Article Clinical and Histopathologic Characteristics Associated with Renal Outcomes in Lupus Nephritis Emilie C. Rijnink,* Y.K. Onno Teng,† Suzanne Wilhelmus,* Mathilde Almekinders,* Ron Wolterbeek,‡ Karlien Cransberg,§ Jan A. Bruijn,* and Ingeborg M. Bajema* Abstract Background and objectives The prognostic significance of histopathologic (sub)classes in the current classification *Departments of of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal outcome in Pathology, fi † LN outside the framework of the classi cation. Nephrology, and ‡Medical Statistics and Design, setting, participants, & measurements Variables (50 histopathologic and ten clinical) were tested in mixed, Bioinformatics, Leiden linear,andCoxregressionmodels for theirassociationwith renal flare,ESRD, andeGFR during follow-up (1,5, and University Medical – Center, Leiden, The 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft Gault (normalized to a Netherlands; and body surface area of 1.73 m2) and Schwartz formulas were used to calculate eGFR for adults and children, §Department of respectively. Pediatric Nephrology, Erasmus University Medical Center– Results During median follow-up of 9.9 years (25th–75th percentile, 5.9–13.8), 47 patients experienced a renal fl fl fi Sophia Children’s are and 21 progressed to ESRD. Renal are was predicted by brinoid necrosis (hazard ratio [HR], 1.04 per %; Hospital, Rotterdam, 95% confidence interval [95% CI], 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was The Netherlands predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) $25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at Correspondence: baseline (HR, 0.98 per ml/min per 1.73 m2; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to Emilie C. Rijnink, Leiden University 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m2 fi Medical Center per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with brous crescents, (LUMC), Department IF/TA$25%, and nonwhite race, as well as with cellular/fibrocellular crescents (20.4 ml/min per 1.73 m2 per %; of Pathology, L1-Q, PO 95% CI, 20.6 to 20.2) and age (20.8 ml/min per 1.73 m2 per year; 95% CI, 21.2 to 20.4). Box 9600, P0-107, 2300 RC Leiden, The fi Netherlands. Email: Conclusion The LN classi cation should include an index of evidence-based prognosticators. Awaiting validation [email protected] of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings. Clin J Am Soc Nephrol 12: 734–743, 2017. doi: https://doi.org/10.2215/CJN.10601016 Introduction results may be due to the grouping of a wide variety of The disease manifestations and outcomes in lupus prognostically, pathogenically, and chronically different nephritis (LN) are heterogeneous, but 10%–30% of glomerular lesions in broad classes, thereby assuming patients progress to ESRD within 15 years (1,2). The that the prognosis of individuals within classes is equal prognosis can usually be improved by immunosup- regardless of the type of lesions. pression; although, there are severe and sometimes A revision of the ISN/RPS classification is called for lethal adverse effects (3). There is a constant need for (19,20). An evidence-based approach, similar to the refined and novel indicators to help clinicians pre- Oxford classification of IgA nephropathy, would be dict outcomes and determine when intensive im- the resolution for a future classification (21,22). In this munosuppression should be initiated for individual study, we aimed to identify evidence-based clinical patients with LN. and histopathologic predictors of renal outcome in LN Currently, clinical guidelines for LN (4–6) reserve outside the framework of the ISN/RPS classification. intensive immunosuppression primarily for patients with class III/IV (6V) LN according to the Interna- tional Society of Nephrology/Renal Pathology Society Materials and Methods (ISN/RPS) classification (7). Although the ISN/RPS We collected a cohort of patients, who underwent classification is useful in terms of standardization and biopsy from 1987 to 2011, with biopsy-confirmed LN reproducibility of diagnosis (8–10), studies concerning from the pathology archives at the Leiden University the power of this classification in predicting disease out- Medical Center (LUMC). Inclusion criteria were: patients come reported conflicting results (9,11–18). Conflicting with a first renal biopsy available for re-evaluation 734 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 May, 2017 Clin J Am Soc Nephrol 12: 734–743, May, 2017 Predictors of Renal Outcome in Lupus Nephritis, Rijnink et al. 735 $ fi $ with 5 scorable glomeruli, ful lling 4oftherevised the time of biopsy (age0), proteinuria at the time of biopsy, American College of Rheumatology (23,24) or Systemic erythrocyturia at the time