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Annals of Medicine

ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20

Clinical usefulness of the Oxford classification indetermining immunosuppressive treatment in IgAnephropathy

Chang-Yun Yoon, Tae Ik Chang, Ea Wha Kang, Beom Jin Lim, Jeong Hae Kie,Youn Kyung Kee, Hyoungnae Kim, Seohyun Park, Hae-Ryong Yun, Su-YoungJung, Jong Hyun Jhee, Young Eun Kwon, Hyung Jung Oh, Jung Tak Park, Tae-Hyun Yoo, Shin-Wook Kang, Hyeon Joo Jeong & Seung Hyeok Han

To cite this article: Chang-Yun Yoon, Tae Ik Chang, Ea Wha Kang, Beom Jin Lim, Jeong HaeKie, Youn Kyung Kee, Hyoungnae Kim, Seohyun Park, Hae-Ryong Yun, Su-Young Jung, JongHyun Jhee, Young Eun Kwon, Hyung Jung Oh, Jung Tak Park, Tae-Hyun Yoo, Shin-Wook Kang,Hyeon Joo Jeong & Seung Hyeok Han (2016): Clinical usefulness of the Oxford classificationin determining immunosuppressive treatment in IgA nephropathy, Annals of Medicine, DOI:10.1080/07853890.2016.1252058

To link to this article: http://dx.doi.org/10.1080/07853890.2016.1252058

View supplementary material Accepted author version posted online: 21Oct 2016.Published online: 29 Nov 2016.

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ORIGINAL ARTICLE

Clinical usefulness of the Oxford classification in determiningimmunosuppressive treatment in IgA nephropathy

Chang-Yun Yoona, Tae Ik Changb, Ea Wha Kangb, Beom Jin Limc, Jeong Hae Kied, Youn Kyung Keea,Hyoungnae Kima, Seohyun Parka, Hae-Ryong Yuna, Su-Young Junga, Jong Hyun Jheea, Young Eun Kwone,Hyung Jung Ohf, Jung Tak Parka, Tae-Hyun Yooa, Shin-Wook Kanga, Hyeon Joo Jeongc andSeung Hyeok Hana

aDepartment of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic ofKorea; bDivision of Nephrology, Department of Internal Medicine, National Health Insurance Service Medical Center, Ilsan Hospital,Goyang, Gyeonggi-do, Republic of Korea; cDepartment of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea;dDepartment of Pathology, National Health Insurance Corporation Ilsan Hospital, Goyang, Republic of Korea; eDivision of Nephrology,Department of Internal Medicine, Myongji Hospital, Seonam University College of Medicine, Goyang, Gyeonggi-do, Republic of Korea;fEwha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Republic of Korea

ABSTRACTBackground: The Oxford classification has been widely used in IgA nephropathy. However, itsclinical usefulness of determining immunosuppression is unknown.Aim: Whether the Oxford classification could predict the development of proteinuria �1 g/g Crand worsening kidney function, as well as the clinical efficacy of corticosteroid treatment accord-ing to each histologic variable of the Oxford-MEST.Methods: We included 377 patients with early-stage IgA nephropathy. The study endpointswere the development of a heavy proteinuria and a decline renal function.Results: The results showed that among the Oxford-MEST lesions, only M1 predicted the risk ofthe development of proteinuria �1.0g/g Cr compared to other lesions in a time-varying Coxmodel adjusted for multiple confounding factors. In addition, the risk of reaching a 30% declinein eGFR was significantly higher in patients with M1 than in those with M0. Furthermore,patients with M1 had a greater decline of eGFR than patients with M0. However, steroid treat-ment in M1 lesion was not associated with improving clinical outcomes in the unmatched andpropensity score matched cohort.Conclusions: This finding may provide a rationale for using the Oxford classification as a guid-ance to initiate immunosuppression in the early stages of IgA nephropathy.

KEY MESSAGES� M1 has independently predictive role among the Oxford lesions in IgA nephropathy.� Oxford classification should be defined during pathologic approach.� Decision of starting immunosuppression according to the Oxford lesions.

ARTICLE HISTORYReceived 22 July 2016Revised 12 October 2016Accepted 18 October 2016Published online 28 Novem-ber 2016

KEYWORDSIgA nephropathy; Oxfordclassification; proteinuria;glucocorticoid treatment

Introduction

Primary IgA nephropathy (IgAN) is the most commontype of glomerulonephritis worldwide, and its inci-dence is particularly higher in Asia than in NorthAmerica or Europe (1). As glomerulonephritis is thethird most common cause of end-stage renal disease(ESRD), and given the devastating medical and socio-economic burdens in patients with chronic kidney dis-ease, diverse therapeutic options should be consideredto slow the progression of kidney disease (2–4).

Several therapeutic strategies, such as inhibition ofthe renin-angiotensin-aldosterone system, strict

control of blood pressure, low protein intake (5), anddyslipidemia regulation (6), have been used in the man-agement of IgAN. However, these treatments are gener-ally effective in the early stages of IgAN, and theirclinical efficacy in the advanced stages is yet unproven.In fact, IgAN often progresses despite the maximal useof renin-angiotensin system blockade (RASB), alone orin combination with other strategies to reduce protein-uria. The 2012 Kidney Disease: Improving GlobalOutcomes (KDIGO) guidelines suggest a 6-month courseof glucocorticoid treatment in patients with persistentlyelevated urinary protein excretion (�1 g/day) despite

CONTACT Seung Hyeok Han hansh@yuhs.ac Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, YonseiUniversity, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea

Supplemental data for this article can be accessed here

� 2016 Informa UK Limited, trading as Taylor & Francis Group

ANNALS OF MEDICINE, 2016http://dx.doi.org/10.1080/07853890.2016.1252058

3–6 months of proper supportive care, and with pre-served kidney function with an estimated glomerular fil-tration rate (eGFR) of �50ml/min/1.73m2 (7). However,findings from previous randomized controlled trials thatexamined the effect of glucocorticoids have yieldedinconclusive results (8–10); thus, the suggestion by theKDIGO guideline is not confirmative. In clinical practice,the use of glucocorticoids is generally determined byusing clinical biomarkers such as declining kidney func-tion and increasing proteinuria. Moreover, whetherpathologic classification systems can aid in determiningimmunosuppression is currently unknown.

