Lupus Nephritis Evidence Report

EVIDENCE REPORT

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

Working Group

UCLA Bevra 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-Harbor

George A. Karpouzas, MD (Rheum)

UCLA and Cedars-Sinai Daniel Wallace, MD (Rheum)

Oklahoma

Joan T. Merrill, MD (Rheum)

UCSF Jinoos 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 Methods a. Methodology 1. Rationale and Development of a uniform Lupus Nephritis Definition 2. Search Strategy 3. Study Selection Based on Title and Abstracts 4. Selection of Studies Based on Full Text of Articles 5. Quality Assessment b. Data Extraction and Synthesis 1. Rating the Strength of Evidence 2. 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 - Pathology 1. Role of the Renal Biopsy in Lupus Nephritis 2. Correlation of Outcome and Biopsy Findings 3. Vascular and Tubulointerstitial Disease in Lupus Nephritis b. Treatment and Monitoring 1. Randomized Control Trials 2. Cohort Studies c. End Stage Renal Disease 1. When to Consider Transplant 2. Graft and Patient Survival 3. Immunosuppressive Medications 4. Predictors of Outcome After Transplant 5. Summary d. Pregnancy in Lupus Nephritis Patients 1. Maternal/Fetal Outcomes of Pregnancy in Women with SLE 2. Relationship of Drugs Used to Treat Nephritis and Outcome of Pregnancy in Lupus Nephritis 4. Biomarkers in SLE Nephritis a. Anti-dsDNA and Complement b. Anti-dsDNA c. Anti-C1Q d. Complement 5. Adjunctive Therapies to Delay Progression of Renal Damage and Development of Co-Morbid Conditions

6. Socio-Economic Costs and Impact of Lupus Nephritis a. Overview of incidence, economic impact and risk factors of lupus nephritis b. Cost of Lupus Nephritis c. Cost Effectiveness Analysis of Specific Treatments 1. IV Cyclophosphamide vs Steroids alone 2. Mycophenalate Mofetil vs IV Cyclophosphamide Tables 1. Task Force Panelists 2. ISN/RPS 2003 Classification of Lupus Nephritis 3. Renal Pathology Scoring System 4. Studies of Poor Prognostic Findings based on Renal Biopsy 5. RCT Inclusion/Exclusion Criteria and Jadad Scores 6. Cohort Studies Inclusion/Exclusion Criteria and Newcastle-Ottawa Scale 7. End Stage Renal Disease/Renal Transplantation Articles 8 Summary of Commonly Used Medications’ Teratogenic Effects 9 Use of Anti-DNA antibodies for prognosis among SLE patients

APPENDICES

A. Search Strategy B. Abstraction Tool – Abstracts C. Abstraction Tool – RCT Articles D. Abstraction Tool – Cohort Articles E. Case Scenarios

REFERENCES

ABBREVIATIONS ACR American College of Rheumatology ANA Anti-nuclear antibody Anti-dsDNA Anti-double strand Deoxynucleic Acid ARA American Rheumatism Association AZA Azathioprine CPH Cr Creatinine CR Complete Response CrCl Creatinine Clearance CYC Cyclophosphamide D Day G Gram Hpf High Power Field ISN/RPS KG Kilogram IV Intervenous LE Lupus Erythematosus MG Miligram MTX Methotrexate PO PR Partial Response Pred Prednisone Prot Protein RBC Red Blood Cell serCr Serum Creatinine SLE Systemic Lupus Erythematosus U Urine WBC White Blood Cell WHO Wk Week Yr 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 Definition After 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 Strategy We 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 Abstracts Our 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-analysis Study population consists of all patients less than age 16 Study 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 Articles At 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 Assessment The 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 Evidence For 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 the appropriateness (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 DIAGNOSIS Lupus 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 NEPHRITIS The 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 FINDINGS The 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. Jadad score 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 Studies In 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 transplant Expert 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 survival Once 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 transplant Risk 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). Summary In 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 recipient outcomes. 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, fetal complications 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 Nephritis We 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 complement There 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 18 months. 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-dsDNA Anti-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-C1Q The 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. Complement The 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, loop diuretics 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 NEPHRITIS There 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 4.9 per 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 outpatient claims 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 alone In a 1994 NIAMS funded study, McInnes and colleagues reported that cyclophosphamide plus steroids 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 Cyclophosphamide In 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 Medicine Northwestern University

Chicago, ILLINOIS

Chi-Chiu Mok, MD* Chief of Rheumatology

Tuen Mun and Pok Oi Hospital HONG KONG

Jill P. Buyon, MD* Professor of Medicine

NYU / Hospital for Joint Diseases New York, NEW YORK

Frederic A. Houssiau, MD, PhD*

Professor and Head Rheumatology

Universite Catholique Louvain Brussels BELGIUM

Liz Shaw-Stabler Executive Director

Center for Lupus Care, Inc. Inglewood, CALIFORNIA

Gabriel Contreras, MD** Associate Professor of Medicine

Div of Nephrology University of Miami Miami, FLORIDA

David A. Isenberg, MD, FRCP* Professor

Center for Rheumatology Research

University College of London London ENGLAND

Brad Rovin, MD** Professor of Medicine Division of Nephrology

The Ohio State University Columbus, OHIO

Karen H. Costenbader, MD, MPH*

Assistant Professor of Medicine Rheumatology Immunology &

Allergy Harvard Med School / Brigham Boston, MASSACHUSETTS

Kenneth C. Kalunian, MD* Professor of Medicine

Center for Innovative Therapy UCSD School of Medicine

La Jolla, CALIFORNIA

Murray B. Urowitz, MD, FRCPC*

Professor in Medicine The Toronto Western Hospital

Toronto, CANADA

Mary Ann Dooley, MD* Associate Professor of Medicine

Nephrology University of North Carolina

Chapel Hill, NORTH CAROLINA

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

System Pittsburgh, PENNSYLVANIA

David Wofsy, MD* Professor of Rheumatology

Arthritis-Immunology VA Medical Center / UCSF

San Francisco, CALIFORNIA

Peng Thim Fan, MD* Rheumatologist, Community

Practice North Hollywood, CALIFORNIA

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

Table 2. ISN/RPS 2003 Classification of Lupus Nephritis Class I Minimal mesangial lupus nephritis Class II Mesangial proliferative lupus nephritis Class III Focal lupus nephritisa

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

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

Class V Membranous lupus nephritis Class VI Advanced sclerotic lupus nephritis

Adapted from Weening et al. (21)

Table 3. Renal Pathology Scoring System Activity Index Chronicity Index Glomerular Abnormallties

1. Cellular proliferation 1. Glomerular sclerosis 2. Fibrinoid necrosis, karyorrhexis 2. Fibrous crescents 3. Cellular crescents 4. Hyaline thrombi, wire loops 5. Leukocyte infiltration

Tubulointerstitial Abnormalities 1. 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 factor of 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 Year Austin 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 & 10 year 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 2005 Esdaile et al (142) Tubulointerstitial fibrosis/atrophy 87 1989 Esdaile et al. (33) Class IV LN Marked subendothelial immune

deposits 87 1991

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

karyorrhexis/fibrinoid necrosis, cellular crescents 71 2001

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

99 2009

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

dose steroids 60 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 2007 Mosca et al. (26) AI 9+, CI 4+ 81 1997 Nossent et al (38) AI 12+, CI 4+ 116 1990 Parichatikanond 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

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS

Table 5. RCT Inclusion/Exclusion Criteria and Jadad Scores Prednisone (Pred) vs Cyclophosphamid (CYC) IV vs Cyclosporin (CSA) Article Inclusion Criteria Exclusion Criteria Jadad

Score Austin et al, NIH, USA 2009 (44)

Diagnosis of SLE by the ACR, a renal biopsy that showed typical lupus membranous nephropathy (LMN) by light and electron microscopy, >= 2g;/d proteinuria, age >=12 year, informed consent

Endocapillary proliferation or subendothelial electron-dense deposits characteristic of proliferative lupus nephritis, clinical or histologic evidence of nonlupus renal disease, cytotoxic drug or CsA use ruing the 30d period before study entry, cytotoxic drug or CsA use for >2wk during the 10 wk period before study entry, cytotoxic drug or CsA use for >10 wk at anytime in the past, requirement for corticosteroids in dosage >20 mg/m2 body surface area per day of prednisone (or equivalent) for control of extrarenal disease at the time of study entry, active or chronic infection (including HIV infection), preexistent malignancy, pregnancy in female patients, nursing mothers, female patients who were not practicing birth control, a single functioning kidney, insulin-treated diabetes, GFR <25ml/min per 1.73m2 body surface area at study entry, and history of allergy or toxicity to cyclophosphamide or CsA.

1

Cyclosporin (CSA) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad

Score Zavada et al, CYCLOFA-LUNE study, Czech Republic, 2010 (146)

Diagnosis of SLE (meeting 4 criteria of the ACR), renal biopsy documenting lupus nephritis according to WHO or ISN/RPS as proliferative glomerulonephritis class III (focal) or IV (diffuse); clinical activity as defined by presence of at least 2 of the following: abnormal proteinuria (more than

Treatment with CPH or Cyclosporin ever before, treatment with other immunosuppressive drugs or high-dose glucocorticoids within the last 3 months, persistent elevation of serum creatinine (>=140micromol/l), pregnancy or lactation, bone marrow insufficiency with cytopenias not

3


Cyclosporin (CSA) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad

Score 500mg of protein in a 24-h urine specimen), abnormal microscopic hematuria, or C3 hypocomplementemia (the latter two were defined according to the norms in the laboratories of the participating center)

attributable to SLE, and severe coexisting conditions, such as infection, liver disease, active peptic ulcer, etc.

Prednisone (Pred) vs Azathioprine (AZA) vs Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Jadad

Score

Steinberg and Decker, NIH, USA, 1974 (147)

Diagnosis of SLE by criteria of ARA, one of the criteria required was positive LE cell test in the course of the disease, kidney disease unaccounted for by other pathologic processes, with at least one of the following: red cell casts in a fresh centrifuged urine sediment; cellular casts and either hematuria (20 RBC/hpf) or pyruia (20 WBC/hpf), proteinuria of at least 1g/24 hr, or the combination of high serum titers of anti-DNA binding activity, low serum complement and a positive renal biopsy, renal biopsy demonstrating diffuse glomerulonephritis with at least a portion of all glomeruli involved.

A major infection within the preceding 2 weeks. Pregnancy. Immunosuppressive therapy within 2 months. Severe liver disease. A history of hypersensitivity to a study drug, or a serum creatinine greater than 4.0mg% (creatinine clearance <20ml/min)

4

Carette et al, NIH, USA, 1983 (148)

Diagnosis of SLE by ARA preliminary criteria, positive lupus erythematosus cell test, and kidney disease unaccounted for by other pathologic processes with at least one of the following: red cell casts in a fresh centrifuged urine sediment; cellular casts and either hematuria (ten erythrocytes per high power field) or pyuria (ten leukocytes per high power field) in the absence of infection; proteinuria of at least 1 g/d or the combination of high serum DNA binding activity, low serum complement and renal biopsy results consistent with lupus glomerulonephritis

A major infection within the preceding 2 weeks, pregnancy, immunosuppressive therapy within 2 months, severe liver disease, a history of hypersensitivity to a study drug, or a serum creatinine greater than 4.0mg% (creatinine clearance <20ml/min)

1

Austin et al, Diagnosis of SLE as defined by ARA, clinical or Creatinine clearance consistently less than 20ml 1



Score NIH, USA, 1986 (149)

histologic evidence of active lupus glomerulonephritis, and informed consent to all aspects of the study.

per minute, major infection within 2 week s of study entry, pregnancy, a leukocyte count of less than 2000 per cubic millimeter, cytotoxic-drug therapy within eight weeks, and sensitivity to the study drug

Steinberg and Steinberg, NIH, USA, 1991 (150)

Diagnosis of systemic lupus erythematosus and clinical/histologic evidence of active lupus glomerulonephritis.

