International Society Of Nephrology/Renal Pathology Society Research Articles

Classification of lupus nephritis

Lupus nephritis manifests as diverse patterns of immune complex-mediated renal disease affecting glomerular, tubulointerstitial, and vascular compartments. This review will focus on the most recent classification, the 'International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Classification of Lupus Nephritis', and will briefly discuss other types of renal disease seen in patients with systemic lupus erythematosus. The ISN/RPS 2003 Classification of lupus nephritis includes multiple changes from its predecessors, most notably removal of the subclasses of lupus nephritis class V (i.e. Va-Vd), elimination of the normal category (WHO class I), clearer definitions for all classes, a standard approach to sclerotic glomeruli, and the division of lupus nephritis class IV into subcategories based on whether the endocapillary involvement is predominantly segmental (lupus nephritis IV-S) or global (lupus nephritis IV-G). These changes have led to a higher level of interobserver reproducibility and a significant increase in the number of cases of class IV, with a reciprocal decline in lupus nephritis class III and lupus nephritis class V. Multiple studies have found that lupus nephritis class IV-S has similar or better outcomes than lupus nephritis class IV-G. The ISN/RPS 2003 classification of lupus nephritis is gaining widespread acceptance and appears to be achieving its goals of reproducibility and clinical relevance.

Usefulness of ISN/RPS classification of lupus nephritis.

About 50-80% of patients with lupus suffer from lupus nephritis which is one of major causes of morbidity and mortality. Renal pathologists and nephrologists should evaluate the degree of histological damages to establish therapeutic plans for lupus nephritis. In order to standardize definitions, to emphasize clinically relevant lesions, and to improve interobserver reproducibility, the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed. Recently, several retrospective validation studies concerning the utility of the ISN/RPS classification, especially among class IV, were performed. In these reports, reproducibility is improved by the definition of diagnostic term, but the outcome related with classification, especially in class IV, is controversial. We performed retrospective analysis of 99 biopsy-proven subjects with lupus nephritis in our facility using the ISN/RPS classification. The class IV-G group tended to exhibit a worse renal outcome, but the difference compared with IV-S was not significant. In a Cox proportional hazards models, Independent histological predictors of poor renal outcome were extracapillary proliferation, glomerular sclerosis and fibrous crescents, while hyaline thrombi and fibrous adhesions were of favorable renal outcome. Both were similarly observed in IV-G and IV-S. The more qualitative categorization by the response to standard treatment may be needed to emphasize clinically relevant lesion related to renal outcome.

Pathology of lupus nephritis is better classified by the International Society of Nephrology‐Renal Pathology Society system

ABSTRACT Background and aims: The goal of this study was to assess the diagnostic value of the new International Society of Nephrology‐Renal Pathology Society (ISN‐RPS) classification system for lupus nephritis (LN). Methods: We reviewed 170 biopsy specimens according to the WHO and the ISN‐RPS systems. Results: The frequencies of class I, class II, class III, class IV, class V, and class VI LN for the WHO/ISN‐RPS systems were 0.6%/1.8%, 2.4%/2.4%, 28.2%/24.7%, 52.4%/60%, 14.7%/9.4%, and 1.8%/1.8%, respectively. Class‐switch events occurred in 22 cases, with 12 cases switched from class III under the WHO system to class IV under the ISN‐RPS system. Class IV‐S LN showed a higher frequency of fibrinoid necrosis than IV‐G LN (P = 0.003), but endocapillary proliferation was more pronounced in class IV‐G than class IV‐S (P = 0.003). The frequency of coexistent class V LN was higher in class III LN than class IV LN (P = 0.008). The interobserver reproducibility of the ISN/RPS system was better (κ = 0.76) than that of the WHO system (κ = 0.33). Conclusions: Interobserver reproducibility for the ISN‐RPS system for lupus nephritis is greater than for the WHO system. The prognostic value of class IV‐S, IV‐G, and coexistent class V should be verified by future study.

Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions

To determine if the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis (LN) is helpful in predicting renal outcome. A total of 92 patients with LN who underwent renal biopsy in our hospital were re-classified according to the ISN/RPS 2003 criteria. The mean patient age was 36.8 yrs and the median observation period was 65 months. The relative frequency for each class was as follows: Class I (minimal mesangial LN) 0%, Class II (mesangial proliferative LN) 13%, Class III (focal LN) 17%, Class IV (diffuse LN) 60% and Class V (membranous LN) 10%. Within Class IV, diffuse segmental (Class IV-S) was 25% and diffuse global (Class IV-G) 75%. During the observation period, renal function was more likely to deteriorate in Class IV-G cases than in Class IV-S cases. Importantly, when Class IV-G was subdivided into cases involving active lesion alone [IV-G (A)] or chronic lesion [IV-G (A/C)], the majority of cases in IV-G (A) was nephrotic, but responded well to therapy. In contrast, renal function declined only in IV-G (A/C) cases. Patients with Class IV-G (A/C) had persistent proteinuria in spite of intensified therapies. Moreover, the higher proportion of chronic lesions was related with the deterioration of renal function. This study showed that in Class IV-G cases, renal outcome differed in the presence of chronicity. Chronicity could be a critical factor in predicting outcome. Thus, the revised classification of LN is clinically valuable in identifying different renal outcomes among patients with diffuse LN.

Two Female Siblings with Childhood-Onset Systemic Lupus Erythematosus

We herein report two female siblings with childhood-onset Systemic Lupus Erythematosus (SLE) who developed membranous lupus nephritis. The children were diagnosed as having SLE in reverse birth order at ages 11 and 14 years. Younger sister's initial symptom was edema and laboratory findings indicated proteinuria, hypocomplementemia and positive ANA/anti-dsDNA antibody. She was diagnosed as being SLE with membranous lupus nephritis based on International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification. Elder sister manifested general fatigue and edema twelve months after her sister. Laboratory findings showed proteinuria, hypocomplementemia, and positive ANA/anti-dsDNA antibody. A renal biopsy revealed mixed form of mesangial proliferative glomerulonephritis and membranous nephritis. Moreover, both of them were complicated with secondary Sjögren's syndrome. HLA typing was performed and the siblings were noted to have the same haplotype; A(*)0207, A(*)2402, B(*)4601, B(*)5201, B(*)5201, Cw(*)0102, Cw(*)1202, DRB1(*)0101, DRB1(*)0803.

The difference between lupus nephritis class IV-G and IV-S in Koreans: focus on the response to cyclophosphamide induction treatment

To evaluate the response to induction therapy with intravenous (i.v.) cyclophosphamide (CYC) in Korean patients with class IV-G (diffuse global proliferative glomerulonephritis) and class IV-S (diffuse segmental proliferative glomerulonephritis) lupus nephritis (LN) according to the classification system of the International Society of Nephrology/Renal Pathology Society (ISN/RPS). Of the 52 patients with biopsy-proven diffuse proliferative LN, who had been treated with i.v. CYC over a 10-yr period, 42 had been treated with i.v. CYC (equal to or more than 500 mg) for 6 consecutive months and had biopsy specimens containing more than nine glomeruli. The renal pathology of these 42 patients was reclassified according to the International Society of Nephrology and the Renal Pathology Society 2003 classification, and their renal response rates and laboratory indices after induction therapy were analysed. Of the 42 patients assessed, 30 (71%) had IV-G and 12 (29%) had IV-S. Pre-treatment 24 h urinary protein was significantly higher and pre-treatment concentration of anti-dsDNA antibody was significantly lower in IV-G than in IV-S patients. Following induction therapy, complete remission rates were significantly higher in patients with IV-S (67%, 8/12) than in patients with IV-G (33%, 10/30) LN. Class IV-G LN responded more poorly to induction therapy with i.v. CYC pulse than class IV-S LN.

Interobserver Reproducibility and Application of the ISN/RPS Classification of Lupus Nephritis—A UK-wide Study

We sought to assess the interobserver variation of the new International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis when compared with the previous World Health Organization classification, when used by pathologists throughout the UK. We also sought differences in how the 2 classifications were applied to a single set of biopsies. Twenty unselected renal biopsies showing lupus nephritis were circulated to pathologists in the UK National Renal Pathology External Quality Assessment Scheme, before the ISN/RPS scheme was published, with a request to apply the World Health Organization classification. The same slides were recirculated approximately 1 year later with a request to apply the ISN/RPS classification. A significant improvement in interobserver reproducibility was demonstrated by the new classification (kappa 0.53 vs. 0.44, P = 0.002). The reproducibility of the assessment of disease activity and chronicity remains suboptimal (kappa = 0.33). The new classification tends to produce more diagnoses of Class IV lupus nephritis, with fewer diagnoses of Classes III and V. The improvement in interobserver reproducibility indicates that an important aim of the new classification has been achieved. Further work is needed to determine whether the increase in diagnosis of Class IV nephritis represents an improvement in biopsy interpretation or a divergence from the previous classification, as the latter could undermine attempts to relate results from the new system to treatment strategies based on clinical trials which used the old.

Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis

The objective of this study was to identify clinical predictors of response to initial mycophenolate mofetil (MMF) therapy for membranous lupus nephritis (MLN). We observed the clinical outcomes of patients in the Hopkins Lupus Cohort within the first year of initiation of treatment with MMF therapy for newly diagnosed MLN, classified according to the new International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification. Complete renal remission was defined as proteinuria less than 500 mg/24 hours. Demographic, clinical, treatment and laboratory data were examined for their association with renal remission. Twenty-nine MLN patients treated with MMF were identified. Eleven (38%) patients achieved complete renal remission by 12 months. Of those taking hydroxychloroquine, 7/11 (64%) were in remission within 12 months compared to only 4/18 (22%) of those not on hyroxychloroquine (P = 0.036 based on a log-rank test). This association persisted after controlling for the presence of anti-ds-DNA (P = 0.026). Our results provide evidence that hydroxychloroquine has a benefit for renal remission when MMF is used as the initial therapy for MLN. Although hydroxychloroquine is frequently stopped in patients with lupus nephritis, this study suggests it should be started or maintained.

Prediction of urinary protein markers in lupus nephritis

Lupus nephritis is divided into six classes and scored according to activity and chronicity indices based on histologic findings. Treatment differs based on the pathologic findings. Renal biopsy is currently the only way to accurately predict class and activity and chronicity indices. We propose to use patterns of abundance of urine proteins to identify class and disease indices. Urine was collected from 20 consecutive patients immediately prior to biopsy for evaluation of lupus nephritis. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) class of lupus nephritis, activity, and chronicity indices were determined by a renal pathologist. Proteins were separated by two-dimensional gel electrophoresis. Artificial neural networks were trained on normalized spot abundance values. Biopsy specimens were classified in the database according to ISN/RPS class, activity, and chronicity. Nine samples had characteristics of more than one class present. Receiver operating characteristic (ROC) curves of the trained networks demonstrated areas under the curve ranging from 0.85 to 0.95. The sensitivity and specificity for the ISN/RPS classes were class II 100%, 100%; III 86%, 100%; IV 100%, 92%; and V 92%, 50%. Activity and chronicity indices had r values of 0.77 and 0.87, respectively. A list of spots was obtained that provided diagnostic sensitivity to the analysis. We have identified a list of protein spots that can be used to develop a clinical assay to predict ISN/RPS class and chronicity for patients with lupus nephritis. An assay based on antibodies against these spots could eliminate the need for renal biopsy, allow frequent evaluation of disease status, and begin specific therapy for patients with lupus nephritis.

The outcome and a new ISN/RPS 2003 classification of lupus nephritis in Japanese

A considerable diversity in prognosis is seen with lupus glomerulonephritis (LGN). Hence, the clinical usefulness of a recent International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification to judge the long-term outcome of human LGN has been investigated. We studied retrospectively 60 subjects with LGN (7 males, 53 females, mean age of 33 years old) who underwent renal biopsies and were followed from 1 to 366 months, with a mean of 187 months. We diagnosed renal pathology as classes, active and sclerosing lesions, according to the new and WHO1995 classification of LGN, and analyzed the clinicopathologic factors affecting to the prognosis of LGN. New classification got much higher consensus in the judgment of classes (98% vs. 83%, P = 0.0084). The group of Class IV-S (N = 6) or IV-G (N = 17) at initial biopsies showed higher rate of end-stage renal failure (ESRF) compared with that of Class I, II, III or V (40.9% vs. 2.6%, P < 0.001). The mean 50% renal survival time of Class IV was 189 +/- 29 months, and patients with Class IV-S tended to have a poorer prognosis (95 +/- 22 months for IV-S vs. 214 +/- 35 months for IV-G, P = 0.1495). Class IV was also selected as the most significant risk factor for ESRF by stepwise model (P = 0.002). In subanalysis for ESRF in Class IV (-S or -G), treatment including methylprednisolone pulse therapy was only selected as a significant improving factor for primary outcome (P = 0.034). In addition, activity index was the significant risk factor of death and/or ESRF after initial renal biopsies (P = 0.043). As for actuarial patient death during all follow-up periods, complications with anti-phospholipid syndrome or nephrotic syndrome were significant risk factors (P = 0.013, P = 0.041, respectively). New ISN/RPS 2003 classification provided beneficial pathologic information relevant to the long-term renal outcome and the optimal therapy preventing ESRF and/or death in patients with LGN.