Recently, the Oxford classification was proposed bythe Working Group of the International IgANephropathy Network and the Renal Pathology Society(11,12), and has been validated through several studies(13–22). This classification identified four pathologicalcomponents: mesangial hypercellularity (M1), endoca-pillary proliferation (E1), segmental glomerulosclerosis/adhesion (S1), and tubular atrophy/interstitial fibrosis(T1 or T2). Of note, this classification aids in predictingpatient outcome (11,12). In line with these studies, wepreviously reported that adding the Oxford classifica-tion to clinical parameters increased the predictabilityfor doubling of the baseline serum creatinine (Cr) lev-els and ESRD (23). Interestingly, a recent study rev-ealed that M1 at biopsy provided a comparableprediction of adverse outcomes to clinical data meas-ured at 2 years, suggesting a potential role of thiscomponent in early risk stratification (21). However,this study examined a 50% reduction in eGFR or ESRDas a study outcome, which develops long after protein-uria appears. From a therapeutic perspective, it wouldbe interesting to investigate which components of theOxford-MEST can predict the development of signifi-cant proteinuria because immunosuppression is gener-ally effective in patients with moderate urinary proteinexcretion and preserved kidney function. Currently, itis unknown whether this classification can aid in thedecision concerning the use of immunosuppression.Thus, we investigated whether individual componentsof the Oxford-MEST could predict the development ofproteinuria (�1.0 g/g Cr) and the progression of kidneydisease in patients with low-grade proteinuria (<1.0 g/g Cr) and early-stage IgAN. We further examined theclinical effectiveness of glucocorticoid treatmentaccording to the Oxford classification.

Materials and methods

Ethics statement

The study was performed in accordance with theDeclaration of Helsinki and approved by the

Institutional Review Board (IRB) of the YonseiUniversity Health System (YUHS) Clinical Trial Center.Although all patients in this study were informedabout the description of investigations, this was con-ducted as a medical record-based retrospective ana-lysis, and the included subjects were anonymized.Therefore, the IRB approved the exemption fromobtaining written consent.

Study participants

We conducted an observational study in 623 patientswith biopsy-proven IgAN between January 2005 andDecember 2014 from the YUHS and National HealthInsurance Service Ilsan Hospital. A flow diagram ofdepicting selection of the participants is presented inFigure 1. We excluded 246 patients who met the fol-lowing criteria: (1) age<18 or>75 years; (2) missingdata during follow-up; (3) history of kidney transplant-ation; 4) eGFR<50ml/min/1.73m2; (5) nephrotic-rangeproteinuria (�3.5 g/g Cr); (6) persistent proteinuria atbiopsy, defined as random urine protein-to-Cr ratio(UPCR)> 1.0 g/g Cr on three consecutive measure-ments; (7) Henoch–Sch€onlein purpura; (8) rapidly pro-gressive glomerulonephritis; or (9) severe fibrosisclassified as T2 in the Oxford-MEST. If laboratory testswere done within 1 month prior to biopsy, these wereconsidered the first measurement. Twenty-seven(7.2%) patients had a single measurement of UPCR�1.0 g/g Cr at or before the time of biopsy and pro-teinuria decreased to<1.0 g/g Cr on two subsequenttests in these patients. These patients were consideredto have transiently elevated proteinuria, and thus wereincluded in the analysis. Therefore, a total of 377 IgANpatients were included for the primary analysis. In thesecondary analysis to examine the effects of glucocor-ticoids, 181 patients with UPCR<1.0 g/g Cr and/or sta-ble kidney function during follow-up were additionallyexcluded (Figure 1). These patients were unlikely torequire glucocorticoids treatment. We generally fol-lowed the glucocorticoid protocol suggested by Pozziet al. (24,25). Glucocorticoid users were defined aspatients who received glucocorticoids for �3 months.The use of RASB was defined as more than 90 days’prescription of RASB during the follow-up period.

Clinical, biochemical, and histologic datacollection

By using the database from the GlomerulonephritisRegistry of the two medical centers, demographic, clin-ical, and biochemical data at the time of renal biopsy,including age, sex, blood pressure, and body mass

2 C.-Y. YOON ET AL.

index, were retrieved and considered baseline data.Body mass index was calculated as weight/height2

(kg/m2). The following biochemical laboratory datawere also collected: blood urea nitrogen, serum Cr,UPCR, serum IgA, hemoglobin, fasting blood glucose,serum albumin, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and high sensitivity C-reactive protein (hs-CRP). The eGFR was calculated byusing the chronic kidney disease epidemiology collab-oration equation (26). Serum total cholesterol, HDL-C,LDL-C, and triglyceride levels were measured throughenzymatic colorimetry with an autoanalyzer (Hitachi7150; Hitachi Ltd., Tokyo, Japan), and hs-CRP levelswere determined through a latex-enhanced immuno-nephelometric method by using a BNII analyzer (DadeBehring, Newark, DE). All renal biopsy specimens werereassessed by one pathologist blinded to the patients’clinical data, according to the Oxford classification.

Follow-up and endpoints

Follow-up data were recorded at 3-month intervals.The study endpoints were the development of persist-ent UPCR �1 g/g Cr and the onset of a 30% decline ineGFR during follow-up. These were defined as a sus-tained increase in UPCR �1 g/g Cr and a sustaineddecrease in eGFR>30% for at least three consecutivemeasurements. The first of these consecutive

measurements was retrospectively designated to bethe study endpoint.