Creatinine clearance consistently <20ml/minute, presence of a major infection within the previous 2 weeks, pregnancy, white blood cell count <2000/mm3, treatment with a cytotoxic drug within the previous 8 weeks, or known sensitivity to any study drug.

2

Grootscholten et al, Netherlands Nephrology, 2006 (151)

The presence of >=4 ACR criteria for SLE, age 18 to 60 years, creatinine clearance (Cockcroft-Gault) >25ml/min, and biopsy-proven proliferative LN. For patients already known to have proliferative LN, the last renal biopsy had to be performed less than one year before. Patients with WHO-class IV or Vd LN were eligible when they had signs of active nephritis or a deterioration of renal function. Patients with WHO-class III or Vc LN had to meet both criteria.

Patients with membranous LN WHO-class Va or Vb were excluded.. Decline in renal function (more than 30% increase in serum creatinine) during treatment with cytotoxic immunosuppressive agents in the month before inclusion. Active infection. Malignancy <5 years before randomization. Pregnancy or refusal to use reliable contraceptives during the first 2.5 years of treatment. Chronic active or persisting hepatitis or cirrhosis of the liver, active peptic ulcer, leukocytopenia (<3.0x10 9 /l) or thrombocytopenia (<100 x 10 9/l), with suppressed bone marrow (as shown in a bone marrow aspirate). Known allergy for azathioprine or cyclophosphamide.

2

Prednisone (Pred) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad

Score

Boumpas et al, NIH, USA 1992 (152)

Patients had 4 or more criteria for SLE and severe lupus nephritis defined by a nephritic urine sediment and impaired renal function with a creatinine clearance between 25 and 80 ml per min. If creatinine clearance was higher than 80 ml per min, the candidate had to have very active renal histology with crescents or necrosis in more

Pregnancy or had received cytotoxic drug therapy for more than 10 weeks at any time, active infections, insulin-dependent diabetes, or previous malignancy.

2



Score than 25% of glomeruli. Renal biopsies were evaluated by light and electron microscopy.

Gourley et al, NIH, USA, 1996 (153)

Patients had to have both glomerulonephritis and a diagnosis of systemic lupus erythematosus. Glomerulonephritis was defined as a sediment on two or more urianlyses that showed either 10 or more erythrocytes per high-power field or erythrocyte or leukocyte casts (without evidence of infection) or both, plus histologic evidence of active proliferative lupus glomerulonephritis on a renal biopsy specimen obtained within 3 months of study entry (provided that a biopsy could be done safely).

Receipt of cytotoxic drug treatment for more than 2 weeks during the 6 weeks before study entry or receipt of cylophosphamide therapy for more than 10 weeks at any time; receipt of pulse therapy with corticosteroids during the 6 weeks before study entry; need (at the time of study entry_ for oral corticosteroids in dosages greater than 0.5mg of a prednisone equivalent per kilogram of body weight per day to control extrarenal disease; active or chronic infection; pregnancy; the presence of only one kidney; insulin-dependent diabetes mellitus; and allergy to methyprednisolone or cylophosphamide.

2

Prednisone (Pred) vs Cyclophosphamide (CYC) PO Article Inclusion Criteria Exclusion Criteria Jadad

Score

Donadio et al, Mayo, USA, 1976 (154)

Clinical diagnosis of SLE and fulfilled 4 or more of the criteria for the classification of SLE as developed by the ARA Committee on Diagnostic and Therapeutic Criteria. Serologic confirmation of the disease was also required, based on finding of a positive LE-cell preparation and an ANA in a titer >= 1:32 – or if a positive LE-cell preparation was not obtained, on finding two doubtful positive (for example, rosettes of neutrophils or nucleolysis) and an ANA titer >= 1:32. In addition, working criteria defining progressive lupus glomerulonephritis on the basis of renal insufficiency based either on reduced initial creatinine clearance to less than 80ml/min per 1.73m2 or on a 25% reduction in creatinine clearance as compared to initial

Cyclophosphamide had been used in the past or if other immunosuppressive drugs had been used within 6 months of entry into the study.

2


Prednisone (Pred) vs Cyclophosphamide (CYC) PO Article Inclusion Criteria Exclusion Criteria Jadad

Score clearance over a maximum period of 3 months, and on a renal morphologic diagnosis of active glomerulonephritis. Arbitrarily established a 25% change in creatinine clearance as indicting an important change in renal function so as to take into consideration the biologic variability of creatinine excretion that influences creatinine clearance. Patients previously untreated or treated with adrenocorticoids were considered to be eligible for the study

Danadio et al, Mayo Clinic, USA 1978 (155)

Clinical diagnosis of systemic lupus erythematosus and have fulfilled 4 or more of the criteria used for the classification of the disease. A positive LE-cell preparation or rosettes of neutrophils or nucleolysis, a positive ANA >= 1:32 or since mid-1973, elevated levels of anti-nDNA, creatinine clearance less than 80ml/min/1.73m2 or a reduction of 25% in creatinine clearance as compared with the initial clearance over a maximal period of 3 months, and adequate renal biopsy showing diffuse proliferative glomerulonephritis. Patients previously untreated or treated with steroid agents were eligible.

Cyclophosphamide had been used in the past or if other immunosuppressive drugs had been used within 6 months of entry into the study.

2

Prednisone (Pred) + Cyclophosphamide (CYC) vs plasmapheresis Article Inclusion Criteria Exclusion Criteria Jadad

Score

Clark et al, Canada and Jamaica, 1983 (156)

4 of the ARA criteria for the diagnosis of SLE and had at least one episode of ANA positivity, elevated DNA binding and complement depression. All had renal biopsy with the diagnosis of diffuse proliferative glomerulonephritis.

Creatinine clerarance was less than 3mg/100ml. 1

Pohl et al, Lupus

Diagnosis of SLE confirmed by at least 4 of the ARA diagnostic criteria with some modifications; by

Serum creatinine concentration of more than 533 micromol/L (6.0mg/dL); previous plasmapheresis

2


Prednisone (Pred) + Cyclophosphamide (CYC) vs plasmapheresis Article Inclusion Criteria Exclusion Criteria Jadad

Score Nephritis Collaborative Study Group, NIH, USA, 1991 (157)

current renal biopsy evidence of severe lupus glomerulonephritis (WHO Class III or IV with more than 50% of glomeruli involved or class V with superimposed diffuse or severe segmental proliferation)

for any reason; a history of steroid psychosis; current pregnancy; a history of neoplasm within the previous 5 years; a neutrophil count of less than 1500/mm3; or age of less than 16 years.

Lewis et al, Lupus Nephritis Collaborative Group, USA, 1992 (158)

16 years of age or older; diagnosis of SLE as defined by ARA and a qualifying renal biopsy.

Pregnancy, serum creatinine concentration above 530 micromol per liter (6mg/dL), previous treatment with plasmapheresis, a history of primary myocardial disease, a history of cancer within the past 5 years, prednisone-associated psychosis, peptic ulcer disase, and active liver disease.

3

Cyclophosphamide (CYC) IV vs Cyclophosphamide (CYC) PO Article Inclusion Criteria Exclusion Criteria Jadad

Score

Mok et al, Hong Kong, 2001 (159)

Fulfilled at least 4 of the ACR criteria for the classification of SLE and had DPGN (WHO Class IVa or IVb) diagnosed and treated in two large regional hospitals in Hong Kong (Queen Mary and Ten Mun Hospitals) between 1995 and 1998 were included in this study.

Refused CYC treatment or in whom renal biopsy showed significant sclerosis or chronic changes but without activity were excluded.

0

High-Dose Cyclophosphamide (CYC) IV vs Low Dose Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad

Score

Houssiau et al, Euro-Lupus Nephritis Trial, 2002 (160)

Diagnosis of SLE according to the ACR criteria, age >= 14 years, biopsy proven proliferative lupus glomerulonephritis (WHO Class II, IV, Vc, or Vd), and proteinuria >= 500mg in 24 hours.

Patients who had taken CYC or AZA during the previous year or had taken >=15mg/day prednisone (or equivalent) during the previous month were excluded (except for a course of glucocorticoids for a maximum of 10 days before the referral). Other exclusion criteria were renal thrombotic microangiopathy, preexisting chronic renal failure, pregnancy, previous malignancy (except skin and cervical intraepithelial neoplasis), diabetes mellitus,

2


High-Dose Cyclophosphamide (CYC) IV vs Low Dose Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad

Score previously documented severe toxicity to immunosuppressive drugs, and anticipated poor compliance with the protocol.

Mycophenolate Mofetil (MMF) + Tacrolimus vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad

Score

Bao et al, Nanjing, 2008 (161)

Eligible patients were either gender and between 12 and 60 yr of age; provided written informed consent; diagnosis of SLE according for ACR (1997); showed an SLE disease activity index >=12; had a diagnosis of Class V+IV LN according to ISN/RPS 2003 classification of LN, with a pathologic chronic index (CI) <4 proved by light, immunofluorescence, and electron microscopy within 3 wk before enrollment; and exhibited overt proteinuria (>=1.5g of protein in a 24-h urine specimen) with or without active urinary sediment (any of urine sediment RBC count >10 x 10 4/ml or white blood cells > 5 per high-power field or red cell casts in the absence of infection or other causes.

Serum creatinine > 3.0mg/dl (265.2 microlmol/L) or estimated Creatinine clearance <30ml/min per 1.73m2 on repeated testing; liver function with ALT, ASST, or bilirubin greater than twice the upper limit of the reference range; abnormal glucose metabolism, defined as a fasting (i.e., no caloric intake for at least 8 h) plasema glucose level > 6.1 mmol/L and/or a 2-h plasma glucose level > 7.8 mmol/L; known hypersensitivity or contraindication to any components of these regimens; use of CTX, MMF, or tacrolimus within the past 12 wk; pregnancy or lactation; life-threatening complications such as cerebral lupus; or other severe coexisting conditions precluding immunosuppressive therapy or conditions requiring intravenous antibiotic therapy.

2

Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad

Score

Hu et al, Nanjing, 2002 (162)

Patients has SLE diagnosis according to ARA criteria; urinalysis showed active urine sediments, proteinuria >2g/d; renal biopsy reviewed lupus nephritis WHO IV within 3 months prior to the study

Severe complication such as infection, leucopenia, heart failure or malfunction of the central nerve system or liver

-1

Ong et al, Malaysia, 2005 (163)

SLE fulfilling ARA criteria with WHO Class III or IV lupus nephritis, aged 16 years or older

Serum creatinine more than 200 micromol/L, white blood cell count < 3.5 x 10 9 L, evidence of major infection, history of cancer, alcohol or substance

2



Score abuse, active peptic ulcer disease, pregnant or lactating women, known allergy to MMF or cyclophosphamide and use of study drugs in the preceding 6 months.

Ginzler et al, USA, 2005 (164)

SLE meeting 4 classification criteria of the ACR; renal biopsy documenting lupus nephritis according to the classification of WHO III, IV, or V; clinical activity as defined by one or more of the following: incidence decrease in renal function (serum creatinine, >1mg/dL (88.4 micromol/L), proteinuria (defined as more than 500mg of protein in a 24-h urine specimen), microscopic hematuria (defined as >5 red cells per high power-field) or the presence of cellular casts, increasing proteinuria with rising levels of serum creatinine, active urine sediment (hematuria or celluar casts), or serologic abnormality (anti-DNA antibodies or hypocomplementemia). Those with Class III or V lupus nephritis were required to have a serum creatinine level greater than 1mg/dL or proteinuria greater than 2g in a 24-h urine specimen.

