

SRD

sec

onda

ry to

SL

E do

ne a

t our

inst

itutio

n be

twee

n 19

71

and

1994

. Our

ent

ire n

on-d

iabe

tic c

ohor

t of

1,96

6 re

nal t

rans

plan

ts is

use

d as

a

com

paris

on g

roup

.

Our

resu

lts s

how

ed e

quiv

alen

t gra

ft su

rviv

al ra

tes

betw

een

lupu

s pa

tient

s an

d th

e co

hort

at 1

, 5 a

nd 1

0 ye

ars

(P =

0.5

6). H

owev

er,

an a

naly

sis

of c

yclo

spor

ine-

era

cada

ver g

rafts

reve

aled

that

the

lupu

s gr

oup

had

poor

er 5

-yea

r gra

ft su

rviv

al th

an th

e co

hort

(41%

vs.

71%

, P =

0.0

2). E

valu

atio

n of

cyc

losp

orin

e-er

a lu

pus

graf

t sur

viva

l sho

wed

sig

nific

antly

impr

oved

out

com

e in

livi

ng-

rela

ted

lupu

s re

cipi

ents

ove

r cad

aver

gra

fts a

t fiv

e ye

ars

(89%

vs

. 41%

, P =

0.0

03).

The

maj

ority

of g

rafts

lost

in th

e lu

pus

cada

ver r

ecip

ient

s w

ere

due

to c

hron

ic re

ject

ion.

Rej

ectio

n w

as

incr

ease

d in

lupu

s re

cipi

ents

: 69%

of l

upus

pat

ient

s ex

perie

nced

re

ject

ion

in th

e fir

st y

ear c

ompa

red

to 5

8% o

f con

trols

(P =

0.0

1).

Stra

tifie

d fo

r age

, sex

, rac

e an

d cy

clos

porin

e us

e, th

is d

iffer

ence

re

mai

ned

sign

ifica

nt (P

=0.

003,

rela

tive

risk

1.7)

. Nep

hrec

tom

y,

sple

nect

omy

and

3 to

6 m

onth

s of

pre

trans

plan

t dia

lysi

s di

d no

t im

prov

e gr

aft s

urvi

val.

A di

alys

is d

urat

ion

of g

reat

er th

an 2

5 m

onth

s pr

edic

ted

wor

se g

raft

surv

ival

(P =

0.0

1). A

mon

g lu

pus

patie

nts,

PR

A di

d no

t cor

rela

te w

ith g

raft

outc

ome

(P =

0.5

), an

d H

LA-id

entic

al c

adav

er g

rafts

had

impr

oved

out

com

es c

ompa

red

to c

adav

er g

rafts

. We

conc

lude

that

acu

te a

nd c

hron

ic re

ject

ion

are

the

maj

or ri

sk fa

ctor

s fo

r gra

ft lo

ss in

lupu

s pa

tient

s. T

he

supe

rior o

utco

me

of li

ving

-rel

ated

ove

r cad

aver

gra

fts in

lupu

s pa

tient

s su

gges

ts a

n in

crea

sed

role

for l

ivin

g-re

late

d gr

afts

. Pr

etra

nspl

ant d

ialy

sis,

nep

hrec

tom

y an

d sp

lene

ctom

y ar

e no

t in

dica

ted.

Hau

bitz

M, K

liem

V,

Koch

KM

, Nas

han

B,

Schl

itt H

J, P

ichl

may

r R

, Bru

nkho

rst R

. M

edic

al S

choo

l H

anno

ver,

Ger

man

y.

Tran

spla

ntat

ion.

199

7 M

ay 1

5;63

(9):1

251-

7.

Ren

al

trans

plan

tatio

n fo

r pa

tient

s w

ith

auto

imm

une

dise

ases

: sin

gle-

cent

er e

xper

ienc

e w

ith 4

2 pa

tient

s.

Long

-term

gra

ft su

rviv

al a

nd g

raft

func

tion

of

rena

l tra

nspl

ant r

ecip

ient

s w

ith S

LE,

Weg

ener

's g

ranu

lom

atos

is, m

icro

scop

ic

poly

angi

itis,

Goo

dpas

ture

's s

yndr

ome,

and

H

enoc

h-Sc

honl

ein

purp

ura

wer

e ev

alua

ted

in a

sin

gle

cent

er. I

n ad

ditio

n, th

e in

cide

nce

of re

nal a

nd e

xtra

rena

l rel

apse

s an

d th

e im

pact

of t

he im

mun

osup

pres

sive

ther

apy

on th

e co

urse

of t

he a

utoi

mm

une

dise

ase

RES

ULT

S: R

enal

tran

spla

nt re

cipi

ents

with

aut

oim

mun

e di

seas

es s

uch

as v

ascu

litis

and

SLE

had

a p

atie

nt s

urvi

val r

ate

(94%

afte

r 5 y

ears

) and

a g

raft

surv

ival

rate

(65%

afte

r 5 y

ears

) co

mpa

rabl

e to

thos

e of

pat

ient

s w

ith o

ther

cau

ses

of e

nd-s

tage

re

nal d

isea

se (p

atie

nt s

urvi

val 8

8% a

nd g

raft

surv

ival

71%

afte

r 5

year

s). G

raft

loss

es d

ue to

the

unde

rlyin

g di

seas

e w

ere

rare

. Ex

trare

nal r

elap

ses

occu

rred

in th

ree

patie

nts

with

Weg

ener

's

gran

ulom

atos

is, o

ne p

atie

nt w

ith m

icro

scop

ic p

olya

ngiit

is, a

nd

thre

e pa

tient

s w

ith S

LE, b

ut w

ere

less

freq

uent

com

pare

d w

ith

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

wer

e st

udie

d.th

e pe

riod

with

chr

onic

dia

lysi

s th

erap

y. A

utoa

ntib

ody

leve

ls in

pa

tient

s w

ith S

LE, W

egen

er's

gra

nulo

mat

osis

, or m

icro

scop

ic

poly

angi

itis

did

not s

eem

toin

fluen

ce th

e ou

tcom

e.

CO

NC

LUSI

ON

S: R

enal

tran

spla

ntat

ion

shou

ld b

e of

fere

d to

pa

tient

s w

ith a

utoi

mm

une

dise

ases

. Fol

low

-up

shou

ld in

clud

e th

e sh

ort-t

erm

con

trol o

f ren

al a

nd e

xtra

rena

l dis

ease

act

ivity

.

Grim

bert

P, L

ang

P,

Frap

pier

J,

Bedr

ossi

an J

, Le

gend

re C

, Hie

sse

C, B

itker

MO

, Sra

er

JD, A

ntoi

ne C

. H

opita

l Hen

ri M

ondo

r, C

rete

il,

Fran

ce.

Tran

spla

nt

Proc

. 199

7 Au

g;29

(5):2

363-

4.

Ren

al

trans

plan

tatio

n in

pa

tient

s w

ith

syst

emic

lupu

s er

ythe

mat

osus

: a

mul

ticen

ter s

tudy

.

Betw

een

Oct

ober

197

1 an

d Au

gust

199

3, 5

3 pa

tient

s w

ith S

LE re

ceiv

ed 6

0 re

nal

trans

plan

ts in

the

diffe

rent

rena

l tra

nspl

anta

tion

cent

ers

in P

aris

. All

patie

nts

met

the

crite

ria o

f the

Am

eric

an

Rhe

umat

ism

Ass

ocia

tion

for S

LE, a

nd

diag

nose

s w

ere

conf

irmed

by

rena

l bio

psy

spec

imen

s in

all

patie

nts.

The

long

-term

ou

tcom

e of

rena

l tra

nspl

anta

tion

in th

ese

patie

nts

was

exa

min

ed, i

nclu

ding

pat

ient

an

d gr

aft s

urvi

val,

post

trans

plan

t lup

us

activ

ity, s

erum

cre

atin

ine

leve

ls, r

ejec

tion

epis

odes

, and

the

caus

es o

f gra

ft lo

ss a

nd

patie

nt d

eath

. All

char

ts w

ere

exam

ined

for

any

evid

ence

of r

ecur

rent

lupu

s ne

phrit

is.

Thes

e 60

rena

l tra

nspl

ants

wer

e co

mpa

red

with

the

patie

nt a

nd g

raft

surv

ival

for 1

06

cont

rols

mat

ched

for a

ge, g

ende

r, m

axim

um

pane

l-rea

ctiv

e an

tibod

y le

vel,

and

date

of

trans

plan

t.

The

popu

latio

n st

udie

d co

nsis

ted

mai

nly

of y

oung

wom

en (m

ean

age,

33.

2 ye

ars;

rang

e, 2

1 to

54,

n =

48

[90%

]). T

he d

urat

ion

of

dise

ase

befo

re tr

ansp

lant

was

93.

6 +-

6.2

mon

ths

and

the

dura

tion

of d

ialy

sis

befo

re tr

ansp

lant

was

48

_~ 6

mon

ths.

At t

he

time

of tr

ansp

lant

, non

e of

the

patie

nts

had

clin

ical

ly a

ctiv

e S

LE,

only

four

had

hyp

ocom

plem

ente

mia

, and

25

had

posi

tive

anti-

DN

A tit

ers.