Statistical analysis

Continuous variables are presented as means and SDfor data with a normal distribution, or median withinterquartile range for data with a skewed distribution.Categorical variables were expressed as counts andpercentages. The normality of distribution was ascer-tained with the Kolmogorov–Smirnov test. To comparedifferences between Oxford classifications, Student’st-test or the Mann–Whitney U test was used for con-tinuous variables, and the chi-square test or Fisher’sexact test was used for categorical variables. Thecumulative renal survival rates were estimated withKaplan–Meier analysis and a log-rank test. Survivaltime was defined as the interval between the time ofbiopsy and the onset of the endpoint or last follow-up. Cox proportional hazard models were constructedto determine the association between the Oxford-MEST and the development of UPCR �1 g/g Cr or a30% decline in eGFR. Because proteinuria, blood pres-sure, and eGFR were highly variable during follow-up,these variables were modeled as time-varying covari-ates (27,28) by using data measured at 3-month inter-vals. We further analyzed whether glucocorticoidtreatment could reduce proteinuria and improve kid-ney function, through propensity score (PS) matching.

Figure 1. Flow diagram of the study. Abbreviation: eGFR: estimated glomerular filtration rate; UPCR: urine protein-to-creatinineratio.

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All results are expressed as the hazard ratio (HR) and95% confidence interval (CI). To determine the predict-ability of each component of the Oxford-MEST for thedevelopment of persistent proteinuria, C-statistics withHarrell’s C-index of each Cox model was performed.The PS for the steroid nonuser or user has been drawnby using multiple logistic regression analysis withoutconsidering outcome. All available covariates wereused for present model. Using the Greedy 5–1 digitmatch algorithm, we constructed PS-matched pairswithout replacement (a 1:1 match) (29,30). To be moreconcrete, each subject in the steroid user group wasmatched to an individual in the steroid nonuser groupwho had a PS that was identical to 5 digits. If thiscould not be done, we then proceeded sequentially tothe next highest digit match (a 4-, 3-, 2-, or 1-digitmatch) on PS to make “next-best” matches. After all PSmatches were created, we evaluated the balance ofbaseline covariates between the two groups by usingpaired t-test or Mann–Whitney U test for continuousvariables, and McNemar test for categorical variables.Statistical analyses were performed with SPSS forWindows version 23.0 (IBM Corp., Armonk, NY) andSAS version 9.2 (SAS Inc., Cary, NC). A p value<.05was considered significant.

Results

Baseline characteristics

The baseline characteristics of the study subjects arepresented in Tables 1 and 2. Their mean age was38.5 ± 13.0 years, and 182 (47.9%) were men. Among377 patients, 74 (19.6%), 85 (22.5%), 231 (61.3%), and

40 (10.6%) were classified as having M1, E1, S1, and T1pathologic lesions according to the Oxford classifica-tion, respectively. The mean eGFR was 106.4 ± 40.4ml/min/1.73m2, and the median UPCR was 0.56(0.33–0.77) g/g Cr. At baseline, eGFR was significantlylower in patients with M1 (97.6 ± 35.7 versus109.0 ± 41.1ml/min/1.73m2, p¼ .03), S1 (103.4 ± 35.9versus 112.0 ± 46.2ml/min/1.73m2, p¼ .04), and T1(87.2 ± 37.6 versus 109.1 ± 40.1ml/min/1.73m2, p¼ .01)than in patients without these components, whereasUPCR was significantly higher across all the Oxford-MEST lesions [M, 0.67 (0.38–0.82) versus 0.54(0.31–0.75) g/g Cr, p¼ .01; E, 0.65 (0.48–0.82) versus0.53 (0.30–0.74) g/g Cr, p¼ .01; S, 0.62 (0.39–0.81) ver-sus 0.46 (0.18–0.70) g/g Cr, p< .001; T, 0.68 (0.41–0.86)versus 0.55 (0.31–0.76) g/g Cr, p¼ .01]. Patientswith T1 were significantly older and had higher meanarterial pressure (MAP) than those with T0 (Tables 1and 2).

M1 is an independent predictor for thedevelopment of persistent proteinuria inearly-stage IgAN

During a median follow-up duration of 43.5 (17.6–68.9)months, persistent proteinuria>1.0 g/g Cr occurred in48 (12.7%) patients. In these patients, the mean dur-ation until UPCR of �1 g/g Cr was 43.6 ± 33.8 months.There were 21 (28.4%, p< .001), 13 (15.3%, p¼ .42), 33(14.3%, p¼ .26), and 12 (30.0%, p¼ .01) patients withM1, E1, S1, and T1 who developed persistent protein-uria, as compared with 27 (8.9%), 35 (15.3%), 15(10.3%), and 36 (10.7%) patients with M0, E0, S0, and

Table 1. Baseline characteristics according to the Oxford classification (M and E, n¼ 377).Variables M0 (n¼ 303, 80.4%) M1 (n¼ 74, 19.6%) p E0 (n¼ 292, 77.5%) E1 (n¼ 85, 22.5%) p

Age (years) 38.7 ± 13.0 37.6 ± 12.9 .52 38.3 ± 12.7 38.8 ± 14.0 .76Sex (male, %) 143 (57.2) 37 (50.0) .67 141 (48.3) 39 (45.9) .70MAP (mmHg) 91.2 ± 12.0 91.0 ± 13.1 .88 91.2 ± 12.2 90.9 ± 12.5 .83Body mass index (kg/m2) 23.0 ± 3.6 22.5 ± 3.7 .42 22.8 ± 3.5 23.4 ± 4.0 .23Hypertension (%) 45 (17.4) 29 (24.4) .12 54 (20.9) 31 (26.1) .27BUN (mg/dl) 13.7 ± 4.4 14.7 ± 5.0 .15 13.8 ± 4.5 14.4 ± 4.5 .25Creatinine (mg/dl) 0.86 ± 0.24 0.96 ± 0.27 .01 0.87 ± 0.23 0.92 ± 0.29 .09eGFR (ml/min/1.73 m2) 109.0 ± 41.1 97.6 ± 35.7 .03 108.7 ± 41.9 100.2 ± 33.6 .09UPCR (g/g Cr) 0.54 (0.31–0.75) 0.67 (0.38–0.82) .01a 0.53 (0.30–0.74) 0.65 (0.48–0.82) .01a