Creatinine clearance of less than 30ml /min, serum creatinine on repeated testing greater than 3mg/dL (265.2 microlmol /L), severe coexisting conditions precluding immunosuppressive therapy or conditions requiring intravenous antibiotic therapy, prior treatment with mycophenolate mofetil, treatment with intravenous cyclophosphamide within the past 12 months, monoclonal antibody therapy within the past 30 days, or pregnancy or lactation.

2

Wang et al, Nanjing, 2007 (165)

ARA criteria of SLE, 18-50 yrs of age; urine protein >= 1g/24h with active urine sediment; serum creatinine <3mg/dL (265microlmol/L) or creatinine clearance >=30mL/min, biopsy proven ISN/RPS Class IV with exception of superimposed membranous changes and NNV lesion shown in arterioles and interlobular arteries and the proportion of glomerular sclerosis <50% and chronic index <4.

Serum creatinine >=3 mg/dL or creatinine clearance <30mL/min; proportion of glomerular sclerosis >=50%, chronicity index >=4 with several renal tubule-interstitial fibrosis; primary or secondary immunodeficiency, especially leukocyte count of <=2 x 19 9 L; any clinically significant infection, pregnancy or lactation, active type B or C hepatitis, tuberculosis and the receipt of CTX, MMF, or other cytotoxic drugs within the past 3 months

3

Appel et al, ALMS, 2009 (166)

Aged 12 to 75 yrs, diagnosis of SLE, LN (active or active/chronic) conformed by kidney biopsy within 6 mo before randomization as ISN/RPS 2003

Treatment with MMF or IVC within the previous year, continuous dialysis for ?2 wk before randomization or anticipated during longer than 8

3



Score Class III, IV-S or IV-G, V, III+V, or IV+V. Patients with class III or V LN must have had proteinuria (at least 2g/d) which was considered clinically significant level of proteinuria, and might indicate a recent deterioration in renal function.

wk, pancreatitis, gastronintestinal hemorrhage within 6 mo or active peptic ulcer within 3 mo, severe viral infection, severe cardiovascular disease, bone marrow insufficiency with cytopenias not attributable to SLE, or current infection requiring intravenous antibiotics. Pulse intravenous corticosteroids were prohibited within 2 wk before first randomization and throughout the study.

Isenberg et al, Sub Analysis of ALMS trial, 2010 (167)

Aged 12 to 75 yrs, diagnosis of SLE, LN (active or active/chronic) conformed by kidney biopsy within 6 mo before randomization as ISN/RPS 2003 Class III, IV-S or IV-G, V, III+V, or IV+V. Patients with class III or V LN must have had proteinuria (at least 2g/d) which was considered clinically significant level of proteinuria, and might indicate a recent deterioration in renal function.

Treatment with MMF or IVC within the previous year, continuous dialysis for ?2 wk before randomization or anticipated during longer than 8 wk, pancreatitis, gastronintestinal hemorrhage within 6 mo or active peptic ulcer within 3 mo, severe viral infection, severe cardiovascular disease, bone marrow insufficiency with cytopenias not attributable to SLE, or current infection requiring intravenous antibiotics. Pulse intravenous corticosteroids were prohibited within 2 wk before first randomization and throughout the study.

Radhakrishnan et al, ALMS + Ginzler et al, 2010 (NOTE COMBINED 2 studies) (43)

Pure Class V LN included in this analysis only. ALMS - Aged 12 to 75 yrs, diagnosis of SLE, LN (active or active/chronic) conformed by kidney biopsy within 6 mo before randomization as ISN/RPS 2003 Class III, IV-S or IV-G, V, III+V, or IV+V. Patients with class III or V LN must have had proteinuria (at least 2g/d) which was considered clinically significant level of proteinuria, and might indicate a recent deterioration in renal function. GINZLER - SLE meeting 4 classification criteria of the ACR; renal biopsy documenting lupus nephritis

ALMS - Treatment with MMF or IVC within the previous year, continuous dialysis for ?2 wk before randomization or anticipated during longer than 8 wk, pancreatitis, gastronintestinal hemorrhage within 6 mo or active peptic ulcer within 3 mo, severe viral infection, severe cardiovascular disease, bone marrow insufficiency with cytopenias not attributable to SLE, or current infection requiring intravenous antibiotics. Pulse intravenous corticosteroids were prohibited within 2 wk before first randomization and throughout the study. GINZLER - Creatinine clearance of less than 30ml

2



Score according to the classification of WHO III, IV, or V; clinical activity as defined by one or more of the following: incidence decrease in renal function (serum creatinine, >1mg/dL (88.4 micromol/L), proteinuria (defined as more than 500mg of protein in a 24-h urine specimen), microscopic hematuria (defined as >5 red cells per high power-field) or the presence of cellular casts, increasing proteinuria with rising levels of serum creatinine, active urine sediment (hematuria or celluar casts), or serologic abnormality (anti-DNA antibodies or hypocomplementemia). Those with Class III or V lupus nephritis were required to have a serum creatinine level greater than 1mg/dL or proteinuria greater than 2g in a 24-h urine specimen.

/min, serum creatinine on repeated testing greater than 3mg/dL (265.2 microlmol /L), severe coexisting conditions precluding immunosuppressive therapy or conditions requiring intravenous antibiotic therapy, prior treatment with mycophenolate mofetil, treatment with intravenous cyclophosphamide within the past 12 months, monoclonal antibody therapy within the past 30 days, or pregnancy or lactation.

El Shafey et al, Egypt, 2010 (168)

SLE meeting 4 classification criteria of the ACR with newly diagnosed active proliferative class III or IV lupus nephritis and aged 15 years or older were enrolled in the study.

Estimated glomerular filtration rate (eGFR) of less than 30ml per minute, serum cereatinine on repeated testing more than 200 micromol/L, white blood cell (WBC) count of less than 3.5 x 19 9/l, evidence of major infection, history of cancer, alcohol or substance abuse, active peptic ulcer disease, pregnant or lactating women, known allergy to MMF or cyclophosphamide, and the use of study drugs in the preceding 6 months.

2

MMF + AZA vs CYC PO + AZA Article Inclusion Criteria Exclusion Criteria Jadad

Score

Chan et al, Hong Kong, 2000 (169)

SLE according to ARA including renal-biopsy evidence of diffuse proliferative lupus nephritis (WHO IV), urinary protein excretion of 1g or more per 24 hours, serum albumin concentration of

Serum creatinine concentration higher than 3.4mg/dL (300 micromol per liter); life-threatening complications such as cerebral lupus or severe infection, history of poor compliance with drug

2


MMF + AZA vs CYC PO + AZA Article Inclusion Criteria Exclusion Criteria Jadad

Score 3.5g/dL or less. regimens, women who were pregnant or unwilling

to use contraception. Patients who had received cyclophosphamide within the previous 6 months or who had taken oral prednisolone at a dose of 0.8mg/kg of body weight per day or more for more than 2 weeks.

Chan et al, Hong Kong, 2005 (170)

SLE defined by 1982 ARA criteria, renal biopsy showing diffuse proliferative lupus nephritis (WHO Class IV) which corresponded to 2003 ISN/RPS class IV-S or IV-G, urinary protein exretion of 1g/24 hours or above, and serum albumin concentration <35g/L.

Serum creatinine concentration >4.52 mg/dL (400micromol/L), life-threatening complications such as cerebral lupus or severe infection, poor drug compliance, treatment with CTX or MMF within 6 mo before baseline, or treatment with prednisolone at dose >0.4mg/kg per d orally for >2 wk before baseline.

3

MMF vs AZA vs CYC IV Article Inclusion Criteria Exclusion Criteria Jadad

Score

Contreras et al, USA, 2004 (171)

SLE according to ARA who had undergone a kidney biopsy. 18 years of age or older. Histologic diagnosis of proliferative lupus nephritis (WHO Class III, IV, or Vb)

Creatinine clearance that was consistently less than 20ml/min, any clinically significant infection, pregnancy, receipt of more than 7 doses of intravenous cyclophosphamide, or the receipt of azathioprine for longer than 8 weeks.

2

MMF vs AZA Article Inclusion Criteria Exclusion Criteria Jadad

Score Houssiau et al, MAINTAIN Nephritis Trial, 2010 (different cohort from ELNT) (172)

Age >=14 years, SLE according to ACR classification criteria, 24h proteinuria >= 500mg, biopsy –proven WHO Class III, IV, Vc or Vd lupus glomerulonephritis (biopsy performed less than 1 month before entry to protocol), contraception (or sexual abstinence)

Non-lupus related renal disease (such as microthrombotic disease associated with antiphospholipid syndrome),treatment with glucocorticoids (GCs) (>15mg equivalent prednisolone/day) in the last month before entry intot he study (except a very short-course high-dose oral GC treatment before referral), treatment with CY, AZA, MMF, or cyclosporine A in the

3


MMF vs AZA Article Inclusion Criteria Exclusion Criteria Jadad

Score previous year, pre-existing chronic renal failure (defined as a serum creatinine value above the upper normal value for the local laboratory) due to a previous episode of LN or other cause, pregnancy, breast feeding, previous malignancy (except for skin and cervical intraepithelial neoplasias), diabetes mellitus, previously documented severe toxicity of immunosuppressants, anticipated non-compliance with the protocol.

Abstract ALMS Maintenance (Wofsy et al, 2010)

0

Leflunomide vs CYC IV Article Inclusion Criteria Exclusion Criteria Jadad

Score Wang et al, Leflunomid Lupus Nephritis Study Group, China, 2008 (173)

SLE according to 1997 ACR criteria; SLEDAI >= 8; clinically evident renal disease and biopsy-documented diffuse proliferative or focal proliferative lupus nephritis (ISN/RPS 2003 Type IV A or A/C and Type III A or A/C) with or without coincident membranous nephropathy and pathological activity index (AI) >=4.

Received cyclophosphamide within the previous 3 months. Cerebral lupus, severe infection, liver disease, pregnancy, and anticipated poor compliance with the protocol.

0

Rituximab Article Inclusion Criteria Exclusion Criteria Jadad

Score ABSTRACT - Furie et al, LUNAR, 2009

Pts with Class III/IV LN and urine protein to creatinine ratio >1


Belimumab Article Inclusion Criteria Exclusion Criteria Jadad

Score ABSTRACT - Manzi et al, BLISS 2010

Seropositive (ANA >=1:30 and/or anti-dsDNA >=30 IU/mL) SLE with SELENA SLEDAI >=6 on stable standard-of –care therapy ofr >=30d were enrolled

No active LN

Tocilizumab Article Inclusion Criteria Exclusion Criteria Jadad

Score

Illei, et al, USA, 2010 (174)

Age >18 years who fulfilled ACR classification criteria for SLE, moderately active lupus defined by 1 of the 2 sets of criteria. Criteria set 1 – presence of chronic glomerulonephritis with an inadequate response to at least 6 months of adequate immunosuppressive therapy (with either methylprednisolone pulse doses, cylcophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, high-dose dialy corticosteroids, methotrexate, or intravenous immunoglobulin, plus the following 4 features: less than a 30% increase in serum creatinine levels as compared with the lowest level achived during treatment; proteinuria at levels <=1.5 times the value at baseline (before treatment); <= 2+ cellular casts in the urinary sediments; and extrarenal disease activity not exceeding a score of 10 on the nonrenal components of the SELENA version of SLEDAI. Creiteria set 2 consisted of moderately active extrarenal lupus, defined as extrarenal SELENA-SLEDAI score in the range of 3-10. SELENA-SLEDAI score must have been stable for

Pregnancy, any therapy with human, murine antibodies, or any experimental therapy within 3 months, therapy with cyclophosphamide, pulse methylprednisolone or IVIG within 4 weeks, or azathioprine, mycophenolate mofetil, cyclosporine, or methotrexate within 2 weeks of the first dose of study medication. Serum creatinine level >3.0 mg/dl, white blood cell count <3500/microL, absolute neutrophil count < 3000 microlL, absolute lymphocyte count <= 500/microlL, hemoglobin value <8.0 gm/dl, platelet count <50000/microlL, AST or ALT levels >1.5 times the upper limits of normal, or >1000 Epstein-Barr virus genome equivalents/10 6 preipheral blood mononuclear cells.