Of t

he 6

0 tra

nspl

ants

, 56

(93%

) wer

e ca

dave

ric a

nd 4

(7

%) w

ere

from

livi

ng re

late

d do

nors

. For

ty-s

ix p

atie

nts

(86%

) ha

d pr

imar

y al

logr

afts

, and

7 (1

4%) w

ere

give

n a

seco

nd

allo

graf

t. D

onor

age

was

38

_+ 2

.4 y

ears

. The

num

ber o

f HLA

m

atch

es w

as 2

.96

-+ 0

.2. P

anel

-rea

ctiv

e an

tibod

y le

vel w

as

>80%

in 1

9 ca

ses

(31%

). O

vera

ll gr

aft s

urvi

val r

ates

for l

upus

pa

tient

s w

ere

83%

and

69%

at 1

and

5 y

ears

, res

pect

ivel

y,

sim

ilar t

o th

ose

of c

ontro

l gra

ft su

rviv

als

of 8

2.5%

and

70%

(P

= .6

0). O

f the

60

kidn

eys

trans

plan

ted

in S

LE p

atie

nts

durin

g th

is

21.5

-yea

r per

iod,

37

(62%

) are

stil

l fun

ctio

ning

, and

the

mea

n se

rum

cre

atin

ine

leve

l is

15 _

+ 2.

5 m

g/L.

Fifte

en g

rafts

wer

e lo

st

due

to c

hron

ic re

ject

ion,

3 to

acu

te re

ject

ion,

3 to

rena

l arte

ry

thro

mbo

sis,

1 to

ure

tera

l nec

rosi

s, a

nd 1

to th

rom

botic

ic

roan

giop

athy

cau

sed

by c

yclo

spor

ine.

For

tyon

e (6

8%) o

f the

ki

dney

tran

spla

nts

had

at le

ast o

ne b

iops

y-do

cum

ente

d ep

isod

e of

acu

te re

ject

ion,

and

ther

e w

as h

isto

logi

cal e

vide

nce

of c

hron

ic

reje

ctio

n in

36

(60%

) kid

ney

trans

plan

ts. T

he s

urvi

val o

f the

lupu

s pa

tient

s w

as s

imila

r to

the

cont

rols

: it w

as 9

8% a

t 1 y

ear a

nd

96%

at 5

yea

rs in

the

lupu

s gr

oup,

and

97%

and

93%

at 1

and

5

year

s in

the

cont

rols

(P =

.96)

. Tw

o of

the

lupu

s pa

tient

s di

ed

from

sep

sis.

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

Ston

e JH

, Mill

war

d C

L, O

lson

JL,

Am

end

WJ,

Cris

wel

l LA

.

Uni

vers

ity o

f C

alifo

rnia

, San

Fr

anci

sco

Arth

ritis

R

heum

. 199

8 Ap

r;41(

4):6

78-8

6.

Freq

uenc

y of

re

curr

ent l

upus

ne

phrit

is a

mon

g ni

nety

-sev

en re

nal

trans

plan

t pat

ient

s du

ring

the

cycl

ospo

rine

era.

We

revi

ewed

the

post

trans

plan

t clin

ical

co

urse

and

rena

l bio

psy

resu

lts in

97

cons

ecut

ive

SLE

patie

nts

who

und

erw

ent a

to

tal o

f 106

rena

l tra

nspl

anta

tion

proc

edur

es

at o

ur c

ente

r fro

m J

anua

ry 1

984

to

Sept

embe

r 199

6.

RES

ULT

S: T

here

wer

e 81

fem

ale

and

16 m

ale

patie

nts,

with

a

mea

n ag

e of

35

year

s. M

ean

dura

tion

of d

ialy

sis

prio

r to

trans

plan

tatio

n w

as 3

3.5

mon

ths;

9 p

atie

nts

wer

e ne

ver d

ialy

zed.

In

all

patie

nts,

the

dise

ase

was

clin

ical

ly a

nd s

erol

ogic

ally

qu

iesc

ent a

t the

tim

e of

tran

spla

ntat

ion.

The

mea

n po

sttra

nspl

anta

tion

follo

wup

per

iod

was

62.

6 m

onth

s. P

atie

nts

unde

rwen

t a to

tal o

f 143

pos

ttran

spla

nt b

iops

ies.

Nin

e pa

tient

s ha

d pa

thol

ogic

evi

denc

e of

recu

rren

t LN

. Six

of t

he p

atie

nts

with

re

curr

ence

had

cad

aver

ic g

rafts

, 2 h

ad li

ving

-rel

ated

gra

fts, a

nd 1

ha

d a

livin

g-un

rela

ted

graf

t. R

ecur

renc

e oc

curr

ed a

n av

erag

e of

3.

1 ye

ars

afte

r tra

nspl

anta

tion;

the

long

est i

nter

val w

as 9

.3 y

ears

an

d th

e sh

orte

st, 5

day

s. H

isto

path

olog

ic d

iagn

oses

on

recu

rren

ce in

clud

ed d

iffus

e pr

olife

rativ

e gl

omer

ulon

ephr

itis,

foca

l pr

olife

rativ

e gl

omer

ulon

ephr

itis,

mem

bran

ous

glom

erul

onep

hriti

s,

and

mes

angi

al g

lom

erul

onep

hriti

s. In

4 p

atie

nts,

recu

rren

t LN

co

ntrib

uted

to g

raft

loss

. Thr

ee o

f the

pat

ient

s w

ith re

curr

ence

ha

d se

rolo

gic

evid

ence

of a

ctiv

e lu

pus,

but

onl

y 1

had

sym

ptom

s of

act

ive

lupu

s (a

rthrit

is).

Thre

e pa

tient

s w

ho lo

st th

eir g

rafts

se

cond

ary

to re

curr

ent L

N u

nder

wen

t sec

ond

rena

l tra

nspl

anta

tion

proc

edur

es a

nd h

ad fu

nctio

ning

graf

ts a

t 7, 3

0,

and

35 m

onth

s, re

spec

tivel

y. C

ON

CLU

SIO

N: I

n th

e la

rges

t sin

gle

med

ical

cen

ter s

erie

s of

rena

l tra

nspl

ant p

atie

nts

with

SLE

, re

curr

ent L

N w

as m

ore

com

mon

than

repo

rted

in th

e lit

erat

ure,

bu

t was

not

alw

ays

asso

ciat

ed w

ith a

llogr

aft l

oss.

Rec

urre

nt L

N

was

ofte

n pr

esen

t in

the

abse

nce

of c

linic

al a

nd s

erol

ogic

ev

iden

ce o

f act

ive

SLE.

Ston

e JH

, Am

end

WJ,

Cris

wel

l LA

. Jo

hns

Hop

kins

U

nive

rsity

Arth

ritis

R

heum

. 199

8 Au

g;41

(8):1

438-

45.

Out

com

e of

rena

l tra

nspl

anta

tion

in

nine

ty-s

even

cy

clos

porin

e-er

a pa

tient

s w

ith

syst

emic

lupu

s er

ythe

mat

osus

and

m

atch

ed c

ontro

ls.

A to

tal o

f 97

SLE

pat

ient

s w

ho u

nder

wen

t re

nal t

rans

plan

tatio

n be

twee

n Ja

nuar

y 19

84

and

Sept

embe

r 199

6 w

ere

sele

cted

for

stud

y an

d w

ere

mat

ched

with

a g

roup

of

non-

SLE

con

trols

(1 c

ontro

l for

eac

h SL

E pa

tient

) who

als

o re

ceiv

ed tr

ansp

lant

s du

ring

that

per

iod.

SLE

pat

ient

s an

d co

ntro

ls

wer

e m

atch

ed o

n 6

cova

riate

s: a

ge, s

ex,

race

, typ

e of

allo

graf

t (ca

dave

ric v

ersu

s liv

ing-

rela

ted)

, num

ber o

f pre

viou

s tra

nspl

ants

, and

yea

r of t

rans

plan

tatio

n. A

ll st

udy

subj

ects

rece

ived

eith

er c

yclo

spor

ine

or F

K-50

6/ta

crol

imus

as

part

of th

eir

imm

unos

uppr

essi

ve re

gim

en. I

n a

rigor

ous

med

ical

reco

rds

revi

ew, t

he s

tatu

s of

eac

h al

logr

aft a

nd th

e ca

use

of e

ach

graf

t los

s

RES

ULT

S: T

he c

ontro

lgro

up in

clud

ed p

atie

nts

with

20

diffe

rent

ca

uses

of e

nd-s

tage

rena

l dis

ease

(ES

RD

). Th

e m

ean

follo

wup

tim

es fo

r the

SLE

pat

ient

s an

d co

ntro

ls w

ere

323

wee

ks a

nd 3

20

wee

ks, r

espe

ctiv

ely.

Dur

ing

the

follo

wup

per

iod,

52

SLE

patie

nts

and

37 c

ontro

ls lo

st th

eir a

llogr

afts

. The

1-,

2-, 5

-, an

d 10

-yea

r al

logr

aft s

urvi

val p

roba

bilit

ies

for t

he 2

gro

ups

(SLE

ver

sus

cont

rols

) wer

e as

follo

ws:

81.

7% v

ersu

s 88

.2%

(1-y

ear)

; 74.

7%

vers

us 8

4.4%

(2-y

ear)

; 45.

9% v

ersu

s 75

.0%

(5-y

ear)

; and

18.