RASB (%) 224 (73.9) 68 (91.9) .01 211 (72.3) 77 (90.6) .01IgA (mg/dl) 323.3 ± 114.3 338.9 ± 111.5 .48 328.4 ± 115.1 319.0 ± 111.0 .59Hemoglobin (g/dl) 13.2 ± 1.6 13.1 ± 1.6 .78 13.2 ± 1.6 13.1 ± 1.5 .66Glucose (mg/dl) 95.1 ± 12.7 93.6 ± 10.7 .48 95.2 ± 13.0 93.6 ± 10.3 .35Serum albumin (g/dl) 4.1 ± 0.4 4.0 ± 0.4 .06 4.1 ± 0.4 3.9 ± 0.4 .01Cholesterol (mg/dl) 184.5 ± 37.9 188.9 ± 36.5 .39 182.1 ± 35.6 196.2 ± 42.1 .01Triglyceride (mg/dl) 96 (69–148) 104 (79–163) .23a 94 (70–147) 108 (74–167) .25a

HDL-C (mg/dl) 52.4 ± 14.0 57.5 ± 17.6 .13 52.3 ± 13.8 55.1 ± 16.2 .25LDL-C (mg/dl) 114.0 ± 32.6 111.7 ± 30.2 .73 109.4 ± 30.5 123.9 ± 34.0 .01hs-CRP (mg/L) 1.27 (0.34–4.50) 1.30 (0.45–4.59) .77a 1.12 (0.10–2.87) 2.12 (0.93–5.58) .03a

Note: Variables are expressed as median (range), mean ± SD, or n (%); aMann–Whitney U test.Abbreviations: MAP: mean arterial pressure; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; UPCR: urine protein-to-creatinine ratio;RASB: renin-angiotensin system blockade; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; hs-CRP: high sensitivityC-reactive protein.

4 C.-Y. YOON ET AL.

T0, respectively. Kaplan–Meier plots also showed thatthe time to the development of persistent proteinuriawas significantly shorter in patients with M1 (p< .001),S1 (p¼ .03), and T1 (p¼ .01) (Figure 2). The timecourse of UPCR at every 6-month follow-up accordingto each component of the Oxford classification isshown in Figure 3. To investigate the associationbetween each component of the Oxford-MEST andpersistent proteinuria, time-varying Cox models wereconstructed. The unadjusted HRs (95% CIs) for eachMEST were 3.039 (1.69–5.48, p< .001), 1.577(0.83–3.02, p¼ .17), 1.995 (1.05–3.79, p¼ .03), and2.241 (1.15–4.36, p¼ .02). In a multivariable Cox modelwith proteinuria, blood pressure, and eGFR being usedas time-varying covariates, M1 was significantly associ-ated with an increased risk of developing persistentproteinuria (HR, 2.643; 95% CI: 2.22–3.15; p< .001)after adjustment for age, sex, MAP, UPCR, and eGFR,whereas E, S, and T lesions failed to predict this end-point. When all four components were entered intothe model, only M1 remained a significant predictor ofpersistent proteinuria (HR, 2.381; 95% CI: 1.98–2.87;p< .001, Table 3).

We validated these findings by performing a sub-group analysis excluding patients who had transientlyelevated proteinuria of at the time of biopsy. Therewere 27 (7.2%) patients whose proteinuria of>1.0 g/gCr at the time of biopsy but declined<1.0 g/g Cr attwo subsequent measurements. In the same analysisexcluding these patients, M1 was significantly associ-ated with the development of persistent proteinuriaof>1.0 g/g Cr [HR 2.596, 95% CI (1.16–5.80), p¼ .02,Supplementary Table S1].

To assess the predictive power of the Oxford-MESTfor persistent proteinuria, Harrell’s C-index for eachCox model (Table 4) was determined. The C-statisticsof a model with M was 0.703 (95% CI: 0.62–0.79) ascompared with those of models with E (0.666; 95% CI:0.57–0.76; p¼ .02), S (0.663; 95% CI: 0.57–0.75; p¼ .01),and T (0.665; 95% CI: 0.57–0.75; p¼ .03). Receiver oper-ating characteristics analysis for the Oxford-MESTrevealed that the area under the curve for a modelwith M was significantly larger than those for E, S, andT lesions (M, 0.749; E, 0.684; S, 0.685; T, 0.650; p¼ .04;Figure 4).

M1 is significantly associated with kidney diseaseprogression

Next, we evaluated whether the Oxford-MEST couldpredict the progression of kidney disease in the earlystages of IgAN. During follow-up, 52 (13.8%) patientsreached a 30% decline in eGFR. Because we includedpatients with early-stage IgAN and preserved kidneyfunction, no patient developed ESRD before reachinga 30% decline in eGFR. Moreover, no cases of deathoccurred during follow-up. A 30% decline in eGFR wasreached more frequently in patients with M1 (18.9%)than in those with M0 (12.5%) (p¼ .15). In a multivari-able analysis adjusted for age, sex, MAP, eGFR, UPCR,RASB, and glucocorticoid treatment, M1 conferred a3.5-fold increased risk of reaching a 30% decline ineGFR (HR, 3.546; 95% CI: 1.19–10.58; p¼ .02, Table 5)compared with M0. There was no significant differencein the development of a 30% decline in eGFR betweenpatients with E1, S1, and T1 and those without these

Table 2. Baseline characteristics according to the Oxford classification (S and T, n¼ 377).Variables S0 (n¼ 146, 38.7%) S1 (n¼ 231, 61.3%) p T0 (n¼ 337, 89.4%) T1 (n¼ 40, 10.6%) p