0


Tocilizumab Article Inclusion Criteria Exclusion Criteria Jadad

Score at least 2 weeks prior to screening. Required presence of at least 1 serological marker of autoantibody production or systemic inflammation, therefore 1 or more of the following 4 features had to be present: serum anti-dsDNA antibody level >= 30IU, an IgG anticardiolipin antibody level >=20 igG phospholipid units/ml, a C-reactive protein level (CRP) > 0.8mg/dl, or an erythrocyte sedimentation rate (ESR) >25 mm/h in men and >42 mm/h in women. Stable dose of Prednisone <=0.3 mg/kg/d for at least 2 weeks before the first dose of study medication. Effective form f contraception.

• Please see enclosed excel sheet for Randomized Controlled Trial (RCT) – Intervention-Outcome (I-O) and Adverse Event (AE) data

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

Table 6. Cohort Studies Inclusion/Exclusion Criteria and Newcastle-Ottawa ScaleRituximab Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Catapano et al, UK and Italy, 2010 (175)

Data extracted from 2 electronic databases and patients’ note in Vasculitis and Lupus Clinic at Addenbrooke’s Hospital, Cambridge, UK. Fulfill at least 4 ACR diagnostic criteria. Patients receiving rituximab for refractory or relapsing SLE.

3

Terrier et al, France, 2010 (176)

Data collected prospectively from 82 centers in the AIR registry. SLE classified according to ACR 1982 revised criteria.

6

Jonsdottir et al, Europe, 2010 (177)

SLE and active LN. Pooled data from 2 cohorts, WHO Class V and WHO Class III or IV.

1

Stem Cell Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Jayne et al, UK, 2004 (178)

Retrospective data from the European Group for Blood and Marrow Transplantation and European League against Rheumatism Registry.

4

Burt et al, USA, 2006 (179)

At least 4 of 11 ACR Criteria for SLE and required more than 20mg/d of prednisone or its equivalent despite use of cyclophosphamide. WHO Class III or IV glomerulonephritis, involvement of lthe lung, involvement of the central nervous system, vasculitis, myositis, transfusion-dependent autoimmune cytopenias, severe serositiis, ulcerative mucocutaneous disease, or antiphospholipid syndrome (definied by Sapporo criteria). Nephritis required failure of 6 or more monthly pulse of cylcophosphamide. Nonrenal visceral organ involvement required failure of at least 3 months of cyclophosphamide.

4

Liang et al, Nanjing,

SLE refractory to standard therapies. All patients had at least 4 of 11 ACR criteria for SLE. Eligibility criteria include one of the

1

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Stem Cell Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

2010 (180) following features: progressive and active disease with SELENA SLEDAI score >=8 despite continuous treatment with IV pulse CYC with a total dosage of 400-800 mg every month for at least 6 months or oral MMF 1000-2000 mg/d for at least 3 months and continued daily dosage of more than 20mg of prednisone or its equivalent; refractory immune-mediated thrombocytopenia; refractor LN defined either as proteinuria >=1000mg/24 h, sercum creatinine >=1.5mg/dL or decreased Creatinine clearance without end-stage renal failure in patients with WHO Class IV/V glomerulonephritis despite 6 months of CYC or MMF.

Sun et al, Nanjing China, 2010 (181)

All patients met at least 4 of the 11 ACR criteria for SLE. SLEDAI socre >=8, lack of response to treatment with monthly IV CYC 500-1000 mg/m2 for >= 6 months or lack of response to treatment with oral MMF (2000 mg/day) for >=3 months, and continued daily doses of >20mg of prednisone or its equivalent. Also if they had refractory immune-mediated transfusion-dependent thrombocytopenia or refractory lupus nephritis defined as either proteinuria >= 1000mg/24 h or serum creatinine >= 1.5mg/dL or decreased creatinine clearance without end-stage renal failure in patients with WHOC IV/V glomerulonephritis despite 6 months treatment of CYC or 3 months of treatment with MMF.

Uncontrolled infection, mean pulmonary artery pressure > 50mm Hg, failure of one of the vital organs, were pregnant or lactating.

3

Antimalarial Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Siso et al, Spain, 2008 (182)

Single center. Fulfilled 1997 revised criteria for SLE classification. Biopsy proven LN. Renal biopsies reviewed by 2 pathologists and categorized according to ISN/RPS in 2004.

5

Pons-Estel et al, USA and Puerto Rico, 2009

Longitudinal observational cohort. Patients were >= 16 years of age and had disease duration of <= 5 years. Each patient had a baseline or enrollment visit (T0) followed by a 6 month visit (T0.5) and subsequently yearly visit. Time of diagnosis (TD)

4

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Antimalarial Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

LUMINA study (183)

was defined as the time when each patient met 4 ACR criteria.

Cyclosporin Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Rihova et al, Czech Republic, 2007 (184)

Retrospective charge review. Patient meet the 1982 ACR criteria for the diagnosis of SLE and have an active LN verified and classified by a renal biopsy, treated with CsA.

2

Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Dooley et al, USA, 1996 (185)

Renal biopsy diagnosis of SLE-DPGN from within the Glomerular Disease Collaborative Network (GDCN) were eligible for inclusion in this study. Patient fulfilled 4 or more criteria from the 1982 ACR revised criteria for classification of SLE. Documentation of treatment or intention to treat with CYC IV was required for study entry.

0

Ioannidis et al, USA and Greece, 2000 (186)

All patients with biopsy-documented diagnosis of proliferative lupus nephritis (WHO type III or IV) treated with IVC.

1

Mok et al, Hong Kong, China, 2004 (187)

SLE patients with biopsy proven DPGN initially treated with regimens that included CYC and corticosteroids between years 1988 and 2001. All fulfilled at least 4 of the ACR criteria for SLE classification.

3

de Castro et al, Brazil, 2007 (188)

SLE classification by ACR classification criteria, treated and followed from July 1988 to December 2003.

Histological class II or V according to 1995 WHO classification.

6

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Mok et al, Hong Kong China, 2006 (189)

Renal biopsy proven diffuse proliferative lupus glomerulonephritis (1995 WHO Class IV) treated in Hong Kong identified by clinical registries or renal biopsy databases. All patients fulfilled at least 4 ACR criteria for SLE classifications and were initially treated with corticosteroids and CYC.

3

Petri et al, USA, 2010 (190)

Prospective randomized trial with 1:1 randomization. SLE patients met >= 4 of revised ACR criteria for SLE with moderate to severe activity in an organ as defined as BILAG A or a high score for that organ on the SLAM or hospitalization for involvement of that organ. Lack of response or expected lack of response to moderate- to high- dose corticosteroids, to the equivalent degree of immunosuppression, or to appropriate other treatment. Combination therapy of both hydroxychorologuine and quinacrine as well as immunosuppression had to have failed for SLE patients with cutaneous lupus.

Musculoskeletal lupus from the category of eligible organ involvement.

4

Immunosuppressives vs Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Urowitz et al, Toronto, Canada, 2007 (191)

SLE >= 4 ACR criteria or 3 ACR criteria plus a typical histological lesion of SLE on renal or skin biopsy. Patients with active renal disease treated with immunosuppressive/cytotoxic medications in the year after diagnosis of active renal disease were selected from clinic database. Active renal disease defined as presence of 2 consecutive visits of one of: red blood cell casts or hemegranular casts, hematuria or pyruia in the absence of other causes, or proteinuria (>500mg/24h or >= 3+ on dipstick) or an abnormal kidney biopsy showing active lupus nephritis.

3

Cyclophosphamide (CYC) vs Azathioprine (AZA)

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Decker et al, NIH, 1975 (192)

Diagnosis of SLE by ARA criteria including a positive erythematosus cell test; kidney disease with either erythrocyte casts, celluar casts, and either hematuria (20 erythrocytes/hpf) or high anti-DNA antibodies, low complement, and a positive renal biopsy, and diffuse glomerulonephritis with at least a portion of all glomeruli involved.

Serum creatinine of greater than 4mg/100ml or creatinine clearance of less than 20ml/min

3

Cyclophosphamide (CYC) + Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Chan et al, Hong Kong, China, 2005 (170)

Prospective cohort. Diagnosis of WHO Class IV lupus nephritis confirmed by renal biopsy, baseline urinary protein excretion exceeding 1g/24h, baseline serum albumin below 35g/L, treatment with sequential immunosuppression. Patients with superimposed membranous changes were included provided that there were concomitant diffuse proliferative features.

Serum creatinine exceeding 400micromol/L, treatment with cyclophosphamide or mycophenolate mofetil within 6 months, or prednisolone dose exceeding 0.4mg/kg/d for more than 2 weeks prior to baseline/

3

High dose cyclophosphamide (CYC) vs Low dose cyclophosphamide followed by Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Houssiau et al, Europe, ELNT, 2004 Subanalysis (193)

SLE patients according to ACR criteria, age 14 years or older with biopsy proven proliferative lupus glomerulonephritis (WHO Class III, IV, Vc, or Vd) and proteinuria >= 500mg/24 h.

Patients who had taken CYC or AZA during the previous year or had taken >=15mg/day prednisone (or equivalent) during the previous month were excluded (except for a course of glucocorticoids for a maximum of 10 days before the referral). Other exclusion criteria were renal thrombotic microangiopathy, preexisting chronic renal failure, pregnancy, previous malignancy (except skin and cervical

3

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS High dose cyclophosphamide (CYC) vs Low dose cyclophosphamide followed by Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

intraepithelial neoplasis), diabetes mellitus, previously documented severe toxicity to immunosuppressive drugs, and anticipated poor compliance with the protocol.

Mycophenolate Mofetil (MMF) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Tang et al, Nanjing Chinca, 2008 (194)

Single center, retrospective. Patients fulfilled 1997 SLE diagnosis criterion of ARA, presentation of clinical renal lesion, crescent formation more than 50% and having undertaken MMF or CTX therapy during their induction period.

5

Rivera et al, 2009 (195)

Single center retrospective chart review of SLE patients with biopsy ISN/RPS criteria Class II, III, IV,V, and VI. Patients must be followed for at least 6 months.

3

Cortez-Hernandez et al, Spain, 2010 (196)

SLE according to ACR criteria, class III/IV/V LN treated with MMF.

3

Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Mok et al, Hong Kong, China, 2004 (197)

Open label - Renal biopsy-proven pure membranous lupus glomerulonephritis (WHO Va and Vb).

WHO Classification Vc and Vd. 3

Leflunomide

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Article Inclusion Criteria Exclusion Criteria Newcastle

Ottawa Scale

Zhang et al, Harbin China, 2009 (198)

Fulfilled 1997 ACR classification criteria for SLE admitted as inpatients undergoing kidney biopsy.

Severe insufficiency of organs besides kidney, including heart failure, liver failure, severe psychosis, leukocyte and platelet count less than 3 x 10 9/L and 50 x 10 9 respectively, pregnant women, lactating women, children of less than 16 age.

3

• Please see enclosed excel sheet for Cohort Trial – Intervention-Outcome (I-O) and Adverse Event (AE) data

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

END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES Authors Title Description/Methods Results/Conclusions Hashemi V, Nadjafi I, Azzordegan F, Ghahramani N, Broumand B. Shariati Hospital, Tehran University of Medical Sciences, Iran. Transplant Proc. 1999 Dec;31(8):3142-3.

Renal transplantation in systemic lupus erythematosus: a multicenter study with 37 patients in Iran.

Looked at 37 pts with LN and ESRD who had undergone renal transplantation. Post-transplant meds = CsA, aza, and pred, except in 1 case aza+pred.