5%

vers

us 3

4.8%

(10-

year

). In

the

mul

tivar

iate

mod

el, t

he re

lativ

e ha

zard

of a

llogr

aft l

oss

asso

ciat

ed w

ith S

LE a

s th

e ca

use

of

ESR

D w

as 2

.1 (9

5% c

onfid

ence

inte

rval

1.0

6-4.

06, P

= 0

.032

8).

The

tota

l num

ber o

f HLA

mis

mat

ches

, sm

okin

g st

atus

, and

de

laye

d al

logr

aft f

unct

ion

wer

e al

so a

ssoc

iate

d w

ith a

llogr

aft l

oss

in th

e m

ultiv

aria

te m

odel

. CO

NC

LUSI

ON

: Com

pare

d w

ith

mat

ched

con

trols

, ren

al tr

ansp

lant

pat

ient

s w

ith S

LE h

ad in

ferio

r tra

nspl

anta

tion

outc

omes

, with

mor

e th

an tw

ice

the

risk

of

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

was

det

erm

ined

.al

logr

aft l

oss.

Grim

bert

P, F

rapp

ier

J, B

edro

ssia

nJ,

Le

gend

re C

, Ant

oine

C

, Hie

sse

C, B

itker

M

O, S

raer

JD

, Lan

g P

. H

ôpita

l Hen

ri M

ondo

r, C

réte

il,

Fran

ce.

Tran

spla

ntat

ion.

199

8 O

ct 2

7;66

(8):1

000-

3.

Long

-term

out

com

e of

kid

ney

trans

plan

tatio

n in

pa

tient

s w

ith

syst

emic

lupu

s er

ythe

mat

osus

: a

mul

ticen

ter s

tudy

. G

roup

e C

oope

ratif

de

Tra

nspl

anta

tion

d'île

de

Fran

ce.

The

patie

nts

rece

ived

thei

r tra

nspl

ants

ove

r a

260-

mon

th p

erio

d (2

1.5

year

s) b

etw

een

Oct

ober

197

1 an

d Au

gust

199

3. T

he

popu

latio

n w

as p

redo

min

antly

wom

en

(90%

), an

d th

e m

ean

age

at th

e tim

e of

the

trans

plan

tatio

n w

as 3

3.2

year

s (r

ange

: 21-

54 y

ears

). Fi

fty-s

ix tr

ansp

lant

s (9

3%) w

ere

from

cad

aver

ic d

onor

s, a

nd 4

(7%

) wer

e fro

m li

ving

-rel

ated

don

ors;

46

patie

nts

(86%

) ha

d pr

imar

y al

logr

afts

, and

7 (1

4%) r

ecei

ved

a se

cond

allo

graf

t. Th

e du

ratio

n of

dis

ease

be

fore

tran

spla

ntat

ion

was

93.

6+/-6

.2

mon

ths,

and

the

dura

tion

of d

ialy

sis

befo

re

trans

plan

tatio

n w

as 4

8+/-6

mon

ths.

RES

ULT

S: N

o pa

tient

had

clin

ical

ly a

ctiv

e sy

stem

ic lu

pus

eryt

hem

atos

us (S

LE) a

t the

tim

e of

tran

spla

ntat

ion.

The

1-y

ear

graf

t and

pat

ient

sur

viva

l rat

es w

ere

83%

and

98%

, and

the

5-ye

ar g

raft

and

patie

nt s

urvi

val r

ates

wer

e 69

% a

nd 9

6%.

Actu

aria

l gra

ft an

d pa

tient

sur

viva

l rat

es in

SLE

pat

ient

s w

ere

not

sign

ifica

ntly

diff

eren

t fro

m th

ose

of th

e m

atch

ed c

ontro

l gro

up.

Chr

onic

reje

ctio

n w

as th

e m

ajor

risk

fact

or fo

r gra

ft lo

ss. L

upus

ne

phrit

is re

curr

ed in

the

graf

t of o

ne p

atie

nt 3

mon

ths

afte

r tra

nspl

anta

tion,

and

ther

e w

ere

extra

rena

l man

ifest

atio

ns o

f SLE

in

four

oth

ers.

CO

NC

LUSI

ON

S: T

he p

rese

nt s

tudy

con

firm

s th

at

patie

nts

with

SLE

can

rece

ive

trans

plan

ts w

ith e

xcel

lent

gra

ft an

d pa

tient

sur

viva

l rat

es a

nd a

low

rate

of c

linic

al re

curr

ent l

upus

ne

phrit

is.

Aze

vedo

LS

, Rom

ão

JE J

r, M

alhe

iros

D,

Sald

anha

LB,

Ianh

ez

LE, S

abba

ga E

.

Uni

vers

ity o

f São

Pa

ulo

Med

ical

Sc

hool

, SP,

Bra

zil.

N

ephr

ol D

ial

Tran

spla

nt. 1

998

Nov

;13(

11):2

894-

8.

Ren

al

trans

plan

tatio

n in

sy

stem

ic lu

pus

eryt

hem

atos

us. A

ca

se c

ontro

l stu

dy o

f 45

pat

ient

s.

Forty

-five

pat

ient

s w

ith s

yste

mic

lupu

s er

ythe

mat

osus

sub

ject

ed to

48

kidn

ey

trans

plan

ts w

ere

stud

ied.

For

com

para

tive

purp

oses

, a c

ase-

cont

rol p

opul

atio

n w

as

sele

cted

, mat

ched

for g

ende

r, ra

ce, t

ype

of

dono

r, ag

e, a

nd ti

me

of tr

ansp

lant

atio

n.

Patie

nts

with

non

-glo

mer

ulon

ephr

itis

dise

ases

wer

e ex

clud

ed.

RES

ULT

S: N

o di

ffere

nces

in a

cute

epi

sode

s of

reje

ctio

n, c

ause

s of

kid

ney

loss

or p

atie

nt d

eath

wer

e ob

serv

ed. G

ener

al a

s w

ell a

s in

fect

ious

com

plic

atio

ns w

ere

sim

ilar.

Preg

nanc

y ra

tes

and

outc

omes

wer

e si

mila

r with

no

dele

terio

us e

ffect

on

patie

nts

or

graf

ts. A

ctua

rial 1

-and

5-y

ear p

atie

nt s

urvi

vals

(97.

7 an

d 91

.1%

fo

r SLE

and

95.

4 an

d 87

% fo

r con

trols

, res

pect

ivel

y) a

nd g

raft

surv

ival

s (9

3.1

and

80.7

% fo

r SLE

and

88.

8 an

d 70

.2%

for

cont

rols

, res

pect

ivel

y) w

ere

sim

ilar.

Long

-term

rena

l fun

ctio

n ex

pres

sed

by s

erum

cre

atin

ine

was

the

sam

e. N

o di

ffere

nces

in

imm

unos

uppr

essi

vedr

ug (a

zath

iopr

ine,

pre

dnis

one,

and

cy

clos

porin

) req

uire

men

ts w

ere

foun

d. C

linic

al S

LE re

curr

ence

w

as s

uspe

cted

onl

y on

ce (a

pat

ient

with

thro

mbo

cyto

peni

a,

hypo

com

plem

enta

emia

with

low

com

plem

ent l

evel

s an

d po

sitiv

e an

tipla

tele

t ant

ibod

ies)

. Tw

o SL

E pa

tient

s sh

owed

mes

angi

al

prol

ifera

tive

glom

erul

onep

hriti

s co

mpa

tible

with

recu

rren

ce. B

oth

graf

ts w

ere

lost

. Tw

o fu

rther

pat

ient

s sh

owed

mem

bran

ous

glom

erul

onep

hriti

s w

ith a

n im

mun

oflu

ores

cenc

e pa

ttern

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

com

patib

le w

ith re

curr

ence

. A fi

fth p

atie

nt h

ad n

ecro

tizin

gar

terit

is w

hich

reco

vere

d af

ter t

reat

men

t with

cyc

loph

osph

amid

e an

d an

othe

r pat

ient

sho

wed

foca

l and

seg

men

tal

glom

erul

oscl

eros

is. H

isto

logy

of b

iops

ies

from

five

pat

ient

s in

the

cont

rol g

roup

sho

wed

sig

ns c

ompa

tible

with

recu

rren

ce o

f foc

al

and

segm

enta

l glo

mer

ulos

cler

osis

and

mem

bran

ous

glom

erul

onep

hriti

s. T

here

was

a w

ide

varia

tion

in s

erum

leve

ls o

f an

tinuc

lear

ant

ibod

ies.

A w

ide

varia

tion

in c

ompl

emen

t lev

els

was

als

o ob

serv

ed, b

ut w

ith a

tend

ency

tow

ards

low

C4

leve

ls.

CO

NC

LUSI

ON

S: T

he s

afet

y of

rena

l tra

nspl

anta

tion

in S

LE

patie

nts

is e

quiv

alen

t to

a m

atch

ed c

ase-

cont

rol g

roup

with

a

sim

ilar r

ate

of re

curr

ence

of d

isea

se.

Con

trera

s G

, M

attia

zzi A

, Gue

rra

G, O

rtega

LM

, To

zman

EC

, Li H

, Ta

mar

iz L

, Car

valh

o C

, Kup

in W

, Lad

ino

M, L

eCle

rcq

B,

Jara

ba I,

Car

valh

o D

, C

arle

s E

, Rot

h D

. M

iller S

choo

l of

Med

icin

e, U

nive

rsity

of

Mia

mi

J Am

Soc

N

ephr

ol. 2

010

Jul;2

1(7)

:120

0-7.