Age (years) 38.0 ± 13.8 38.7 ± 12.5 .61 37.8 ± 12.9 44.1 ± 12.5 .01Sex (male, %) 75 (51.4) 105 (45.5) .26 155 (46.0) 25 (62.5) .05MAP (mmHg) 90.4 ± 12.2 91.7 ± 12.2 .32 90.6 ± 12.0 96.2 ± 13.3 .01Body mass index (kg/m2) 22.5 ± 3.7 23.1 ± 3.6 .21 22.8 ± 3.7 24.1 ± 3.1 .18Hypertension (%) 145 (56.2) 86 (72.3) .01 25 (9.7) 15 (12.6) .39BUN (mg/dl) 13.5 ± 4.9 14.2 ± 4.3 .19 13.5 ± 4.0 17.3 ± 6.8 .01Creatinine (mg/dl) 0.86 ± 0.24 0.89 ± 0.25 .22 0.86 ± 0.23 1.06 ± 0.29 <.001eGFR (ml/min/1.73 m2) 112.0 ± 46.2 103.4 ± 35.9 .04 109.1 ± 40.1 87.2 ± 37.6 .01UPCR (g/g Cr) 0.46 (0.18–0.70) 0.62 (0.39–0.81) <.001a 0.55 (0.31–0.76) 0.68 (0.41–0.86) .01a

RASB total (%) 94 (64.4) 191 (82.7) .01 254 (75.4) 40 (100.0) .03b

IgA (mg/dl) 300.8 ± 116.2 336.7 ± 111.2 .04 322.3 ± 113.5 397.8 ± 97.4 .05Hemoglobin (g/dl) 13.3 ± 1.6 13.1 ± 1.6 .56 13.2 ± 1.6 13.3 ± 1.8 .70Glucose (mg/dl) 97.3 ± 16.7 93.7 ± 9.7 .03 94.4 ± 11.9 101.7 ± 18.4 .15Serum albumin (g/dl) 4.1 ± 0.5 4.0 ± 0.4 .01 4.0 ± 0.4 4.0 ± 0.4 .26Cholesterol (mg/dl) 177.6 ± 35.4 190.2 ± 38.3 .01 184.0 ± 36.9 197.5 ± 42.4 .04Triglyceride (mg/dl) 98 (65–139) 97 (74–154) .16a 95 (70–147) 136 (75–225) .07a

HDL-C (mg/dl) 50.5 ± 12.9 54.2 ± 15.2 .12 52.9 ± 14.4 55.6 ± 16.8 .52LDL-C (mg/dl) 106.0 ± 28.9 117.1 ± 33.0 .03 113.8 ± 32.2 112.1 ± 32.6 .86hs-CRP (mg/L) 1.20 (0.10–4.24) 1.34 (0.45–4.55) .71a 1.24 (0.38–4.31) 2.08 (0.75–16.30) .32a

Note: Variables are expressed as median (range), mean ± SD, or n (%); aMann–Whitney U test, bFisher’s exact test.Abbreviations: MAP: mean arterial pressure; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; UPCR: urine protein-to-creatinine ratio;RASB: renin-angiotensin system blockade; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; hs-CRP: high sensitivityC-reactive protein.

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components. Furthermore, patients with M1 had agreater eGFR decline than those with M0 (�1.68 ± 0.91versus �0.73 ± 0.92ml/min/1.73m2/year, p< .001; datanot shown). We also constructed similar analysis innonsteroid user group, but the results showed similarfindings (M1, p¼ .03; E1, p¼ .54; S1, p¼ .11; T1,p¼ .9).

Glucocorticoid treatment reduced proteinuria butdid not prevent kidney disease progression inIgAN patients with M1

Because the current guideline suggests the use of glu-cocorticoids in patients with proteinuria>1.0 g/day,and we found that M1 predicted the development ofpersistent proteinuria better than E1, S1, and T1lesions, we further analyzed whether glucocorticoidscould attenuate the progression of kidney disease inpatients with M1. Because this study only includedearly IgAN subjects, and nephrotic syndrome or severe

IgAN such as RPGN or T2 lesion were initially excluded,there were no patients receiving immunosuppressiveagent including cyclophosphamide or cyclosporine. Atotal 67 (17.8%) patients received any steroid therapyin present analysis. Among them, seven patientsstopped earlier before 3 months of treatment durationdue to non-compliance or side effects. Excluding thesepatients, there were 21 (28.4%), 24 (28.2%), 50 (21.7%),and 14 (35.0%) patients with M1, E1, S1, and T1,respectively, who were treated with steroid therapy>3months.

Among 74 (19.6%) patients with M1, 16 (21.6%)patients were excluded from this second analysisbecause these patients maintained UPCR levels of<1.0 g/g Cr and stable kidney function throughout thestudy. The remaining 58 (78.4%) M1 patients devel-oped persistent increased UPCR of >1.0 g/g Cr duringfollow-up. Of these patients, 21 (36.2%) were treatedwith glucocorticoids. The mean duration from the timepoint of UPCR of >1.0 g/g Cr to initiation of steroid

Figure 2. Kaplan–Meier plots for the development of persistent proteinuria according to the Oxford-MEST.

6 C.-Y. YOON ET AL.

treatment was 5.7 ± 3.2 months. Because we generallyfollowed the 6-month glucocorticoid treatment proto-col of Pozzi et al. (24,25), we compared the differencein proteinuria during the 6-month treatment period.Glucocorticoid administration significantly reducedproteinuria from 1.71 to 0.69 g/g Cr in 21 glucocortic-oid users (p< .001; Figure 5(A)). Maximal supportivecare without glucocorticoid decreased proteinuria, butit did not reach statistical significance (Figure 5(B)). Wealso evaluated renal outcome between glucocorticoidusers and nonusers in 58 patients with M1 who hadpersistent proteinuria. There were significant differen-ces in baseline characteristics between the two groups.To minimize biased results caused by these

unbalanced baseline characteristics, 1:1 PS matchingwas applied. PS matching yielded 18 matched pairs ofpatients. As a result, the baseline characteristics werewell balanced between glucocorticoid users and non-users (Table 6). In the unmatched cohort, there was nodifference in the development of a 30% decline ineGFR with various Cox models. Similarly, in thematched cohort, glucocorticoid use was notassociated with a decreased risk of reaching a 30%

Figure 3. Time course of UPCR according to Oxford classification. Each point was demonstrated as the mean values with standarderrors of UPCR on every 6-month follow-up. Abbreviation: UPCR: urine protein-to-creatinine ratio.