Graft survival at 1 yr = 85.6%, 3 yr = 73%. No correlation w/ gender, age at transplant, and donor source. Causes of graft loss: chronic graft rejection 11/37, acute rejection 2/37, recurrence of LN 1/37. Patient survival at 1 yr 94.4%, at 3 yrs 91.7%. 2/37 died of MI, 1/37 died of pneumococcal infection/sepsis, 1/37 died of opium toxicity.

Ward MM. Palo Alto Health Care System, Palo Alto, CA Kidney Int. 2000 May;57(5):2136-43.

Outcomes of renal transplantation among patients with end-stage renal disease caused by lupus nephritis.

Graft failure and patient mortality after the first cadaveric renal transplantation were compared between 772 adults with ESRD caused by lupus nephritis and 32,644 adults with ESRD caused by other causes who received a transplant between 1987 and 1994 and were included in the United States Renal Data System. The median follow-up times were 4.9 and 5.0 years in the two groups, respectively. Multivariate Cox regression models were used to adjust the risks of graft failure and mortality for group differences in recipient and donor characteristics. Similar comparisons were performed between 390 adults with ESRD caused by lupus nephritis and 10,512 adults with ESRD caused by other causes after first living-related renal transplantation.

RESULTS: In an unadjusted analysis, the risk of graft failure after first cadaveric transplant was slightly but significantly greater among patients with ESRD caused by lupus nephritis than among those with ESRD caused by other causes [hazard ratio (HR), 1.13; 95% CI, 1.01 to 1. 26, P = 0.04]. However, after adjustment for potential confounding factors, the risk of graft failure was not increased in patients with ESRD caused by lupus nephritis (HR, 1.08; 95% CI, 0.94 to 1.23, P = 0.28). Mortality after the first cadaveric transplantation did not differ between groups. The adjusted risks of graft failure (HR, 1.06; 95% CI, 0.84 to 1.32, P = 0.62) and patient mortality (HR = 0. 69; 95% CI, 0.45 to 1.05, P = 0.09) after the first living-related renal transplant were also not significantly higher among patients with ESRD caused by lupus nephritis. CONCLUSIONS: Graft and patient survival after first cadaveric and first living-related renal transplants are similar in patients with ESRD caused by lupus nephritis and patients with ESRD from other causes.

Goral S, Ynares C, Shappell SB, Snyder S, Feurer ID, Kazancioglu R, Fogo AB, Helderman JH. University of Pennsylvania School of Medicine Transplantation. 2003 Mar 15;75(5):651-6.

Recurrent lupus nephritis in renal transplant recipients revisited: it is not rare.

The records of 54 renal transplant recipients with SLE were reviewed. Thirty-one patients underwent biopsy because of worsening renal function and proteinuria. All biopsy specimens were evaluated by light microscopy, immunofluorescence (IF), and electron microscopy (EM).

RESULTS: Among the 50 patients with at least 3 months of follow-up, RLN was present in 15 (52% of patients who underwent biopsy, 30% of total patients): mesangial lupus nephritis (LN) (class II) in eight, focal proliferative LN (class III) in four, and membranous LN (class Vb) in three patients. One patient had graft loss because of RLN (class II) at 10.5 years. The duration of dialysis before transplantation was not different between patients with RLN compared to patients without RLN (P=0.40). Overall patient survival (n=50) was 96% at 1 year and 82% at 5 years, and graft survival was 87% at 1 year and 60% at 5 years. Graft survival was worse in patients who underwent biopsy compared with patients who never underwent biopsy (P<0.01). CONCLUSIONS: RLN is more common than

GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions

previously reported, but in our series, graft loss because of RLN was rare. Aggressive use of allograft biopsies and morphologic evaluation with IF and EM are important factors in the diagnosis of RLN. The impact of new immunosuppressive agents on the incidence of RLN remains to be seen.

Deegens JK, Artz MA, Hoitsma AJ, Wetzels JF. University Medical Center of Nijmegen, The Netherlands. Transpl Int. 2003 Jun;16(6):411-8. Epub 2003 Mar 19.

Outcome of renal transplantation in patients with systemic lupus erythematosus.

We studied the outcome of renal transplantation in patients with SLE who underwent transplantations in our center between 1968 and 2001. Patient and graft survival were compared with a matched control group. We specifically looked for any evidence of recurrent disease. There were 23 patients (two male, 21 female) with a mean +/-SD age of 34+/-12 years at transplantation.

One patient developed renal failure with serological evidence of SLE activity at 61 months after transplantation. In the absence of urine abnormalities we favored the diagnosis of rejection, although recurrence of lupus nephritis could not formally be excluded. This was the only case of a possible recurrence of lupus nephritis. Two other patients developed extra-renal manifestations of SLE at 6 and 17 months after transplantation. Patient and graft survival rates at 5 years after transplantation were 86% and 68%, respectively. Survival rates were not significantly different from those of a matched control group, 95% and 78%, respectively. Recurrence of SLE after transplantation is rare. The results of renal transplantation in patients with SLE do not differ significantly from a matched control group. Renal transplantation is a good alternative for renal replacement therapy in patients with lupus nephritis.

Moroni G, Tantardini F, Gallelli B, Quaglini S, Banfi G, Poli F, Montagnino G, Meroni P, Messa P, Ponticelli C. Centro Trasfusionale e di Immunologia dei Trapianti IRCCS, Ospedale Maggiore Milano, Italy Am J Kidney Dis. 2005 May;45(5):903-11.

The long-term prognosis of renal transplantation in patients with lupus nephritis.

Between June 1982 and 2004, a total of 33 adults with lupus nephritis received 35 kidney allografts. Outcomes of these grafts and those of 70 controls matched for age, sex, and donor source who underwent transplantation during the same period were compared.

RESULTS: Mean follow-up after renal transplantation was 91 +/- 59 months for patients with lupus and 90 +/- 64 months for controls. Actuarial 15-year patient (80% versus 83%) and death-censored graft survival rates (69% versus 67%) were not significantly different between patients with lupus and controls. Risks for acute and chronic rejection, arterial hypertension, and infection were not different between the 2 groups. Mean serum creatinine levels also were similar in the 2 groups at the last follow-up visit. Intravascular thrombotic events occurred in 9 patients with SLE (26%) and 6 controls (8.6%; P = 0.038). In the SLE group, 6 of 7 antiphospholipid (aPL) antibody-positive versus 3 of 17 aPL antibody-negative patients experienced thrombotic events ( P = 0.015). Recurrence of lupus nephritis was documented in 3 renal grafts (8.6%), but no graft was lost because of recurrent lupus nephritis. CONCLUSION: Long-term patient and graft survival probabilities were similar in patients



with SLE and matched controls. The risk for thrombotic complications was greater in patients with SLE, particularly aPL-positive patients. Nephritis recurred in less than 10% of patients with SLE and did not influence graft survival.

Bunnapradist S, Chung P, Peng A, Hong A, Chung P, Lee B, Fukami S, Takemoto SK, Singh AK. Transplantation. 2006 Sep 15;82(5):612-8.

Outcomes of renal transplantation for recipients with lupus nephritis: analysis of the Organ Procurement and Transplantation Network database.

Here, we compared patient and graft outcomes in lupus and non-lupus recipients transplanted between 1996 to 2000 using the United Network of Organ Sharing/Organ Procurement Transplant Network database. We evaluated the impact of recipient and donor demographic factors, time on dialysis and the initial immunosuppression regimen on rejection rates and transplant outcomes.

Univariate analysis showed similar graft but better patient survival rates for primary lupus and non-lupus transplant recipients (5-year patient survival rates for lupus cohort 85.2% for deceased donor transplants and 92.1% for living donor transplants as opposed to 82.1% and 89.8% respectively for the non-lupus cohort; P=0.05 and 0.03) but similar patient survival rates for deceased donor retransplant patients. After controlling for confounding factors, no differences in patient or graft survival were seen between the two groups. No difference in acute rejection rates were observed in deceased donor transplants, but there was a small but significant increase in the risk of acute rejection in living donor lupus transplant recipients (hazard ratio=1.19, P=0.05). Risk of graft failure was lower for deceased donor recipients receiving MMF (five-year graft loss rate=29.6% for MMF vs. 40.2% for those not receiving MMF, P<0.0001), but no differences were seen among living donor recipients. Outcomes were similar regardless of type of calcineurin inhibitor, induction therapy, and time on dialysis. We conclude that lupus transplant recipients have outcomes generally equivalent to non-lupus transplant recipients.

Chelamcharla M, Javaid B, Baird BC, Goldfarb-Rumyantzev AS. University of Utah Health Sciences Center Nephrol Dial Transplant. 2007 Dec;22(12):3623-30. Epub 2007 Jul 19.

The outcome of renal transplantation among systemic lupus erythematosus patients.

We conducted the retrospective analysis using data from USRDS and UNOS databases. Patients were divided into five groups based on the cause of end-stage renal disease (ESRD): diabetes mellitus (DM), SLE, glomerulonephritis, hypertension and other causes. Between 1990 and 1999, 2886 renal transplantation recipients with ESRD due to SLE were identified from a total of 92 844 patients.

RESULTS: The mean follow-up period of this study was 4.7 +/- 2.4 years. While unadjusted analysis using Kaplan-Meier curves demonstrated an association between SLE and improved allograft survival compared with DM, in multivariate analysis the SLE group had worse allograft [hazard ratio (HR) 1.09, P < 0.05] and recipient (HR 1.19, P < 0.05) survival compared with the DM group. Subgroup analysis based on the type of donor showed that SLE patients who received deceased donor allograft had worse allograft and recipient survival (HR 1.14, P = 0.002 and HR 1.30, P = 0.001, respectively) compared with non-SLE deceased donor allograft recipients. Among living allograft



recipients, there were no significant differences in either allograft or recipient survival compared with non-SLE recipients. CONCLUSIONS: SLE as a cause of ESRD in renal transplant recipients is associated with worse allograft and recipient survival compared with DM; this association is true for the entire population and for the recipients of deceased donor (but not living donor) transplant. Deceased donor allograft recipients have worse outcomes compared with living allograft recipients.

Tang H, Chelamcharla M, Baird BC, Shihab FS, Koford JK, Goldfarb-Rumyantzev AS. University of Utah School of Medicine Clin Transplant. 2008 May-Jun;22(3):263-72.

Factors affecting kidney-transplant outcome in recipients with lupus nephritis.

Using the data from the United States Renal Data System of patients transplanted between January 1, 1995 through December 31, 2002 (and followed through December 31, 2003) (n = 2882), we performed a retrospective analysis of factors associated with long-term death-censored graft survival and recipient survival.