Ep

ub 2

010

May

20.

Rec

urre

nce

of lu

pus

neph

ritis

afte

r kid

ney

trans

plan

tatio

n.

The

frequ

ency

and

out

com

e of

recu

rren

t lu

pus

neph

ritis

(RLN

) am

ong

reci

pien

ts o

f a

kidn

ey a

llogr

aft v

ary

amon

g si

ngle

-cen

ter

repo

rts. F

rom

the

Uni

ted

Net

wor

k fo

r Org

an

Shar

ing

files

, we

estim

ated

the

perio

d pr

eval

ence

and

pre

dict

ors

of R

LN in

re

cipi

ents

who

rece

ived

a tr

ansp

lant

be

twee

n 19

87 a

nd 2

006

and

asse

ssed

the

effe

cts

of R

LN o

n al

logr

aft f

ailu

re a

nd

reci

pien

ts' s

urvi

val.

Amon

g 68

50 re

cipi

ents

of a

kid

ney

allo

graf

t with

sys

tem

ic lu

pus

eryt

hem

atos

us, 1

67 re

cipi

ents

had

RLN

, 177

0 ex

perie

nced

re

ject

ion,

and

491

3 co

ntro

l sub

ject

s di

d no

t exp

erie

nce

reje

ctio

n.

The

perio

d pr

eval

ence

of R

LN w

as 2

.44%

. Non

-His

pani

c bl

ack

race

, fem

ale

gend

er, a

nd a

ge <

33 y

ears

eac

h in

depe

nden

tly

incr

ease

d th

e od

ds o

f RLN

. Gra

ft fa

ilure

occ

urre

d in

156

(93%

) of

thos

e w

ith R

LN, 1

517

(86%

) of t

hose

with

reje

ctio

n, a

nd 9

23

(19%

) of c

ontro

l sub

ject

s w

ithou

t rej

ectio

n. A

lthou

gh re

cipi

ents

w

ith R

LN h

ad a

four

fold

gre

ater

risk

for g

raft

failu

re c

ompa

red

with

con

trol s

ubje

cts

with

out r

ejec

tion,

onl

y 7%

of g

raft

failu

re

epis

odes

wer

e at

tribu

tabl

e to

RLN

com

pare

d an

d 43

% to

re

ject

ion.

Dur

ing

follo

w-u

p, 8

67 (1

3%) r

ecip

ient

s di

ed: 2

7 (1

6%)

in th

e R

LN g

roup

, 313

(18%

) in

the

reje

ctio

n gr

oup,

and

527

(1

1%) i

n th

e co

ntro

l gro

up. I

n su

mm

ary,

sev

ere

RLN

is

unco

mm

on in

reci

pien

ts o

f a k

idne

y al

logr

aft,

but b

lack

reci

pien

ts,

fem

ale

reci

pien

t, an

d yo

unge

r rec

ipie

nts

are

at in

crea

sed

risk.

Al

thou

gh R

LN s

igni

fican

tly in

crea

ses

the

risk

for g

raft

failu

re, i

t co

ntrib

utes

far l

ess

than

reje

ctio

n to

its

over

all i

ncid

ence

; th

eref

ore,

thes

e fin

ding

s sh

ould

not

kee

p pa

tient

s w

ith lu

pus

from

se

ekin

g a

kidn

ey tr

ansp

lant

.Ja

kez-

Oca

mpo

J,

Arre

ola-

Zava

la R

, R

icha

ud-P

atin

Y,

Rom

ero-

Día

z J,

Ll

oren

te L

. In

stitu

to

Nac

iona

l de

Cie

ncia

s M

édic

as y

Nut

rició

n Sa

lvad

or Z

ubirá

n,

Méx

ico

City

J C

lin

Rhe

umat

ol. 2

004

Lupu

s ne

phrit

is

outc

ome

with

and

w

ithou

t ren

al b

iops

y:

a 5-

year

co

mpa

rativ

e st

udy.

The

no-b

iops

y gr

oup

cons

iste

d of

30

patie

nts

with

lupu

s w

ith s

trong

clin

ical

and

la

bora

tory

sus

pici

on o

f pro

lifer

ativ

e gl

omer

ulon

ephr

itis

in w

hom

a re

nal b

iops

y w

as u

nava

ilabl

e ei

ther

bec

ause

of m

edic

al

cont

rain

dica

tion

or th

e pa

tient

's re

fusa

l. Th

e bi

opsy

gro

up in

clud

ed 3

0 pa

tient

s un

derg

oing

bio

psy

and

a hi

stol

ogic

di

agno

sis

of D

PGN

. Pat

ient

s w

ere

follo

wed

fro

m th

e on

set o

f nep

hriti

s an

d at

18,

36,

RES

ULT

S: A

t ons

et, t

he n

o-bi

opsy

gro

up s

how

ed lo

wer

C3

leve

ls a

nd h

ighe

r pro

tein

uria

, alth

ough

bot

h gr

oups

sho

wed

ev

iden

t det

erio

ratio

n of

the

rena

l fun

ctio

n. N

o si

gnifi

cant

di

ffere

nces

wer

e fo

und

in tr

eatm

ent,

outc

ome,

sur

viva

l, re

nal

func

tion

test

s, o

r in

the

deve

lopm

ent o

f kid

ney

failu

re.

CO

NC

LUSI

ON

S: P

rolif

erat

ive

glom

erul

onep

hriti

s de

serv

es

prom

pt d

iagn

osis

and

trea

tmen

t. Th

is s

tudy

dem

onst

rate

s th

at

expe

rienc

e in

the

man

agem

ent o

f lup

us n

ephr

opat

hy, t

oget

her

with

clin

ical

and

labo

rato

ry d

ata,

are

ofte

n en

ough

info

rmat

ion

to

adeq

uate

ly tr

eat p

rolif

erat

ive

glom

erul

onep

hriti

s ev

en in

the

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

Dec

;10(

6):2

89-9

4.an

d 60

mon

ths.

abse

nce

of a

rena

l bio

psy.

Nyb

erg

G, K

arlb

erg

I, Sv

alan

der C

, H

edm

an L

, Blo

hmé

I. Sa

hlgr

ensk

a H

ospi

tal,

Göt

ebor

g,

Sw

eden

. Sc

and

J U

rol N

ephr

ol.

1990

;24(

4):3

07-1

3.

Ren

al

trans

plan

tatio

n in

pa

tient

s w

ith

syst

emic

lupu

s er

ythe

mat

osus

: in

crea

sed

risk

of

early

gra

ft lo

ss.

The

outc

ome

of p

rimar

y re

nal

trans

plan

tatio

n in

31

SLE

pat

ient

s w

as

eval

uate

d in

rela

tion

to tw

o co

ntem

pora

ry

cont

rols

per

pat

ient

, mat

ched

for a

ge, s

ex

and

imm

unos

uppr

essi

ve th

erap

y. T

he

prop

ortio

n of

livi

ng d

onor

s w

as o

ne th

ird in

bo

th g

roup

s.

Patie

nt s

urvi

val d

id n

ot d

iffer

, but

gra

ft su

rviv

al a

t 6 a

nd 1

2 m

onth

s po

st tr

ansp

lant

atio

n w

as s

igni

fican

tly re

duce

d in

SLE

pa

tient

s (p

less

than

0.0

01).

Whe

n di

vide

d in

to g

roup

s us

ing

eith

er a

zath

iopr

ine

and

ster

oids

or c

ombi

natio

ns in

clud

ing

cycl

ospo

rin A

(14

and

17 S

LE p

atie

nts

in e

ach

grou

p), g

raft

surv

ival

was

sig

nific

antly

redu

ced

for t

he a

zath

iopr

ine-

treat

ed

SLE

patie

nts,

36%

vs.

82%

for t

heir

cont

rols

at o

ne y

ear.

For

cycl

ospo

rin-tr

eate

d SL

E pa

tient

s, o

ne-y

ear g

raft

surv

ival

was

59

% v

s. 8

5% fo

r the

ir co

ntro

ls, a

nd 6

out

of 1

7 gr

afts

in th

e cy

clos

porin

-trea

ted

grou

p w

ere

lost

with

in th

e fir

st m

onth

vs.

onl

y 4

out o

f 34

cont

rols

. The

se d

iffer

ence

s w

ere,

how

ever

, not

st

atis

tical

ly d

iffer

ent.

Mos

t fai

led

graf

ts w

ere

lost

from

reje

ctio

n,

with

a h

igh

prop

ortio

n of

acu

te v

ascu

lar r

ejec

tion,

isol

ated

or i

n co

mbi

natio

n w

ith c

ellu

lar r

ejec

tion.

The

re w

as n

o ap

pare

nt

asso

ciat

ion

betw

een

reje

ctio

n an

d H

LA-m

atch

ed o

r pre

senc

e of

H

LA a

ntib

odie

s. R

etra

nspl

anta

tion

was

suc

cess

ful i

n6

out o

f 7

case

s. W

e co

nclu

de th

at S

LE p

atie

nts

have

an

incr

ease

d ris

k of

ea

rly g

raft

reje

ctio

n, b

ut th

at th

is m

ay b

e ov

erco

me

by m

ore

pow

erfu

l im

mun

osup

pres

sive

ther

apy.

el-S

haha

wy

MA,

As

wad

S, M

ende

z R

G, B

angs

il R

, M

ende

z R

, Mas

sry

SG. U

nive

rsity

of

Sout

hern

Cal

iforn

ia

Scho

ol o

f M

edic

ineA

m J

N

ephr

ol.