Table 3. Cox regression model with time-dependent covari-ates for the association of Oxford classification with develop-ment of persistent proteinuria (n¼ 377).M1 lesion HR (95% CI) p

Crude 3.039 (1.69–5.48) <.001Adjusted

Model 1a 2.643 (2.22–3.15) <.001Model 2b 2.381 (1.98–2.87) <.001

aModel 1: adjusted for age, sex, MAP, UPCR, and eGFR.bModel 2: adjusted for age, sex, MAP, UPCR, eGFR, E, S, and T.Abbreviations: HR: hazard ratio; CI: confidence interval; MAP: mean arterialpressure; UPCR: urine protein-to-creatinine ratio; eGFR: estimated glom-erular filtration rate.

Table 4. C-Statistics for prediction of the development of per-sistent proteinuria using multivariate Cox’s regression models.

p for difference of C-statisticscompared with models

Model C-statistics (95% CI) Model 1a Model 2b Model 3c

Model 1a 0.703 (0.616–0.791) NA – –Model 2b 0.666 (0.574–0.758) 0.02 NA –Model 3c 0.663 (0.571–0.754) 0.01 0.52 NAModel 4d 0.665 (0.574–0.756) 0.03 0.61 0.11aModel 1: Age, sex, MAP, UPCR, eGFR, RASB, glucocorticoid treatment,and M.bModel 2: Age, sex, MAP, UPCR, eGFR, RASB, glucocorticoid treatment,and E.

cModel 3: Age, sex, MAP, UPCR, eGFR, RASB, glucocorticoid treatment,and S.dModel 4: Age, sex, MAP, UPCR, eGFR, RASB, glucocorticoid treatment,and T.Abbreviations: CI: confidence interval; NA: not applicable; MAP: meanarterial pressure; UPCR: urine protein-to-creatinine ratio; eGFR: estimatedglomerular filtration rate; RASB: renin-angiotensin system blockade.

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decline in eGFR and the rates of decline in eGFR didnot differ between two groups (HR, 2.360; 95% CI:0.63–8.78; p¼ .20; Table 7, Figure 6(A,B)). Althoughglucocorticoid treatment initially reduced proteinuria,proteinuria level slightly increased after discontinu-ation of this drug, and the overall proteinuria levelbecame similar between two groups during follow-upperiod (Figure 6(C)). We also performed similar analy-ses for E, S, and T scores to evaluate the effect ofglucocorticoid treatment on kidney disease progres-sion, but significant associations were not observed for

Figure 5. The changes in UPCR after 6 months with (A) and without (B) glucocorticoids treatment. Abbreviation: UPCR: urine pro-tein-to-creatinine ratio.

Table 6. Baseline characteristics in the unmatched and matched cohort according to glucocorticoids treatment.Unmatched M1 (n¼ 58) Matched M1 (n¼ 36)

Variables Nonuser (n¼ 37, 63.8%) User (n¼ 21, 36.2%) p Nonuser (n¼ 18, 50.0%) User (n¼ 18, 50.0%) p

Age (years) 40.5 ± 12.3 41.3 ± 13.0 .84 41.3 ± 12.0 41.4 ± 13.9 .9Sex (male, %) 17 (46.0) 11 (52.4) .43 8 (44.4) 9 (50.0) .74MAP (mmHg) 92.4 ± 13.8 93.4 ± 14.1 .82 96.1 ± 14.5 91.7 ± 14.6 .37Creatinine (mg/dl) 0.91 ± 0.26 1.16 ± 0.26 .01 1.11 ± 0.30 1.13 ± 0.28 .80eGFR (ml/min/1.73 m2) 98.8 ± 37.2 72.7 ± 22.1 .01 76.7 ± 25.6 75.5 ± 26.2 .89UPCR (g/g Cr) 1.69 (1.33–2.09) 2.29 (1.34–2.74) .11a 1.42 (0.58–2.08) 1.65 (0.71–2.64) .28a

IgA (mg/dl) 355.9 ± 87.0 317.2 ± 84.6 .34 343.1 ± 88.9 325.2 ± 89.5 .51Hemoglobin (g/dl) 13.2 ± 1.8 12.6 ± 1.4 .38 12.8 ± 1.9 12.7 ± 1.6 .39Serum albumin (g/dl) 3.9 ± 0.3 3.7 ± 0.5 .16 3.8 ± 0.4 3.7 ± 0.5 .45Cholesterol (mg/dl) 203.7 ± 40.0 204.3 ± 31.8 .9 201.5 ± 44.7 205.1 ± 34.1 .9hs-CRP (mg/L) 1.34 (0.47–16.37) 2.89 (1.15–48.50) .52a 2.34 (0.98–24.65) 2.84 (1.66–39.10) .73a

Note: Variables are expressed as median (range), mean ± SD, or n (%); aMann–Whitney U test.Abbreviations: MAP: mean arterial pressure; eGFR: estimated glomerular filtration rate; UPCR: urine protein-to-creatinine ratio; hs-CRP: high sensitivityC-reactive protein.

Table 7. Cox proportional hazard analysis for the effect ofglucocorticoid treatment on a 30% decline in eGFR with theunmatched and matched M1 cohort.

Unmatched M1 (n¼ 58) Matched M1 (n¼ 36)

HR (95% CI) p HR (95% CI) p

Crude 2.604 (0.82–8.24) .10 2.006 (0.58–6.90) .27Model 1a 3.081 (0.94–8.10) .06 1.992 (0.57–6.96) .28Model 2b 1.177 (0.35–4.01) .79 2.216 (0.64–7.73) .21Model 3c 2.551 (0.78–8.37) .12 1.932 (0.55–6.78) .30aModel 1: adjusted for glucocorticoid treatment, age, and sex.bModel 2: adjusted for glucocorticoid treatment, RASB, and eGFR.cModel 3: adjusted for glucocorticoid treatment, UPCR, and MAP.Abbreviations: eGFR: estimated glomerular filtration rate; HR: hazard ratio;CI: confidence interval; RASB: renin-angiotensin system blockade; UPCR:urine protein-to-creatinine ratio; MAP: mean arterial pressure.