RESULTS: The number of pretransplant pregnancies incrementally increased the risk of graft failure [hazard ratio (HR) 1.54, p < 0.05] in the entire subgroup of females and in the subgroup of recipients aged 25-35 yr. Recipient and donor age had an association with both the risk of graft failure (HR 0.96, p < 0.001; HR 1.01, p < 0.005) and recipient death (HR 1.04, p < 0.001; HR 1.01, p < 0.05). Greater graft-failure risk accompanied increased recipient weight (HR 1.01, p < 0.001); African Americans compared with whites (HR 1.55, p < 0.001); greater Charlson comorbidity index (HR 1.17, p < 0.05); and greater panel reactive antibody (PRA) levels (HR 1.06, p < 0.001). Pretransplant peritoneal dialysis as the predominant modality had an association with decreased risk of graft failure (HR 0.49, p < 0.001), while prior transplantation was associated with greater risk of graft failure and recipient death (HR 2.29, p < 0.001; HR 3.59, p < 0.001, respectively) compared with hemodialysis (HD). The number of matched human leukocyte antigens (HLA) antigens and living donors (HR 0.92, p < 0.05; HR 0.64, p < 0.001, respectively) was associated with decreased risk of graft failure. Increased risk of graft failure and recipient death was associated with nonuse of calcineurin inhibitors (HR 1.89, p < 0.005; HR 1.80, p < 0.005) and mycophenolic acid (MPA) (including mycophenolate mofetil and MPA) or azathioprine (HR 1.41, p < 0.05; HR 1.66, p < 0.01). Using both cyclosporine and tacrolimus was associated with increased risk of graft failure (HR 2.09, p < 0.05). Using MPA is associated with greater risk of recipient death compared with azathioprine (HR 1.47, p < 0.05). CONCLUSION: In renal transplant recipients with lupus nephritis, multiple pregnancies, multiple blood transfusions, greater comorbidity index, higher body weight, age and African American race of the donor or recipient, prior history of



transplantation, greater PRA levels, lower level of HLA matching, deceased donors, and HD in pretransplant period have an association with increased risk of graft failure. Similarly, higher recipient and donor age, prior transplantations, and higher rate of pretransplant transfusions are associated with greater risk of recipient mortality. Using neither cyclosporine nor tacrolimus or using both (compared with tacrolimus) and neither MPA nor azathioprine (compared with azathioprine) was associated with increased risk of graft failure and recipient death. Using MPA is associated with greater risk of recipient death compared with azathioprine. Testing these results in a prospective study might provide important information for clinical practice.

Ward MM. NIH/NIAMS/IRP J Rheumatol. 2009 Jan;36(1):63-7.

Changes in the incidence of endstage renal disease due to lupus nephritis in the United States, 1996-2004.

Patients age 15 years or older with incident ESRD due to lupus nephritis in 1996-2004 and living in one of the 50 United States or the District of Columbia were identified using the US Renal Data System, a national population-based registry of all patients receiving renal replacement therapy for ESRD. Incidence rates were computed for each calendar year, using population estimates of the US census as denominators.

RESULTS: Over the 9-year study period, 9199 new cases of ESRD due to lupus nephritis were observed. Incidence rates, adjusted to the age, sex, and race composition of the US population in 2000, were 4.4 per million in 1996 and 4.9 per million in 2004. Compared to the pooled incidence rate in 1996-1998, the relative risk of ESRD due to lupus nephritis in 1999-2000 was 0.99 (95% CI 0.93-1.06), in 2001-2002 was 0.99 (95% CI 0.92-1.06), and in 2003-2004 was 0.96 (95% CI 0.89-1.02). Findings were similar in analyses stratified by sex, age group, race, and socioeconomic status. CONCLUSION: There was no decrease in the incidence of ESRD due to lupus nephritis between 1996 and 2004. This may reflect the limits of effectiveness of current treatments, or limitations in access, use, or adherence to treatment.

Burgos PI, Perkins EL, Pons-Estel GJ, Kendrick SA, Liu JM, Kendrick WT, Cook WJ, Julian BA, Alarcón GS, Kew CE 2nd. University of Alabama at Birmingham Arthritis Rheum. 2009 Sep;60(9):2757-66.

Risk factors and impact of recurrent lupus nephritis in patients with systemic lupus erythematosus undergoing renal transplantation: data from a single US institution.

The archival records of all kidney transplant recipients with a prior diagnosis of SLE (according to the American College of Rheumatology criteria) from June 1977 to June 2007 were reviewed. Patients who had died or lost the allograft within 90 days of engraftment were excluded. Time-to-event data were examined by univariable and multivariable Cox proportional hazards regression analyses.

RESULTS: Two hundred twenty of nearly 7,000 renal transplantations were performed in 202 SLE patients during the 30-year interval. Of the 177 patients who met the criteria for study entry, the majority were women (80%) and African American (65%), the mean age was 35.6 years, and the mean disease duration was 11.2 years. Recurrent lupus nephritis was noted in 20 patients (11%), allograft loss in 69 patients (39%), and death in 36 patients (20%). African American ethnicity was found to be associated with a shorter time-to-event for recurrent lupus nephritis (hazard ratio [HR] 4.63, 95% confidence interval [95% CI] 1.29-16.65) and death (HR 2.47, 95% CI 0.91-6.71), although, with the latter, the association was not statistically significant. Recurrent lupus nephritis and chronic rejection of the kidney transplant were found to be risk factors for allograft loss (HR 2.48, 95% CI 1.09-5.60 and HR 2.72, 95% CI 1.55-4.78, respectively). In patients with recurrent lupus nephritis, the lesion



in the engrafted kidney was predominantly mesangial, compared with a predominance of proliferative or membranous lesions in the native kidneys. CONCLUSION: African American ethnicity was independently associated with recurrent lupus nephritis. Allograft loss was associated with chronic transplant rejection and recurrence of lupus nephritis. Recurrent lupus nephritis is infrequent and relatively benign, without influence on a patient's survival.

Liang CC, Huang CC, Wang IK, Chang CT, Chen KH, Weng CH, Lin JL, Hung CC, Yang CW, Yen TH. China Medical University Hospital, Taichung, Taiwan Ther Apher Dial. 2010 Feb;14(1):35-42.

Impact of renal survival on the course and outcome of systemic lupus erythematosus patients treated with chronic peritoneal dialysis.

This longitudinal study investigated whether renal survival can affect the course and outcome of systemic lupus erythematosus (SLE) patients treated with chronic peritoneal dialysis (PD). Thirty-five SLE patients, out of 1115 end-stage renal disease (ESRD) patients treated with chronic PD, were seen between 1990 and 2007 at the Chang Gung Memorial Hospital. Patients were followed up for a mean of 38.8 +/- 22.9 months.

There were no significant differences between patients with short renal survival (<3 years) and long renal survival (>3 years) for the various demographic variables such as age, sex, PD duration, immunosuppressive drug administration, or exchange system (P > 0.05). Interestingly, before PD, patients with short renal survival had lower serum complement levels than patients with long renal survival (C3, 40.2 +/- 14.4 vs 76.3 +/- 18.5 mg/dL, P < 0.001; and C4, 14.8 +/- 4.7 vs 22.4 +/- 8.1 mg/dL, P < 0.05). However, the differences in complement levels between the groups disappeared after PD (C3, 76.5 +/- 27.3 vs 84.2 +/- 27.8 mg/dL; and C4, 26.7 +/- 11.3 vs 22.6 +/- 10.8 mg/dL, both P > 0.05). Patients with short renal survival were more likely to have a high peritoneal solute transporter rate (PSTR) than their long renal survival counterparts (chi(2)-test, P = 0.02, and AUROC = 0.744 and P = 0.040); however, there were no significant differences for other variables such as cardiothoracic ratio (CTR), Kt/V, residual renal function, exit site infection, and peritonitis (P > 0.05). Finally, Kaplan-Meier analysis revealed that the two groups did not differ in patient and technical survival (P > 0.05). Therefore it was concluded that renal survival might be associated with PSTR, but not with patient and technical survival in SLE patients treated with PD.


Authors Title Description/Methods Results/Conclusions Norby GE, Strøm EH, Midtvedt K, Hartmann A, Gilboe IM, Leivestad T, Stenstrøm J, Holdaas H. Oslo University Hospital, Norway. Ann Rheum Dis. 2010 Aug;69(8):1484-7. Epub 2010 May 24.

Recurrent lupus nephritis after kidney transplantation: a surveillance biopsy study.

All patients with SLE that had undergone transplant with a functioning graft were asked in 2008 to participate in a cross-sectional study. The study included a standardised clinical examination, laboratory tests and a biopsy of the transplanted kidney.

RESULTS: A total of 41 (93%) of a cohort of 44 patients with SLE with renal transplants participated. Of the biopsies, 3 were indication biopsies and 38 were surveillance biopsies. In all, 22 patients (54%) had biopsy-proven recurrence of LN. The majority of the cases were subclinical and characterised as class I/class II LN. Proteinuria (mg protein/mmol creatinine) was significantly increased in patients with recurrence, 70.6 (104.9) mg/mmol versus 11.9 (6.7) mg/mmol in patients without recurrence (p=0.038). Lupus anticoagulant was found more frequently in the patients with recurrence, nine versus two patients (p=0.033). Recurrence of LN was associated with receiving a kidney from a living donor (p=0.049). In all, 83% (34 of 41) had chronic allograft nephropathy in the transplanted kidneys with no difference between patients with recurrence or without. CONCLUSIONS: Subclinical recurrence of LN is common in patients with renal transplants with SLE. The majority of the patients have chronic allograft nephropathy.

Bumgardner GL, Mauer SM, Payne W, Dunn DL, Sutherland DE, Fryd DS, Ascher NL, Simmons RL, Najarian JS. University of Minnesota, Minneapolis Transplantation. 1988 Nov;46(5):703-9.

Single-center 1-15-year results of renal transplantation in patients with systemic lupus erythematosus.

However, since the long-term outcome after transplantation in this group of patients is not well established, we have examined the long-term outcome in SLE patients who underwent renal transplantation at the University of Minnesota. Thirty-two SLE patients receiving 33 transplants between December 1969 and December 1987 were studied retrospectively and compared with controls matched for age, sex, donor source, HLA match, date of transplant, and diabetic status.

A total of 69% (22/32) of patients underwent less than 1 year of dialysis prior to transplantation, and 50% (16/32) experienced biopsy-proved acute rejection, which was reversible in 67% (11/16). Actuarial graft function and patient survival rate in SLE patients were not significantly different from those in the matched control group. Duration of prior dialysis did not affect outcome. Surviving grafts have excellent function as measured by serum creatinine (1.3 +/- 0.4 mg/dl, means +/- SD). Causes of death were sepsis (5) and myocardial infarction (1). One patient lost the graft from rejection after withdrawal of immunosuppression because of a malignancy one month posttransplant. Three patients lost graft function due to chronic rejection. To date no patients have had evidence of recurrent SLE nephritis.

Pollock CA, Ibels LS. Royal North Shore Hospital, NSW. Aust N Z J Med. 1987 Jun;17(3):321-5.

Dialysis and transplantation in patients with renal failure due to systemic lupus erythematosus. The Australian and New Zealand experience.

Between 1977 and 1985, 5726 patients in Australia and New Zealand entered end stage renal failure programmes. Of these, 63 patients had renal failure due to systemic lupus erythematosus (a prevalence of 1.1% of patients entering renal replacement programmes).

When compared with patients with other forms of glomerulonephritis, there was a female preponderance and a younger age distribution in patients with renal failure due to lupus nephritis. Integrated patient, dialysis, and transplant survival data showed that results in patients with renal failure due to lupus nephritis were comparable with those in patients with other forms of glomerulonephritis or in patients with renal failure due to any cause. Age at entry significantly affected survival, with significant differences being found in those patients under as opposed to over 50 years of age. Causes of death in patients with lupus nephritis were similar to those in patients with renal failure due to other causes. It is concluded that dialysis and transplantation are



acceptable forms of treatment for patients with end stage renal failure due to systemic lupus erythematosus.

Lochhead KM, Pirsch JD, D'Alessandro AM, Knechtle SJ, Kalayoglu M, Sollinger HW, Belzer FO. University of Wisconsin Hospital and Clinics Kidney Int. 1996 Feb;49(2):512-7.

Risk factors for renal allograft loss in patients with systemic lupus erythematosus.

This study is a retrospective evaluation of each of these independent risk factors in 80 renal transplants for ESRD secondary to SLE done at our institution between 1971 and 1994. Our entire non-diabetic cohort of 1,966 renal transplants is used as a comparison group.