1995

;15(

2):1

23-8

.

Ren

al

trans

plan

tatio

n in

sy

stem

ic lu

pus

eryt

hem

atos

us: a

si

ngle

-cen

ter

expe

rienc

e w

ith

sixt

y-fo

ur c

ases

.

The

outc

ome

of re

nal t

rans

plan

tatio

n in

64

patie

nts

with

end

-sta

ge re

nal d

isea

se(E

SRD

) sec

onda

ry to

lupu

s ne

phrit

is is

the

subj

ect o

f thi

s re

port.

The

pat

ient

s w

ere

trans

plan

ted

over

a 1

50-m

onth

(12.

5-ye

ar)

perio

d (b

etw

een

July

5, 1

979,

and

Jan

uary

30

, 199

2). T

he s

tudy

pop

ulat

ion

is

pred

omin

antly

mad

e up

of y

oung

fem

ales

(m

ean

age,

34.

7 +/

-9 y

ears

, n =

54,

81.

3%).

Fifty

-one

tran

spla

nts

(79.

7%) a

re c

adav

eric

, an

d 13

(20.

3%) a

re fr

om li

ving

-rel

ated

do

nors

. Fift

y-ei

ght p

atie

nts

(90.

6%) h

ad

prim

ary

(firs

t) al

logr

afts

, and

6 (9

.4%

) re

ceiv

ed a

sec

ond

allo

graf

t.

For a

ll 64

pat

ient

s co

mbi

ned,

the

1-ye

ar g

raft

and

patie

nt s

urvi

val

rate

s ar

e 68

.8 a

nd 8

6.5%

, res

pect

ivel

y, w

here

as 5

-yea

r gra

ft an

d pa

tient

sur

viva

l rat

es a

re 6

0.9

and

85.9

%, r

espe

ctiv

ely.

Pat

ient

s w

hose

imm

unos

uppr

essi

ve re

gim

en w

as C

sA-b

ased

had

a 1

-ye

ar g

raft

surv

ival

of 7

1.5

vers

us 6

3.6%

in th

e AZ

A gr

oup.

H

owev

er, t

his

7.9%

diff

eren

ce d

id n

ot re

ach

stat

istic

al

sign

ifica

nce

(p =

0.9

5). T

he 5

-yea

r gra

ft su

rviv

al o

f the

CsA

-ba

sed

grou

p w

as 6

9.1

vers

us 4

5.5%

for t

he A

ZA g

roup

, p <

0.0

5.

One

-yea

r pat

ient

sur

viva

l was

77.

3% fo

r the

AZA

gro

up a

nd

92.9

% fo

r the

CsA

gro

up, p

< 0

.05)

. The

dat

a sh

ow th

at p

atie

nts

with

ESR

D s

econ

dary

to lu

pus

neph

ritis

can

und

ergo

rena

l tra

nspl

anta

tion

with

sat

isfa

ctor

y ou

tcom

e. Im

mun

osup

pres

sion

ba

sed

upon

CsA

impr

oves

firs

t-yea

r pat

ient

and

allo

graf

t sur

viva

l by

15.

6 an

d 7.

9%. r

espe

ctiv

ely.

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, T

RE

AT

ME

NT

AN

D M

ON

ITO

RIN

G O

F L

UPU

S N

EPH

RIT

IS IN

AD

UL

TS

END

STA

GE

REN

AL

DIS

EASE

/ R

ENA

L TR

AN

SPLA

NTA

TIO

N A

RTI

CLE

S

Aut

hors

Title

Des

crip

tion/

Met

hods

Res

ults

/Con

clus

ions

Post

trans

plan

tatio

n im

mun

osup

pres

sion

co

nsis

ted

of a

zath

iopr

ine

and

pred

niso

ne

(AZA

gro

up, n

= 2

2, 3

4.3%

) or A

ZA,

pred

niso

ne a

nd c

yclo

spor

ine

(CsA

gro

up, n

=

42, 6

5.6%

).

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, D

IAG

NO

SIS,

TR

EA

TM

EN

T A

ND

MO

NIT

OR

ING

OF

LU

PUS

NE

PHR

ITIS

IN A

DU

LT

S

Tabl

e 8.

Sum

mar

y of

Com

mon

ly U

sed

Med

icat

ions

’Ter

atog

enic

Effe

cts

PREG

NA

NC

Y A

ND

LU

PUS

NEP

HR

ITIS

Trea

tmen

tPr

egna

ncy

C

ateg

ory

Cro

sses

Pl

acen

ta?

Anim

al

Stud

ies

Hum

an S

tudi

es

Cyc

loph

osph

ami

deD

yes

Tera

toge

nic

Tera

toge

nic

effe

cts

have

bee

n re

porte

d in

ass

ocia

tion

with

the

use

of

cycl

opho

spha

mid

e. In

gen

eral

, alk

ylat

ing

agen

ts w

hen

give

n du

ring

the

first

tri

mes

ter a

re b

elie

ved

to c

ause

slig

ht in

crea

ses

in th

e ris

k of

con

geni

tal

mal

form

atio

ns, b

ut w

hen

give

n du

ring

the

seco

nd o

r thi

rd tr

imes

ters

are

bel

ieve

d to

onl

y in

crea

se th

e ris

k of

gro

wth

retri

ctio

n (G

lant

z, 1

994)

. In

one

cas

e se

ries

of

4 pa

tient

s tre

ated

with

cyc

loph

osph

amid

e fo

r lup

us d

urin

g pr

egna

ncy

(2 d

urin

g fir

st tr

imes

ter,

2 du

ring

2ndtri

mes

ter),

all

4 re

sulte

d in

pre

gnan

cy lo

ss (C

low

se

Lupu

s 20

05)

Azat

hiop

rine

D

Yes

(but

feta

l liv

er la

cks

enzy

me

whi

ch

conv

erts

dr

ug to

ac

tive

met

abol

ites)

Tera

toge

nic

Azat

hiop

rine

has

been

use

d du

ring

preg

nanc

y in

org

an tr

ansp

lant

reci

pien

ts.

Dur

ing

over

40

year

s of

exp

erie

nce

with

aza

thio

prin

e as

an

imm

unos

uppr

essa

nt

in o

rgan

tran

spla

nt p

atie

nts,

no

pred

omin

ant o

r spe

cific

mal

form

atio

n pa

ttern

has

be

en id

entif

ied

whi

ch is

attr

ibut

able

to th

is d

rug.

Ret

rosp

ectiv

e re

view

of

preg

nanc

y ou

tcom

es re

veal

ed th

at in

fant

s ex

pose

d to

aza

thio

prin

e m

ay d

evel

op

the

follo

win

g ad

vers

e ef

fect

s: th

ymic

atro

phy,

leuk

open

ia, a

nem

ia,

thro

mbo

cyto

peni

a, c

hrom

osom

e ab

erra

tions

, red

uced

imm

unog

lobu

lin le

vels

, an

d in

fect

ions

. Adj

ustm

ent o

f aza

thio

prin

e do

sage

to m

aint

ain

norm

al m

ater

nal

leuk

ocyt

e co

unts

may

dec

reas

e or

pre

vent

neo

nata

l leu

kope

nia

and

thro

mbo

cyto

peni

a (A

rmen

ti et

al,

1998

). C

urre

nt g

uide

lines

rega

rdin

g pr

egna

nt

rena

l tra

nspl

ant p

atie

nts

stat

e th

at im

mun

osup

pres

sive

ther

apy

with

or w

ithou

t st

eroi

ds a

nd a

zath

iopr

ine

may

be

cont

inue

d du

ring

preg

nanc

y (E

BPG

Exp

ert

Gro

up o

n R

enal

Tra

nspl

anta

tion,

200

2).

MM

FD

Unk

now

nTe

rato

geni

c

The

Nat

iona

l Tra

nspl

anta

tion

Preg

nanc

y R

egis

try (N

TPR

) rep

orts

24

fem

ale

kidn

ey re

cipi

ents

with

33

preg

nanc

ies

expo

sed

to m

ycop

heno

late

mof

etil.

The

re

wer

e 15

spo

ntan

eous

abo

rtion

s (4

5%) a

nd 1

8 liv

e bi

rths,

with

stru

ctur

al

abno

rmal

ities

wer

e pr

esen

t in

4 of

thes

e 18

infa

nts

(22%

). Ba

sed

on

post

mar

ketin

g da

ta c

olle

cted

by

the

NTP

R fr

om 1

995

to 2

007

amon

g w

omen

(n

=77)

with

sys

tem

ic e

xpos

ure

to m

ycop

heno

late

mof

etil

durin

g pr

egna

ncy,

sp

onta

neou

s ab

ortio

ns o

ccur

red

in 2

5 w

omen

and

feta

l/inf

ant m

alfo

rmat

ions

oc

curr

ed in

14

offs

prin

g. E

ar a

bnor

mal

ities

wer

e pr

esen

t in

6 of

the

14

mal

form

ed in

fant

s. W

ith d

oses

bel

ow e

quiv

alen

t hum

an c

linic

al d

oses

, fet

al

reso

rptio

ns a

nd/o

r mal

form

atio

ns in

the

abse

nce

of m

ater

nal t

oxic

ity h

ave

occu

rred

in ra

ts a

nd ra

bbits

(Pro

d In

fo C

ellC

ept(R

) ora

l cap

sule

s, ta

blet

s,

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, D

IAG

NO

SIS,

TR

EA

TM

EN

T A

ND

MO

NIT

OR

ING

OF

LU

PUS

NE

PHR

ITIS

IN A

DU

LT

SPR

EGN

AN

CY

AN

D L

UPU

S N

EPH

RIT

IS

Trea

tmen

tPr

egna

ncy

C

ateg

ory

Cro

sses

Pl

acen

ta?