of biopsy, MAP at the time of fi Lupus International Collaborating Clinics (25) classi ca- biopsy (MAP0), induction immunosuppression, and decade tion criteria for SLE, and with clinical follow-up at the during which the patient underwent biopsy. LUMC, Bronovo hospital (The Hague, The Netherlands), Renal Flare and ESRD. Time to first LN flare was cal- or Erasmus Medical Center (Rotterdam, The Netherlands). culated for patients who achieved (partial) remission from In accordance with the ethics committee guidelines at the the date of biopsy until the date of flare for patients who LUMC, all patient data were coded and kept anonymous. reached this endpoint; the remaining patients were censored Biopsy specimens were processed for light and immuno- at the last follow-up or at the time of ESRD. Time to ESRD fluorescence microscopy according to standard techniques was calculated analogously. Patients who reached ESRD in our center, including hematoxylin and eosin, periodic before 10 years’ follow-up were regarded as having eGFR=0 acid–Schiff, and methenamine-silver staining. Immunofluo- ml/min per 1.73 m2 at the remaining time points. Multivari- rescence reports were originally prepared by four experi- able Cox proportional-hazards models included the pre- enced nephropathologists who consistently scored specified variables and were simplified by stepwise removal immunofluorescence intensity on a 0–3+ scale. of the least significant variables. eGFR During Follow-Up. The extent by which variables Histopathology Definitions and Scoring were associated with irreversible nephron loss was in- Definitions of histopathologic lesions are shown in vestigated by modeling eGFR during follow-up. The fi Supplemental Material 1. Slides were scored by an expe- prespeci ed variables were tested for their potential to rienced nephropathologist (I.M.B.). All glomerular vari- predict a change in the intercept of the adjusted average ables were determined for each scorable glomerulus level of decline in multivariable random intercept/slope fi separately and tubulointerstitial parameters were scored linear mixed-effects models, which were simpli ed by fi categorically (Supplemental Material 1). We treated glo- removing the least signi cant variables (Wald test) and fi merular parameters as continuous variables and expressed comparing the goodness of t of nested models (maximum them as the percentage involved of all scorable glomeruli. likelihood ratio test). We considered 50 histopathologic variables (Figure 1). To Progressive eGFR Decline. To investigate progressive reduce the number of candidate variables, we excluded eGFR decline that did not necessarily result in ESRD and/ fl lesions with low prevalence (occurring in #5 patients) and or renal are, variables were analyzed in association with included only one of two strongly correlated variables progressive eGFR decline over 1, 5, and 10 years relative to (Pearson’s r/Spearman’srho.0.8). The decision on its linear prediction based upon eGFR at the time of biopsy which of the correlated variables to be included was on (eGFR0). 6 the basis of relevance and ease of scoring. Normally distributed data were expressed as mean SD. Non-normally distributed data were expressed as median (25th–75th percentile). Correlations between clinical and Clinical Dataset histopathologic variables were assessed using Pearson and The following clinical parameters were recorded for each Spearman tests, as appropriate. Given the chance of false patient at the time of biopsy: age, sex, race, mean arterial positives by multiple correlations of histopathologic vari- pressure (MAP; diastolic BP + 1/3 pulse pressure), anti- ables, Bonferroni correction was performed (Supplemental hypertensive medication, previous immunosuppression, Material 3). All other P values were two-tailed and consid- induction immunosuppression, time since SLE diagnosis, ered significant at P,0.05. All analyses were performed eGFR, 24-hour proteinuria, erythrocyturia, and the pres- using SPSS 23.0 (IBM, Armonk, NY). ence of antinuclear, antidouble-stranded DNA, and anti- phospholipid antibodies. The Cockcroft–Gault (normalized 2 to a body surface area of 1.73 m [26]) and Schwartz formulas Results were used to calculate eGFR for adults and children, respec- We retrieved 293 reports of patients with LN from the tively (27–29). The eGFR and 24-hour proteinuria were 6 pathology archives at the LUMC. Of these, 134 patients registered at 1, 5, and 10 years ( 0.5 year) and at the last were not followed at any of the specified centers, and 54 did follow-up. Clinical data were studied throughout follow- fl not have a retrievable renal biopsy specimen or their biopsy up for the occurrence of renal are and/or ESRD. specimen was of insufficient quality.