Our results showed equivalent graft survival rates between lupus patients and the cohort at 1, 5 and 10 years (P = 0.56). However, an analysis of cyclosporine-era cadaver grafts revealed that the lupus group had poorer 5-year graft survival than the cohort (41% vs. 71%, P = 0.02). Evaluation of cyclosporine-era lupus graft survival showed significantly improved outcome in living-related lupus recipients over cadaver grafts at five years (89% vs. 41%, P = 0.003). The majority of grafts lost in the lupus cadaver recipients were due to chronic rejection. Rejection was increased in lupus recipients: 69% of lupus patients experienced rejection in the first year compared to 58% of controls (P = 0.01). Stratified for age, sex, race and cyclosporine use, this difference remained significant (P = 0.003, relative risk 1.7). Nephrectomy, splenectomy and 3 to 6 months of pretransplant dialysis did not improve graft survival. A dialysis duration of greater than 25 months predicted worse graft survival (P = 0.01). Among lupus patients, PRA did not correlate with graft outcome (P = 0.5), and HLA-identical cadaver grafts had improved outcomes compared to cadaver grafts. We conclude that acute and chronic rejection are the major risk factors for graft loss in lupus patients. The superior outcome of living-related over cadaver grafts in lupus patients suggests an increased role for living-related grafts. Pretransplant dialysis, nephrectomy and splenectomy are not indicated.

Haubitz M, Kliem V, Koch KM, Nashan B, Schlitt HJ, Pichlmayr R, Brunkhorst R. Medical School Hannover, Germany. Transplantation. 1997 May 15;63(9):1251-7.

Renal transplantation for patients with autoimmune diseases: single-center experience with 42 patients.

Long-term graft survival and graft function of renal transplant recipients with SLE, Wegener's granulomatosis, microscopic polyangiitis, Goodpasture's syndrome, and Henoch-Schonlein purpura were evaluated in a single center. In addition, the incidence of renal and extrarenal relapses and the impact of the immunosuppressive therapy on the course of the autoimmune disease

RESULTS: Renal transplant recipients with autoimmune diseases such as vasculitis and SLE had a patient survival rate (94% after 5 years) and a graft survival rate (65% after 5 years) comparable to those of patients with other causes of end-stage renal disease (patient survival 88% and graft survival 71% after 5 years). Graft losses due to the underlying disease were rare. Extrarenal relapses occurred in three patients with Wegener's granulomatosis, one patient with microscopic polyangiitis, and three patients with SLE, but were less frequent compared with



were studied. the period with chronic dialysis therapy. Autoantibody levels in patients with SLE, Wegener's granulomatosis, or microscopic polyangiitis did not seem to influence the outcome. CONCLUSIONS: Renal transplantation should be offered to patients with autoimmune diseases. Follow-up should include the short-term control of renal and extrarenal disease activity.

Grimbert P, Lang P, Frappier J, Bedrossian J, Legendre C, Hiesse C, Bitker MO, Sraer JD, Antoine C. Hopital Henri Mondor, Creteil, France. Transplant Proc. 1997 Aug;29(5):2363-4.

Renal transplantation in patients with systemic lupus erythematosus: a multicenter study.

Between October 1971 and August 1993, 53 patients with SLE received 60 renal transplants in the different renal transplantation centers in Paris. All patients met the criteria of the American Rheumatism Association for SLE, and diagnoses were confirmed by renal biopsy specimens in all patients. The long-term outcome of renal transplantation in these patients was examined, including patient and graft survival, posttransplant lupus activity, serum creatinine levels, rejection episodes, and the causes of graft loss and patient death. All charts were examined for any evidence of recurrent lupus nephritis. These 60 renal transplants were compared with the patient and graft survival for 106 controls matched for age, gender, maximum panel-reactive antibody level, and date of transplant.

The population studied consisted mainly of young women (mean age, 33.2 years; range, 21 to 54, n = 48 [90%]). The duration of disease before transplant was 93.6 +- 6.2 months and the duration of dialysis before transplant was 48 _~ 6 months. At the time of transplant, none of the patients had clinically active SLE, only four had hypocomplementemia, and 25 had positive anti-DNA titers. Of the 60 transplants, 56 (93%) were cadaveric and 4 (7%) were from living related donors. Forty-six patients (86%) had primary allografts, and 7 (14%) were given a second allograft. Donor age was 38 _+ 2.4 years. The number of HLA matches was 2.96 -+ 0.2. Panel-reactive antibody level was >80% in 19 cases (31%). Overall graft survival rates for lupus patients were 83% and 69% at 1 and 5 years, respectively, similar to those of control graft survivals of 82.5% and 70% (P = .60). Of the 60 kidneys transplanted in SLE patients during this 21.5-year period, 37 (62%) are still functioning, and the mean serum creatinine level is 15 _+ 2.5 mg/L. Fifteen grafts were lost due to chronic rejection, 3 to acute rejection, 3 to renal artery thrombosis, 1 to ureteral necrosis, and 1 to thrombotic icroangiopathy caused by cyclosporine. Fortyone (68%) of the kidney transplants had at least one biopsy-documented episode of acute rejection, and there was histological evidence of chronic rejection in 36 (60%) kidney transplants. The survival of the lupus patients was similar to the controls: it was 98% at 1 year and 96% at 5 years in the lupus group, and 97% and 93% at 1 and 5 years in the controls (P = .96). Two of the lupus patients died from sepsis.


Authors Title Description/Methods Results/Conclusions Stone JH, Millward CL, Olson JL, Amend WJ, Criswell LA. University of California, San Francisco Arthritis Rheum. 1998 Apr;41(4):678-86.

Frequency of recurrent lupus nephritis among ninety-seven renal transplant patients during the cyclosporine era.

We reviewed the posttransplant clinical course and renal biopsy results in 97 consecutive SLE patients who underwent a total of 106 renal transplantation procedures at our center from January 1984 to September 1996.

RESULTS: There were 81 female and 16 male patients, with a mean age of 35 years. Mean duration of dialysis prior to transplantation was 33.5 months; 9 patients were never dialyzed. In all patients, the disease was clinically and serologically quiescent at the time of transplantation. The mean posttransplantation followup period was 62.6 months. Patients underwent a total of 143 posttransplant biopsies. Nine patients had pathologic evidence of recurrent LN. Six of the patients with recurrence had cadaveric grafts, 2 had living-related grafts, and 1 had a living-unrelated graft. Recurrence occurred an average of 3.1 years after transplantation; the longest interval was 9.3 years and the shortest, 5 days. Histopathologic diagnoses on recurrence included diffuse proliferative glomerulonephritis, focal proliferative glomerulonephritis, membranous glomerulonephritis, and mesangial glomerulonephritis. In 4 patients, recurrent LN contributed to graft loss. Three of the patients with recurrence had serologic evidence of active lupus, but only 1 had symptoms of active lupus (arthritis). Three patients who lost their grafts secondary to recurrent LN underwent second renal transplantation procedures and had functioning grafts at 7, 30, and 35 months, respectively. CONCLUSION: In the largest single medical center series of renal transplant patients with SLE, recurrent LN was more common than reported in the literature, but was not always associated with allograft loss. Recurrent LN was often present in the absence of clinical and serologic evidence of active SLE.

Stone JH, Amend WJ, Criswell LA. Johns Hopkins University Arthritis Rheum. 1998 Aug;41(8):1438-45.

Outcome of renal transplantation in ninety-seven cyclosporine-era patients with systemic lupus erythematosus and matched controls.

A total of 97 SLE patients who underwent renal transplantation between January 1984 and September 1996 were selected for study and were matched with a group of non-SLE controls (1 control for each SLE patient) who also received transplants during that period. SLE patients and controls were matched on 6 covariates: age, sex, race, type of allograft (cadaveric versus living-related), number of previous transplants, and year of transplantation. All study subjects received either cyclosporine or FK-506/tacrolimus as part of their immunosuppressive regimen. In a rigorous medical records review, the status of each allograft and the cause of each graft loss

RESULTS: The control group included patients with 20 different causes of end-stage renal disease (ESRD). The mean followup times for the SLE patients and controls were 323 weeks and 320 weeks, respectively. During the followup period, 52 SLE patients and 37 controls lost their allografts. The 1-, 2-, 5-, and 10-year allograft survival probabilities for the 2 groups (SLE versus controls) were as follows: 81.7% versus 88.2% (1-year); 74.7% versus 84.4% (2-year); 45.9% versus 75.0% (5-year); and 18.5% versus 34.8% (10-year). In the multivariate model, the relative hazard of allograft loss associated with SLE as the cause of ESRD was 2.1 (95% confidence interval 1.06-4.06, P = 0.0328). The total number of HLA mismatches, smoking status, and delayed allograft function were also associated with allograft loss in the multivariate model. CONCLUSION: Compared with matched controls, renal transplant patients with SLE had inferior transplantation outcomes, with more than twice the risk of



was determined. allograft loss.

Grimbert P, Frappier J, Bedrossian J, Legendre C, Antoine C, Hiesse C, Bitker MO, Sraer JD, Lang P. Hôpital Henri Mondor, Créteil, France. Transplantation. 1998 Oct 27;66(8):1000-3.

Long-term outcome of kidney transplantation in patients with systemic lupus erythematosus: a multicenter study. Groupe Cooperatif de Transplantation d'île de France.

The patients received their transplants over a 260-month period (21.5 years) between October 1971 and August 1993. The population was predominantly women (90%), and the mean age at the time of the transplantation was 33.2 years (range: 21-54 years). Fifty-six transplants (93%) were from cadaveric donors, and 4 (7%) were from living-related donors; 46 patients (86%) had primary allografts, and 7 (14%) received a second allograft. The duration of disease before transplantation was 93.6+/-6.2 months, and the duration of dialysis before transplantation was 48+/-6 months.

RESULTS: No patient had clinically active systemic lupus erythematosus (SLE) at the time of transplantation. The 1-year graft and patient survival rates were 83% and 98%, and the 5-year graft and patient survival rates were 69% and 96%. Actuarial graft and patient survival rates in SLE patients were not significantly different from those of the matched control group. Chronic rejection was the major risk factor for graft loss. Lupus nephritis recurred in the graft of one patient 3 months after transplantation, and there were extrarenal manifestations of SLE in four others. CONCLUSIONS: The present study confirms that patients with SLE can receive transplants with excellent graft and patient survival rates and a low rate of clinical recurrent lupus nephritis.

Azevedo LS, Romão JE Jr, Malheiros D, Saldanha LB, Ianhez LE, Sabbaga E. University of São Paulo Medical School, SP, Brazil. Nephrol Dial Transplant. 1998 Nov;13(11):2894-8.

Renal transplantation in systemic lupus erythematosus. A case control study of 45 patients.

Forty-five patients with systemic lupus erythematosus subjected to 48 kidney transplants were studied. For comparative purposes, a case-control population was selected, matched for gender, race, type of donor, age, and time of transplantation. Patients with non-glomerulonephritis diseases were excluded.

RESULTS: No differences in acute episodes of rejection, causes of kidney loss or patient death were observed. General as well as infectious complications were similar. Pregnancy rates and outcomes were similar with no deleterious effect on patients or grafts. Actuarial 1- and 5-year patient survivals (97.7 and 91.1% for SLE and 95.4 and 87% for controls, respectively) and graft survivals (93.1 and 80.7% for SLE and 88.8 and 70.2% for controls, respectively) were similar. Long-term renal function expressed by serum creatinine was the same. No differences in immunosuppressive drug (azathioprine, prednisone, and cyclosporin) requirements were found. Clinical SLE recurrence was suspected only once (a patient with thrombocytopenia, hypocomplementaemia with low complement levels and positive antiplatelet antibodies). Two SLE patients showed mesangial proliferative glomerulonephritis compatible with recurrence. Both grafts were lost. Two further patients showed membranous glomerulonephritis with an immunofluorescence pattern



compatible with recurrence. A fifth patient had necrotizing arteritis which recovered after treatment with cyclophosphamide and another patient showed focal and segmental glomerulosclerosis. Histology of biopsies from five patients in the control group showed signs compatible with recurrence of focal and segmental glomerulosclerosis and membranous glomerulonephritis. There was a wide variation in serum levels of antinuclear antibodies. A wide variation in complement levels was also observed, but with a tendency towards low C4 levels. CONCLUSIONS: The safety of renal transplantation in SLE patients is equivalent to a matched case-control group with a similar rate of recurrence of disease.