Anim

al

Stud

ies

Hum

an S

tudi

es

susp

ensi

on, I

V in

ject

ion,

200

9).

Not

e th

at in

200

7, th

e pr

egna

ncy

cate

gory

was

ch

ange

d fro

m C

to D

bec

ause

of t

he n

oted

pat

tern

of a

bnor

mal

ities

Leflu

nom

ide

XU

nkno

wn

Tera

toge

nic

Leflu

nom

ide

use

is c

ontra

indi

cate

d in

wom

en w

ho a

re o

r may

bec

ome

preg

nant

. Ba

sed

on a

nim

al d

ata,

leflu

nom

ide

may

incr

ease

the

risk

of fe

tal d

eath

or

tera

toge

nic

effe

cts

in p

regn

ant w

omen

. Prio

r to

initi

atio

n of

leflu

nom

ide,

pr

egna

ncy

mus

t be

excl

uded

and

the

use

of re

liabl

e co

ntra

cept

ion

mus

t be

conf

irmed

. P O

f 168

pre

gnan

t wom

en e

valu

ated

as

of J

anua

ry 2

004

in a

co

ntro

lled,

coh

ort s

tudy

(OTI

S R

heum

atoi

d Ar

thrit

is in

Pre

gnan

cy),

wom

en w

ith

rheu

mat

oid

arth

ritis

(RA)

exp

osed

to le

fluno

mid

e ea

rly in

pre

gnan

cy (n

=43)

and

th

ose

with

RA

not e

xpos

ed to

leflu

nom

ide

durin

g pr

egna

ncy

(n=7

8) w

ere

a si

gnifi

cant

12

times

(95%

con

fiden

ce in

terv

al (C

I) 2.

5, 5

9.2)

and

a s

igni

fican

t 10

.1 ti

mes

(95%

CI 2

.2, 4

7.3)

, res

pect

ivel

y, m

ore

likel

y to

del

iver

pre

term

infa

nts

com

pare

d w

ith th

ose

in th

e no

n-di

seas

ed c

ontro

l gro

up (n

=47)

. The

adj

uste

d m

ean

birth

wei

ght o

f ful

l ter

m in

fant

s w

as a

lso

sign

ifica

ntly

low

er in

the

RA

leflu

nom

ide

grou

p (3

158

g, 9

5% C

I 297

9, 3

336)

and

the

RA

cont

rol g

roup

(325

0 g,

95%

CI 3

124,

337

5) c

ompa

red

with

the

non-

dise

ased

con

trol g

roup

(361

8 g,

95

% C

I 348

7, 3

748;

p le

ss th

an 0

.001

). O

vera

ll, a

ll gr

oups

had

the

sam

e pr

opor

tion

of in

fant

s bo

rn w

ith m

ajor

and

/or m

inor

mal

form

atio

ns (C

ham

bers

et

al, 2

004)

. H

owev

er, i

n a

follo

w-u

p st

udy

publ

ishe

d in

201

0, a

mon

g 64

wom

en

who

wer

e ex

pose

dto

leflu

nom

ide

early

in p

regn

ancy

, but

sto

pped

the

drug

and

w

ere

treat

ed w

ith c

hole

styr

amin

e, th

ere

was

no

subs

tant

ial i

ncre

ase

in a

dver

se

preg

nanc

y ou

tcom

es (C

ham

bers

Arth

ritis

Rhe

um 2

010)

.

Chl

oram

buci

lD

Yes

Tera

toge

nic

Tera

toge

nic

effe

cts

have

bee

n re

porte

d in

ass

ocia

tion

with

the

use

of

chlo

ram

buci

l. Th

e te

rato

geni

c ef

fect

s of

chl

oram

buci

l may

be

pote

ntia

ted

by

caffe

ine

(Ber

mas

& H

ill, 1

995)

. In

gene

ral,

alky

latin

g ag

ents

, whe

n gi

ven

durin

g th

e fir

st tr

imes

ter,

are

belie

ved

to c

ause

slig

ht in

crea

ses

in th

e ris

k of

con

geni

tal

mal

form

atio

ns, b

ut w

hen

give

n du

ring

the

seco

nd o

r thi

rd tr

imes

ters

are

bel

ieve

d to

onl

y in

crea

se th

e ris

k of

gro

wth

rest

rictio

n (G

lant

z, 1

994a

)..

Tacr

olim

usC

Yes

Ret

rosp

ectiv

e ca

se a

naly

sis:

100

pre

gnan

cies

(84

wom

en) 7

1 pr

egna

ncie

s pr

ogre

ssed

to d

eliv

ery,

resu

lting

in 6

8 liv

e bi

rths

and

24 p

regn

anci

es th

at w

ere

spon

tane

ousl

y or

ele

ctiv

ely

abor

ted.

Fou

r of t

he 6

8 su

rviv

ing

neon

ates

had

co

ngen

ital m

alfo

rmat

ions

, whe

reas

non

e of

the

24 a

borte

d fe

tuse

s ex

hibi

ted

dete

ctab

le m

alfo

rmat

ions

. Pre

mat

urity

rate

of 5

9% ;o

nly

10%

of t

he in

fant

s w

ere

outs

ide

of th

e 10

th to

90t

h pe

rcen

tile

rang

e fo

r birt

h w

eigh

t whe

n co

nsid

erin

g th

e ge

stat

iona

l age

of t

he n

eona

te (K

ainz

et a

l, 20

00).

GU

IDE

LIN

ES

FOR

TH

E S

CR

EE

NIN

G, D

IAG

NO

SIS,

TR

EA

TM

EN

T A

ND

MO

NIT

OR

ING

OF

LU

PUS

NE

PHR

ITIS

IN A

DU

LT

SPR

EGN

AN

CY

AN

D L

UPU

S N

EPH

RIT

IS

Trea

tmen

tPr

egna

ncy

C

ateg

ory

Cro

sses

Pl

acen

ta?

Anim

al

Stud

ies

Hum

an S

tudi

es

Cyc

losp

orin

eC

Yes

No

In a

stu

dy o

f 48

preg

nant

wom

en b

eing

trea

ted

with

ther

apeu

tic d

oses

of

cycl

ospo

rine,

no

evid

ence

of d

irect

haz

ard

to th

e fe

tus

was

dem

onst

rate

d.

(Coc

kbur

n et

al,

1989

). N

o sp

ecifi

c bi

rth d

efec

t has

bee

n as

soci

ated

with

CSA

, al

thou

gh m

any

spor

adic

con

geni

tal a

nom

alie

s ha

ve b

een

repo

rted

(Pet

ri Au

toim

mun

ity 2

003)

. In

pos

t-mar

ketin

g su

rvei

llanc

e of

166

pre

gnan

cies

, 45%

w

ere

pre-

term

, and

the

med

ian

birth

wei

ght w

as 2

300

g (A

rella

no M

ed C

lin 1

991)

.

GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS

Miniter, et al. (209) RIA 0.68 0.82 3.76 0.39

Ballou,et al. (210) Crithidia 0.53 0.64 1.46 0.73

Isenberg, et al.

(211)

ELISA 0.76 0.54 1.65 0.44

Abrass, et al. (102) RIA 0.33 0.68 1.03 0.97 0.44 0.57 1.02 0.98

Davis, et al. (212) RIA 0.93 0.78 3.48 0.1

Feldman, et al.

(213)

Farr 0.2 0.88 1.6 0.9 0.25 0.93 3.6 0.8 NA NA NA NA

Weighted means 0.66 0.66 4.14 0.51 0.65 0.41 1.7 0.76 0.86 0.45 1.7 0.3

Table 9 . Use of anti-DNA antibodies for prognosis among SLE patients.