Figure 4. Receiver operating characteristics curve for thedevelopment of persistent proteinuria by the Oxford-MEST.

Table 5. Cox proportional hazard regression analysis for theassociation of Oxford classification with a 30% decline ineGFR (n¼ 377).M1 Hazard ratio (95% CI) p

Crude 1.250 (0.676–2.314) .48Adjusteda 3.546 (1.189–10.576) .02aModel was adjusted for age, sex, MAP, eGFR, UPCR, RASB, and gluco-corticoid treatment.Abbreviations: CI: confidence interval; eGFR: estimated glomerular filtra-tion rate; MAP: mean arterial pressure; UPCR: urine protein-to-creatinineratio; RASB: renin-angiotensin system blockade.

8 C.-Y. YOON ET AL.

these scores in all models (Supplementary Table S2).These results were similar in matched models (datanot shown).

Discussion

We investigated which components of the Oxford-MEST can predict the development of persistent pro-teinuria in the early stages of IgAN, and whetherpathologic classification can aid in determining theuse of glucocorticoids. We showed that the M1 com-ponent of the Oxford classification was significantlyassociated with the development of persistent protein-uria and predicted the progression of kidney diseasein patients with IgAN. Furthermore, glucocorticoidadministration reduced proteinuria in patients with M1and UPCR �1.0 g/g Cr. However, immunosuppressiondid not improve kidney function in these patients. Ourfindings suggest that M1 can be an early biomarkerfor predicting adverse outcomes and can also help inthe decision-making concerning initiating immunosup-pression in IgAN.

It has been controversial whether pathologic classi-fication can improve the predictability of kidney

disease progression in addition to clinical factors suchas proteinuria, kidney function, and blood pressure(31). To overcome this limitation, the Oxford classifica-tion was proposed by the Working Group of theInternational IgA Nephropathy Network and the RenalPathology Society in 2009 (11) and has been widelyused in clinical practice. Many studies have attemptedto validate the clinical usefulness of this classification,and found that the Oxford-MEST is useful in determin-ing prognosis independent of well-known clinical riskfactors (12–23,32). However, the endpoint of thesestudies was the progression of kidney disease, such asa 50% decline in eGFR and the development of ESRD.These outcomes occur at the later stages of IgAN,long after proteinuria develops. Proteinuria is a strongpredictor of adverse renal outcomes, and substantialproteinuria generally precedes deterioration in kidneyfunction (33). Accordingly, identifying an early bio-marker to predict the development of proteinuriawould be valuable. Therefore, we sought to establishsuch a biomarker among four components of theOxford-MEST. To this end, we included 377 patientswith IgAN who had eGFR>50ml/min/1.73m2 andinitially had persistent proteinuria of<1.0 g/g Cr.

Figure 6. A Kaplan–Meier plot and eGFR decline rate in the matched cohort of glucocorticoid users versus nonusers with M1 (A).The mean with standard errors were used in time course of eGFR (B) and UPCR figures (C). Abbreviation: eGFR: estimated glomeru-lar filtration rate; UPCR: urine protein-to-creatinine ratio.

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Our results showed that M1 was significantly associ-ated with an increased risk of developing persistentproteinuria, suggesting the clinical utility of the Mscore as an early indicator of progression.

Our findings corroborated those from a recentstudy by Barbour et al. (21) They performed a post-hoc analysis of patients from the Oxford derivation,North American validation, and VALIGA studies, andfound that M score at the time of biopsy was superiorto 2-year clinical factors, such as 2-year average of pro-teinuria and MAP, and baseline eGFR at biopsy, in pre-dicting the development of a 50% decline in eGFR orESRD. However, Gutierrez et al. (34) evaluated 141patients with early-stage IgAN and found that segmen-tal lesion was the only factor that predicted the devel-opment of a 50% increase in serum Cr level. Moreover,they also showed that the presence of M1 showed asignificant association with the absence of clinicalremission of disease, suggesting that proteinuria orhematuria was unlikely to disappear in patients withM1. The heterogeneity of the study population canexplain these discrepant findings among studies. Infact, Barbour et al. studied patients from three differ-ent cohorts, thus involving a wide spectrum of pro-teinuria and kidney function. In contrast, patients inthe latter study had minimal or no proteinuria at pres-entation, and the median proteinuria in these patientswas 0.2 (0.1–0.4) g/24 h. Our study cohort was closerto that of Barbour et al. because we included patientswho had preserved kidney function and mild protein-uria at presentation. Of note, proteinuria and eGFRbecome highly variable as kidney disease progresses;thus, we applied the Cox model with these variablesbeing considered as time-varying covariates. Previousstudies used baseline proteinuria or time-averagedproteinuria; however, these may not reflect a true riskthat can vary depending on changing covariates bytime. We clearly showed that, in this time-varying Coxmodel, M1 predicted adverse renal outcomes betterthan the other lesions. It should be noted that thestudy endpoint was the development of persistentproteinuria>1.0 g/g Cr, which is the time point whenglucocorticoid treatment can be initiated as suggestedby the current guideline on IgAN (7). Therefore, ourrobust findings can provide a rationale for the use ofthe Oxford classification as an indicator in determiningimmunosuppressive therapy in IgAN patients.