Contreras G, Mattiazzi A, Guerra G, Ortega LM, Tozman EC, Li H, Tamariz L, Carvalho C, Kupin W, Ladino M, LeClercq B, Jaraba I, Carvalho D, Carles E, Roth D. Miller School of Medicine, University of Miami J Am Soc Nephrol. 2010 Jul;21(7):1200-7. Epub 2010 May 20.

Recurrence of lupus nephritis after kidney transplantation.

The frequency and outcome of recurrent lupus nephritis (RLN) among recipients of a kidney allograft vary among single-center reports. From the United Network for Organ Sharing files, we estimated the period prevalence and predictors of RLN in recipients who received a transplant between 1987 and 2006 and assessed the effects of RLN on allograft failure and recipients' survival.

Among 6850 recipients of a kidney allograft with systemic lupus erythematosus, 167 recipients had RLN, 1770 experienced rejection, and 4913 control subjects did not experience rejection. The period prevalence of RLN was 2.44%. Non-Hispanic black race, female gender, and age <33 years each independently increased the odds of RLN. Graft failure occurred in 156 (93%) of those with RLN, 1517 (86%) of those with rejection, and 923 (19%) of control subjects without rejection. Although recipients with RLN had a fourfold greater risk for graft failure compared with control subjects without rejection, only 7% of graft failure episodes were attributable to RLN compared and 43% to rejection. During follow-up, 867 (13%) recipients died: 27 (16%) in the RLN group, 313 (18%) in the rejection group, and 527 (11%) in the control group. In summary, severe RLN is uncommon in recipients of a kidney allograft, but black recipients, female recipient, and younger recipients are at increased risk. Although RLN significantly increases the risk for graft failure, it contributes far less than rejection to its overall incidence; therefore, these findings should not keep patients with lupus from seeking a kidney transplant.

Jakez-Ocampo J, Arreola-Zavala R, Richaud-Patin Y, Romero-Díaz J, Llorente L. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City J Clin Rheumatol. 2004

Lupus nephritis outcome with and without renal biopsy: a 5-year comparative study.

The no-biopsy group consisted of 30 patients with lupus with strong clinical and laboratory suspicion of proliferative glomerulonephritis in whom a renal biopsy was unavailable either because of medical contraindication or the patient's refusal. The biopsy group included 30 patients undergoing biopsy and a histologic diagnosis of DPGN. Patients were followed from the onset of nephritis and at 18, 36,

RESULTS: At onset, the no-biopsy group showed lower C3 levels and higher proteinuria, although both groups showed evident deterioration of the renal function. No significant differences were found in treatment, outcome, survival, renal function tests, or in the development of kidney failure. CONCLUSIONS: Proliferative glomerulonephritis deserves prompt diagnosis and treatment. This study demonstrates that experience in the management of lupus nephropathy, together with clinical and laboratory data, are often enough information to adequately treat proliferative glomerulonephritis even in the


Authors Title Description/Methods Results/Conclusions Dec;10(6):289-94. and 60 months. absence of a renal biopsy.

Nyberg G, Karlberg I, Svalander C, Hedman L, Blohmé I. Sahlgrenska Hospital, Göteborg, Sweden. Scand J Urol Nephrol. 1990;24(4):307-13.

Renal transplantation in patients with systemic lupus erythematosus: increased risk of early graft loss.

The outcome of primary renal transplantation in 31 SLE patients was evaluated in relation to two contemporary controls per patient, matched for age, sex and immunosuppressive therapy. The proportion of living donors was one third in both groups.

Patient survival did not differ, but graft survival at 6 and 12 months post transplantation was significantly reduced in SLE patients (p less than 0.001). When divided into groups using either azathioprine and steroids or combinations including cyclosporin A (14 and 17 SLE patients in each group), graft survival was significantly reduced for the azathioprine-treated SLE patients, 36% vs. 82% for their controls at one year. For cyclosporin-treated SLE patients, one-year graft survival was 59% vs. 85% for their controls, and 6 out of 17 grafts in the cyclosporin-treated group were lost within the first month vs. only 4 out of 34 controls. These differences were, however, not statistically different. Most failed grafts were lost from rejection, with a high proportion of acute vascular rejection, isolated or in combination with cellular rejection. There was no apparent association between rejection and HLA-matched or presence of HLA antibodies. Retransplantation was successful in 6 out of 7 cases. We conclude that SLE patients have an increased risk of early graft rejection, but that this may be overcome by more powerful immunosuppressive therapy.

el-Shahawy MA, Aswad S, Mendez RG, Bangsil R, Mendez R, Massry SG. University of Southern California School of MedicineAm J Nephrol. 1995;15(2):123-8.

Renal transplantation in systemic lupus erythematosus: a single-center experience with sixty-four cases.

The outcome of renal transplantation in 64 patients with end-stage renal disease (ESRD) secondary to lupus nephritis is the subject of this report. The patients were transplanted over a 150-month (12.5-year) period (between July 5, 1979, and January 30, 1992). The study population is predominantly made up of young females (mean age, 34.7 +/- 9 years, n = 54, 81.3%). Fifty-one transplants (79.7%) are cadaveric, and 13 (20.3%) are from living-related donors. Fifty-eight patients (90.6%) had primary (first) allografts, and 6 (9.4%) received a second allograft.

For all 64 patients combined, the 1-year graft and patient survival rates are 68.8 and 86.5%, respectively, whereas 5-year graft and patient survival rates are 60.9 and 85.9%, respectively. Patients whose immunosuppressive regimen was CsA-based had a 1-year graft survival of 71.5 versus 63.6% in the AZA group. However, this 7.9% difference did not reach statistical significance (p = 0.95). The 5-year graft survival of the CsA-based group was 69.1 versus 45.5% for the AZA group, p < 0.05. One-year patient survival was 77.3% for the AZA group and 92.9% for the CsA group, p < 0.05). The data show that patients with ESRD secondary to lupus nephritis can undergo renal transplantation with satisfactory outcome. Immunosuppression based upon CsA improves first-year patient and allograft survival by 15.6 and 7.9%. respectively.



Posttransplantation immunosuppression consisted of azathioprine and prednisone (AZA group, n = 22, 34.3%) or AZA, prednisone and cyclosporine (CsA group, n = 42, 65.6%).

GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Table 8. Summary of Commonly Used Medications’ Teratogenic Effects

PREGNANCY AND LUPUS NEPHRITIS

Treatment Pregnancy Category

Crosses Placenta?

Animal Studies

Human Studies

Cyclophosphamide D yes Teratogenic

Teratogenic effects have been reported in association with the use of cyclophosphamide. In general, alkylating agents when given during the first trimester are believed to cause slight increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth retriction (Glantz, 1994). In one case series of 4 patients treated with cyclophosphamide for lupus during pregnancy (2 during first trimester, 2 during 2nd trimester), all 4 resulted in pregnancy loss (Clowse Lupus 2005)

Azathioprine D

Yes (but fetal liver lacks enzyme which converts drug to active metabolites)

Teratogenic

Azathioprine has been used during pregnancy in organ transplant recipients. During over 40 years of experience with azathioprine as an immunosuppressant in organ transplant patients, no predominant or specific malformation pattern has been identified which is attributable to this drug. Retrospective review of pregnancy outcomes revealed that infants exposed to azathioprine may develop the following adverse effects: thymic atrophy, leukopenia, anemia, thrombocytopenia, chromosome aberrations, reduced immunoglobulin levels, and infections. Adjustment of azathioprine dosage to maintain normal maternal leukocyte counts may decrease or prevent neonatal leukopenia and thrombocytopenia (Armenti et al, 1998). Current guidelines regarding pregnant renal transplant patients state that immunosuppressive therapy with or without steroids and azathioprine may be continued during pregnancy (EBPG Expert Group on Renal Transplantation, 2002).

MMF D Unknown Teratogenic

The National Transplantation Pregnancy Registry (NTPR) reports 24 female kidney recipients with 33 pregnancies exposed to mycophenolate mofetil. There were 15 spontaneous abortions (45%) and 18 live births, with structural abnormalities were present in 4 of these 18 infants (22%). Based on postmarketing data collected by the NTPR from 1995 to 2007 among women (n=77) with systemic exposure to mycophenolate mofetil during pregnancy, spontaneous abortions occurred in 25 women and fetal/infant malformations occurred in 14 offspring. Ear abnormalities were present in 6 of the 14 malformed infants. With doses below equivalent human clinical doses, fetal resorptions and/or malformations in the absence of maternal toxicity have occurred in rats and rabbits (Prod Info CellCept(R) oral capsules, tablets,

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


Crosses Placenta?

Animal Studies

Human Studies

suspension, IV injection, 2009). Note that in 2007, the pregnancy category was changed from C to D because of the noted pattern of abnormalities

Leflunomide X Unknown Teratogenic

Leflunomide use is contraindicated in women who are or may become pregnant. Based on animal data, leflunomide may increase the risk of fetal death or teratogenic effects in pregnant women. Prior to initiation of leflunomide, pregnancy must be excluded and the use of reliable contraception must be confirmed. P Of 168 pregnant women evaluated as of January 2004 in a controlled, cohort study (OTIS Rheumatoid Arthritis in Pregnancy), women with rheumatoid arthritis (RA) exposed to leflunomide early in pregnancy (n=43) and those with RA not exposed to leflunomide during pregnancy (n=78) were a significant 12 times (95% confidence interval (CI) 2.5, 59.2) and a significant 10.1 times (95% CI 2.2, 47.3), respectively, more likely to deliver preterm infants compared with those in the non-diseased control group (n=47). The adjusted mean birth weight of full term infants was also significantly lower in the RA leflunomide group (3158 g, 95% CI 2979, 3336) and the RA control group (3250 g, 95% CI 3124, 3375) compared with the non-diseased control group (3618 g, 95% CI 3487, 3748; p less than 0.001). Overall, all groups had the same proportion of infants born with major and/or minor malformations (Chambers et al, 2004). However, in a follow-up study published in 2010, among 64 women who were exposed to leflunomide early in pregnancy, but stopped the drug and were treated with cholestyramine, there was no substantial increase in adverse pregnancy outcomes (Chambers Arthritis Rheum 2010).

Chlorambucil D Yes Teratogenic

Teratogenic effects have been reported in association with the use of chlorambucil. The teratogenic effects of chlorambucil may be potentiated by caffeine (Bermas & Hill, 1995). In general, alkylating agents, when given during the first trimester, are believed to cause slight increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth restriction (Glantz, 1994a)..

Tacrolimus C Yes

Retrospective case analysis: 100 pregnancies (84 women) 71 pregnancies progressed to delivery, resulting in 68 live births and 24 pregnancies that were spontaneously or electively aborted. Four of the 68 surviving neonates had congenital malformations, whereas none of the 24 aborted fetuses exhibited detectable malformations. Prematurity rate of 59% ;only 10% of the infants were outside of the 10th to 90th percentile range for birth weight when considering the gestational age of the neonate (Kainz et al, 2000).

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


Crosses Placenta?

Animal Studies

Human Studies

Cyclosporine C Yes No

In a study of 48 pregnant women being treated with therapeutic doses of cyclosporine, no evidence of direct hazard to the fetus was demonstrated. (Cockburn et al, 1989). No specific birth defect has been associated with CSA, although many sporadic congenital anomalies have been reported (Petri Autoimmunity 2003). In post-marketing surveillance of 166 pregnancies, 45% were pre-term, and the median birthweight was 2300 g (Arellano Med Clin 1991).

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


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Lupus Nephritis Evidence Report