Reference Technique

Overall SLE active vs. inactive

Renal involvement present vs. absent

Renal disease active vs. inactive

Sen Spec +LR -LR Sen Spec +LR -LR Sen Spec +LR -LR

Froelich, et al. (199). ELISA 0.75 0.75 3.0 0.33

Emlen, et al.(200) ELISA 0.69 0.77 3.05 0.4

Farr 0.98 0.97 25.2 0.02

Crithidia 0.56 0.97 24.1 0.45

Isenberg, et al.(201) Crithidia 0.62 0.75 1.8 0.5 0.92 0.55 2.1 0.14

Ter Borg, et al. (90) ELISA 0.32 0.64 0.88 1.06

Crithidia 0.14 0.91 1.55 0.94

Farr 0.41 0.73 1.5 0.81

Chubick et al. (202) ELISA 0.92 0.44 1.6 0.18 0.97 0.44 1.7 0.07

Farr 0.73 0.72 2.6 0.38 0.76 0.72 2.7 0.33

Kalmin, et al. (203) ELISA 0.71 0.33 1.05 0.88 0.91 0.08 0.99 1.12

Crithidia 0.43 0.6 1.07 0.95 0.46 0.6 1.15 0.9

Cameron, et al. (103) Farr 0.89 0.25 1.2 0.44

Bootsma, et al. (204) Crithidia 1.00 0.13 1.15 0.38

Farr 0.89 0.4 1.48 0.28

Pincus, et al. (205) Farr 0.82 0.18 1.0 0.97 0.91 0.33 1.4 0.26

Ballou, et al. (206) Crithidia 0.74 0.95 14.8 0.27 0.88 0.41 1.5 0.29

Garcia, et al. (207) Crithidia 0.85 0.33 2.6 0.45

Weitzman, et al.

(208)

Farr 0.76 0.66 2.28 0.36 0.82 0.32 1.2 0.56

GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS

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77. Kavanaugh AF, Solomon DH. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests. Arthritis Rheum. 2002;47(5):546-55.

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93. Swaak AJ, Groenwold J, Aarden LA, Statius van Eps LW, Feltkamp EW. Prognostic value of anti-dsDNA in SLE. Ann Rheum Dis. 1982;41(4):388-95.

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95. Swaak AJ, Groenwold J, Bronsveld W. Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis. 1986;45(5):359-66.

96. Zonana-Nacach A, Salas M, Sanchez ML, Camargo-Coronel A, Bravo-Gatica C, Mintz G. Measurement of clinical activity of systemic lupus erythematosus and laboratory abnormalities: a 12-month prospective study. J Rheumatol. 1995;22(1):45-9.

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105. van den Berg L, Nossent H, Rekvig O. Prior anti-dsDNA antibody status does not predict later disease manifestations in systemic lupus erythematosus. Clin Rheumatol. 2006;25(3):347-52.

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106. Arbuckle MR, James JA, Kohlhase KF, Rubertone MV, Dennis GJ, Harley JB. Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus. Scand J Immunol. 2001;54(1-2):211-9.

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108. Mosca M, Chimenti D, Pratesi F, Baldini C, Anzilotti C, Bombardieri S, et al. Prevalence and clinico-serological correlations of anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic lupus erythematosus. J Rheumatol. 2006;33(4):695-7.

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110. Esdaile JM, Abrahamowicz M, MacKenzie T, Hayslett JP, Kashgarian M. The time-dependence of long-term prediction in lupus nephritis. Arthritis Rheum. 1994;37(3):359-68.

111. Esdaile JM, Joseph L, Abrahamowicz M, Li Y, Danoff D, Clarke AE. Routine immunologic tests in systemic lupus erythematosus: is there a need for more studies? J Rheumatol. 1996;23(11):1891-6.

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116. Nagy G, Brozik M, Varga L, Fust G, Kirschfink M, Kiss E, et al. Usefulness of detection of complement activation products in evaluating SLE activity. Lupus. 2000;9(1):19-25.

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118. Sullivan KE, Wisnieski JJ, Winkelstein JA, Louie J, Sachs E, Choi R, et al. Serum complement determinations in patients with quiescent systemic lupus erythematosus. J Rheumatol. 1996;23(12):2063-7.

119. Ho A, Barr SG, Magder LS, Petri M. A decrease in complement is associated with increased renal and hematologic activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44(10):2350-7.

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125. Norby GE, Holme I, Fellstrom B, Jardine A, Cole E, Abedini S, et al. Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: a randomized placebo-controlled study. Arthritis Rheum. 2009;60(4):1060-4.

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128. Wilson EC, Jayne DR, Dellow E, Fordham RJ. The cost-effectiveness of mycophenolate mofetil as firstline therapy in active lupus nephritis. Rheumatology (Oxford). 2007;46(7):1096-101.

129. Ward MM. Access to care and the incidence of endstage renal disease due to systemic lupus erythematosus. J Rheumatol. 2010;37(6):1158-63.

130. Hopkinson ND, Jenkinson C, Muir KR, Doherty M, Powell RJ. Racial group, socioeconomic status, and the development of persistent proteinuria in systemic lupus erythematosus. Ann Rheum Dis. 2000;59(2):116-9.

131. Ward MM. Medical insurance, socioeconomic status, and age of onset of endstage renal disease in patients with lupus nephritis. J Rheumatol. 2007;34(10):2024-7.

132. Contreras G, Lenz O, Pardo V, Borja E, Cely C, Iqbal K, et al. Outcomes in African Americans and Hispanics with lupus nephritis. Kidney Int. 2006;69(10):1846-51.

133. Barr RG, Seliger S, Appel GB, Zuniga R, D'Agati V, Salmon J, et al. Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity. Nephrol Dial Transplant. 2003;18(10):2039-46.

134. Petri M, Perez-Gutthann S, Longenecker JC, Hochberg M. Morbidity of systemic lupus erythematosus: role of race and socioeconomic status. Am J Med. 1991;91(4):345-53.

135. Fernandez M, Alarcon GS, Calvo-Alen J, Andrade R, McGwin G, Jr., Vila LM, et al. A multiethnic, multicenter cohort of patients with systemic lupus erythematosus (SLE) as a model for the study of ethnic disparities in SLE. Arthritis Rheum. 2007;57(4):576-84.

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136. Ward MM. Access to renal transplantation among patients with end-stage renal disease due to lupus nephritis. Am J Kidney Dis. 2000;35(5):915-22.

137. Carls G, Li T, Panopalis P, Wang S, Mell AG, Gibson TB, et al. Direct and indirect costs to employers of patients with systemic lupus erythematosus with and without nephritis. J Occup Environ Med. 2009;51(1):66-79.

138. Clarke AE, Petri M, Manzi S, Isenberg DA, Gordon C, Senecal JL, et al. The systemic lupus erythematosus Tri-nation Study: absence of a link between health resource use and health outcome. Rheumatology (Oxford). 2004;43(8):1016-24.

139. Li T, Carls GS, Panopalis P, Wang S, Gibson TB, Goetzel RZ. Long-term medical costs and resource utilization in systemic lupus erythematosus and lupus nephritis: a five-year analysis of a large medicaid population. Arthritis Rheum. 2009;61(6):755-63.

140. Pelletier EM, Ogale S, Yu E, Brunetta P, Garg J. Economic outcomes in patients diagnosed with systemic lupus erythematosus with versus without nephritis: results from an analysis of data from a US claims database. Clin Ther. 2009;31(11):2653-64.

141. Contreras G, Pardo V, Cely C, Borja E, Hurtado A, De La Cuesta C, et al. Factors associated with poor outcomes in patients with lupus nephritis. Lupus. 2005;14(11):890-5.

142. Esdaile JM, Levinton C, Federgreen W, Hayslett JP, Kashgarian M. The clinical and renal biopsy predictors of long-term outcome in lupus nephritis: a study of 87 patients and review of the literature. Q J Med. 1989;72(269):779-833.

143. Hill GS, Delahousse M, Nochy D, Remy P, Mignon F, Mery JP, et al. Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int. 2001;59(1):304-16.

144. Magil AB, Puterman ML, Ballon HS, Chan V, Lirenman DS, Rae A, et al. Prognostic factors in diffuse proliferative lupus glomerulonephritis. Kidney Int. 1988;34(4):511-7.

145. Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P, Ponticelli C. The long-term outcome of 93 patients with proliferative lupus nephritis. Nephrol Dial Transplant. 2007;22(9):2531-9.

146. Zavada J, Pesickova S, Rysava R, Olejarova M, Horak P, Hrncir Z, et al. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Lupus. 2010;19(11):1281-9.

147. Steinberg AD, Decker JL. A double-blind controlled trial comparing cyclophosphamide, azathioprine and placebo in the treatment of lupus glomerulonephritis. Arthritis Rheum. 1974;17(6):923-37.

148. Carette S, Klippel JH, Decker JL, Austin HA, Plotz PH, Steinberg AD, et al. Controlled studies of oral immunosuppressive drugs in lupus nephritis. A long-term follow-up. Ann Intern Med. 1983;99(1):1-8.

149. Austin HA, 3rd, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986;314(10):614-9.

150. Steinberg AD, Steinberg SC. Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum. 1991;34(8):945-50.

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151. Grootscholten C, Ligtenberg G, Hagen EC, van den Wall Bake AW, de Glas-Vos JW, Bijl M, et al. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial. Kidney Int. 2006;70(4):732-42.

152. Boumpas DT, Austin HA, 3rd, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet. 1992;340(8822):741-5.

153. Gourley MF, Austin HA, 3rd, Scott D, Yarboro CH, Vaughan EM, Muir J, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med. 1996;125(7):549-57.

154. Donadio JV, Jr., Holley KE, Ferguson RH, Ilstrup DM. Progressive lupus glomerulonephritis. Treatment with prednisone and combined prednisone and cyclophosphamide. Mayo Clin Proc. 1976;51(8):484-94.

155. Donadio JV, Jr., Holley KE, Ferguson RH, Ilstrup DM. Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. N Engl J Med. 1978;299(21):1151-5.