The underlying mechanistic link responsible for therelationship between M1 and persistent proteinuriaremains largely speculative. There has been experi-mental evidence supporting this association. Thehallmark of IgAN is the mesangial deposition of IgA1-immune complexes (22,35). Generally, the deposition

of IgA1 within the mesangium is the first event thatcan subsequently damage other glomerular structuresbefore E, S, and T lesions develop (35). In the a1KImodel, in which mouse immunoglobulin is replacedby IgA1 with human heavy chains and immuneresponses, IgA1 deposition within the mesangium pre-ceded hematuria, proteinuria, or increased Cr levels,indicating mesangial deposition is the early lesionbefore clinical prognostic factors becomes evident dur-ing the pathophysiologic process of IgAN (36). Anotherin vitro study suggested dysregulated mesangial cellsas an initiating factor leading to podocytopathy (37).The authors found that humoral factors, includingtumor necrosis factor-a and transforming growth fac-tor-b, released from mesangial cells altered the glom-erular permeability, thus resulting in proteinuria. Thisexperimental evidence can be extrapolated to clinicalhuman IgAN. In fact, many studies have reported thatM1 remained an independent predictor of adverserenal outcomes regardless of clinical factors, whereas Eand/or S showed conflicting results (12,15,19,21,22).

Because M1 was found to be an independent pre-dictor of persistent proteinuria in our study, we furtheranalyzed whether immunosuppression could improverenal outcomes in patients with M1. We showed thatglucocorticoid administration resulted in proteinuriareduction. However, there was no significant differencein the progression of kidney disease between gluco-corticoid users and nonusers. It has long been debatedwhether immunosuppression can improve renal out-comes in IgAN. The KDIGO guidelines suggest the useof glucocorticoids in patients with persistent protein-uria �1 g/day despite optimal supportive care for 3–6months (7). This suggestion was made largely basedon three prior randomized controlled trials (24,38,39).However, these studies have been criticized becauseRASBs were not fully administered during the studyperiod, and blood pressure was not adequately con-trolled in their extended observation (25). A recentlypublished randomized controlled trial by theSupportive Versus Immunosuppressive Therapy for theTreatment of Progressive IgA Nephropathy (STOP-IgAN) investigators raised question against the prevail-ing notion about the protective effects of immunosup-pression (8). They failed to prove the superiority ofimmunosuppression over intensive supportive care inattenuating eGFR decline, although clinical remissiondefined as a UPCR<0.2 g/g Cr was more oftenachieved with immunosuppression. Our findings werepartly in agreement with those of the STOP-IgAN trial.We further analyzed the effects of glucocorticoids inall 377 patients, and found that immunosuppressivetherapy did not improve renal outcomes compared

10 C.-Y. YOON ET AL.

with those without immunosuppression (data notshown). However, our study was not a randomizedcontrolled trial and was observational in nature; thus,the results should be interpreted with caution. It ispossible that glucocorticoids were given to patientswith more advanced stages of IgAN, as evidenced byan unbalanced baseline proteinuria in the unmatchedcohort (Table 5). Nevertheless, given the positiveeffects of immunosuppression on full remission andthe relative short follow-up in the STOP-IgAN trial, fur-ther investigation on whether immunosuppression canresult in improved kidney function is required with alonger follow-up.

Our study has several limitations. First, this is anobservational study in which the influences of con-founding factors could not be fully excluded.Particularly, in the analysis of the effects of glucocorti-coids, several clinically important variables were notbalanced between groups. To overcome these limita-tions, we used PS matching and mitigated differencesin baseline characteristics at biopsy. Despite theseefforts, unknown confounding factors might stillremain. In addition, one may raise a concern regardingpotential impact of treatment bias because corticoste-roids were more administered in patients having thepositive Oxford-MEST score. To clarify this, we analyzedthe data excluding corticosteroid users and found thatonly M1 was a significant predictor of adverse renaloutcome. Furthermore, there were no interactionterms between steroid therapy and pathologic lesions(data not shown). The observational nature of ourstudy and a relatively small number of patients limitin-depth analysis on the relationship between patho-logical lesions and steroid responsiveness. Given thestrengths of the Oxford classification that specificallyrecognize pathological features associated with pro-gression, further well-designed randomized controlledstudies are required to delineate the relationshipsbetween the Oxford-MEST lesions and treatmentresponsiveness. Second, the administration ofimmunosuppression was dependent on the decisionof individual physicians. Furthermore, the concept ofintensive supportive care was not fully established.Other therapeutic strategies to reduce proteinuria,such as a low protein diet or combination treatmentwith other medications, were not standardized.Nevertheless, RASBs were used in 283 (75.1%) patientsduring follow-up, and blood pressure was main-tained<130/85mmHg in approximately 80% ofpatients. This means that we attempted to providemaximal supportive care, as the guideline suggested.Third, our findings may not be extrapolated to otherpopulations because this study included only Korean

subjects. It should be noted that ethnicity may affectclinical outcomes according to the Oxford-MEST score.Interestingly, M1 but not E1 lesion had prognosticimplication in Chinese patients with IgAN (16,18,22,40),and pathologic lesions did not influence E lesionappeared to have a lesser impact on renal outcome inAsian patients (41). Studies involving diverse ethnicpopulations are rare. Even though there was, fewAsian subjects were included, thus detailed compara-tive analysis was not feasible. Finally, in this study,patients with T1 did not confer an increased risk ofdeveloping persistent proteinuria. Many studies haveuniversally shown that tubulointerstitial fibrosis is thestrongest predictor of adverse outcomes(12–23,34,41,42). Because patients had preserved kid-ney function and a UPCR of<1.0 g/g Cr, there wereonly 42 (11.1%) patients who had T1 in our study.Thus, the sample size is too small to identify an inde-pendent association with adverse outcome, althoughT1 was more likely to reach a 30% decline in eGFR inthe univariate analysis.

In conclusion, we showed that the Oxford M1 com-ponent predicted the development of persistent pro-teinuria, which was significantly associated withworsening kidney function. This finding suggests thatthe Oxford classification can aid in determiningimmunosuppression in the early stages of IgAN.However, steroid treatment was not associated withimproving clinical outcomes. Further randomized con-trolled studies are required to investigate whether ear-lier steroid administration in patients with M1 wouldresult in better outcomes.

Acknowledgements

None.

Disclosure statement

The authors have no conflicts of interest to declare and nofinancial disclosures to make with respect to this work. Theresults presented in this paper have not been published pre-viously in whole or part, except in abstract format.

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