156. Clark WF, Cattran DC, Balfe JW, Williams W, Lindsay RM, Linton AL. Chronic plasma exchange in systemic lupus erythematosus nephritis. Proc Eur Dial Transplant Assoc. 1983;20:629-35.

157. Pohl MA, Lan SP, Berl T. Plasmapheresis does not increase the risk for infection in immunosuppressed patients with severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. Ann Intern Med. 1991;114(11):924-9.

158. Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med. 1992;326(21):1373-9.

159. Mok CC, Ho CT, Siu YP, Chan KW, Kwan TH, Lau CS, et al. Treatment of diffuse proliferative lupus glomerulonephritis: a comparison of two cyclophosphamide-containing regimens. Am J Kidney Dis.2001;38(2):256-64.

160. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121-31.

161. Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J Am Soc Nephrol. 2008;19(10):2001-10.

162. Hu W, Liu Z, Chen H, Tang Z, Wang Q, Shen K, et al. Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chin Med J (Engl). 2002;115(5):705-9.

163. Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R, et al. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology (Carlton). 2005;10(5):504-10.

164. Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353(21):2219-28.

165. Wang J, Hu W, Xie H, Zhang H, Chen H, Zeng C, et al. Induction therapies for class IV lupus nephritis with non-inflammatory necrotizing vasculopathy: mycophenolate mofetil or intravenous cyclophosphamide. Lupus. 2007;16(9):707-12.

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166. Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103-12.

167. Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford). 2010;49(1):128-40.

168. El-Shafey EM, Abdou SH, Shareef MM. Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients? Clin Exp Nephrol. 2010;14(3):214-21.

169. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343(16):1156-62.

170. Chan TM, Tse KC, Tang CS, Lai KN, Li FK. Long-term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus. 2005;14(4):265-72.

171. Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004;350(10):971-80.

172. Houssiau FA, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Petrovic R, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69(12):2083-9.

173. Wang HY, Cui TG, Hou FF, Ni ZH, Chen XM, Lu FM, et al. Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study. Lupus. 2008;17(7):638-44.

174. Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010;62(2):542-52.

175. Catapano F, Chaudhry AN, Jones RB, Smith KG, Jayne DW. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant. 2010;25(11):3586-92.

176. Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, et al. Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum. 2010;62(8):2458-66.

177. Jonsdottir T, Gunnarsson I, Mourao AF, Lu TY, van Vollenhoven RF, Isenberg D. Clinical improvements in proliferative vs membranous lupus nephritis following B-cell depletion: pooled data from two cohorts. Rheumatology (Oxford). 2010;49(8):1502-4.

178. Jayne D, Passweg J, Marmont A, Farge D, Zhao X, Arnold R, et al. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus. 2004;13(3):168-76.

179. Burt RK, Traynor A, Statkute L, Barr WG, Rosa R, Schroeder J, et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA. 2006;295(5):527-35.

180. Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis. 2010;69(8):1423-9.

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181. Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum. 2010;62(8):2467-75.

182. Siso A, Ramos-Casals M, Bove A, Brito-Zeron P, Soria N, Munoz S, et al. Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus. 2008;17(4):281-8.

183. Pons-Estel GJ, Alarcon GS, McGwin G, Jr., Danila MI, Zhang J, Bastian HM, et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 2009;61(6):830-9.

184. Rihova Z, Vankova Z, Maixnerova D, Dostal C, Jancova E, Honsova E, et al. Treatment of lupus nephritis with cyclosporine - an outcome analysis. Kidney Blood Press Res. 2007;30(2):124-8.

185. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 1997;51(4):1188-95.

186. Ioannidis JP, Boki KA, Katsorida ME, Drosos AA, Skopouli FN, Boletis JN, et al. Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney Int. 2000;57(1):258-64.

187. Mok CC, Ying KY, Tang S, Leung CY, Lee KW, Ng WL, et al. Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum. 2004;50(8):2559-68.

188. de Castro WP, Morales JV, Wagner MB, Graudenz M, Edelweiss MI, Goncalves LF. Hypertension and Afro-descendant ethnicity: a bad interaction for lupus nephritis treated with cyclophosphamide? Lupus. 2007;16(9):724-30.

189. Mok CC, Ying KY, Ng WL, Lee KW, To CH, Lau CS, et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide. Am J Med. 2006;119(4):355 e25-33.

190. Petri M, Brodsky RA, Jones RJ, Gladstone D, Fillius M, Magder LS. High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial. Arthritis Rheum. 2010;62(5):1487-93.

191. Urowitz MB, Ibanez D, Ali Y, Gladman DD. Outcomes in patients with active lupus nephritis requiring immunosuppressives who never received cyclophosphamide. J Rheumatol. 2007;34(7):1491-6.

192. Decker JL, Klippel JH, Plotz PH, Steinberg AD. Cyclophosphamide or azathioprine in lupus glomerulonephritis. A controlled trial: results at 28 months. Ann Intern Med. 1975;83(5):606-15.

193. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. Arthritis Rheum. 2004;50(12):3934-40.

194. Tang Z, Yang G, Yu C, Yu Y, Wang J, Hu W, et al. Effects of mycophenolate mofetil for patients with crescentic lupus nephritis. Nephrology (Carlton). 2008;13(8):702-7.

195. Rivera TL, Belmont HM, Malani S, Latorre M, Benton L, Weisstuch J, et al. Current therapies for lupus nephritis in an ethnically heterogeneous cohort. J Rheumatol. 2009;36(2):298-305.

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196. Cortes-Hernandez J, Torres-Salido MT, Medrano AS, Tarres MV, Ordi-Ros J. Long-term outcomes--mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant. 2010;25(12):3939-48.

197. Mok CC, Ying KY, Lau CS, Yim CW, Ng WL, Wong WS, et al. Treatment of pure membranous lupus nephropathy with prednisone and azathioprine: an open-label trial. Am J Kidney Dis. 2004;43(2):269-76.

198. Zhang FS, Nie YK, Jin XM, Yu HM, Li YN, Sun Y. The efficacy and safety of leflunomide therapy in lupus nephritis by repeat kidney biopsy. Rheumatol Int. 2009;29(11):1331-5.

199. Froelich CJ, Wallman J, Skosey JL, Teodorescu M. Clinical value of an integrated ELISA system for the detection of 6 autoantibodies (ssDNA, dsDNA, Sm, RNP/Sm, SSA, and SSB). J Rheumatol. 1990;17(2):192-200.

200. Emlen W, Jarusiripipat P, Burdick G. A new ELISA for the detection of double-stranded DNA antibodies. J Immunol Methods. 1990;132(1):91-101.

201. Isenberg DA, Ehrenstein MR, Longhurst C, Kalsi JK. The origin, sequence, structure, and consequences of developing anti-DNA antibodies. A human perspective. Arthritis Rheum. 1994;37(2):169-80.

202. Chubick A, Sontheimer RD, Gilliam JN, Ziff M. An appraisal of tests for native DNA antibodies in connective tissue diseases. Clinical usefulness of Crithidia luciliae assay. Ann Intern Med. 1978;89(2):186-92.

203. Kalmin ND, Bartholomew WR, Wicher K. Relative values of laboratory assays in systemic lupus erythematosus. Am J Clin Pathol. 1981;75(6):846-51.

204. Bootsma H, Spronk PE, Hummel EJ, de Boer G, ter Borg EJ, Limburg PC, et al. Anti-double stranded DNA antibodies in systemic lupus erythematosus: detection and clinical relevance of IgM-class antibodies. Scand J Rheumatol. 1996;25(6):352-9.

205. Pincus T, Schur PH, Rose JA, Decker JL, Talal N. Measurement of serum DNA-binding activity in systemic lupus erythematosus. N Engl J Med. 1969;281(13):701-5.

206. Ballou SP, Kushner I. Anti-native DNA detection by the Crithidia luciliae method: an improved guide to the diagnosis and clinical management of systemic lupus erythematosus. Arthritis Rheum. 1979;22(4):321-7.

207. Garcia CO, Molina JF, Gutierrez-Urena S, Scopelitis E, Wilson WA, Gharavi AE, et al. Autoantibody profile in African-American patients with lupus nephritis. Lupus. 1996;5(6):602-5.

208. Weitzman RJ, Walker SE. Relation of titred peripheral pattern ANA to anti-DNA and disease activity in systemic lupus erythematosus. Ann Rheum Dis. 1977;36(1):44-9.

209. Miniter MF, Stollar BD, Agnello V. Reassessment of the clinical significance of native DNA antibodies in systemic lupus erythematosus. Arthritis Rheum. 1979;22(9):959-68.

210. Ballou SP, Kushner I. Lupus patients who lack detectable anti-DNA: clinical features and survival. Arthritis Rheum. 1982;25(9):1126-9.

211. Isenberg DA, Shoenfeld Y, Schwartz RS. Multiple serologic reactions and their relationship to clinical activity in systemic lupus erythematosus. Arthritis Rheum. 1984;27(2):132-8.

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212. Davis P, Percy JS, Russell AS. Correlation between levels of DNA antibodies and clinical disease activity in SLE. Ann Rheum Dis. 1977;36(2):157-9.

213. Feldman MD, Huston DP, Karsh J, Balow JE, Klima E, Steinberg AD. Correlation of serum IgG, IgM, and anti-native-DNA antibodies with renal and clinical indexes of activity in systemic lupus erythematosus. J Rheumatol. 1982;9(1):52-8.