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NDT Advance Access published online on November 28, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm775
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The Prognosis and Pathogenesis of Severe Lupus Glomerulonephritis

Melvin M. Schwartz1, Stephen M. Korbet2, Edmund J. Lewis2 and for the Collaborative Study Group3

1 The Department of Pathology, Rush University Medical College, Chicago, IL 60612, USA 2 The Section of Nephrology, Department of Medicine, Rush University Medical College, Chicago, IL 60612, USA

Correspondence and offprint requests to: Melvin M. Schwartz, Department of Pathology, Rush University Medical College, 1753 W. Congress Parkway, Chicago, IL 60612, USA. Tel: +1-312-942-5262; Fax: +1-312-942-4228; E-mail: Melvin_Schwartz{at}rush.edu



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Appendix
 References
 
Background. The International Society of Nephrology/ Renal Pathology Society classification (ISN/RPS) of lupus glomerulonephritis (GN) divides diffuse GN (≥50% involvement) into diffuse segmental (IV-S) and diffuse global GN (IV-G). This division tests whether the pathogenesis and clinical outcomes are the same as when similar patients are classified using the World Health Organization (WHO) classification into severe segmental (WHO III ≥50%) and diffuse global (WHO-IV) GN.

Methods. Thirty-nine renal biopsies with WHO class IV and 44 with WHO III ≥ 50% were reclassified using the ISN/RPS and were correlated with pathogenesis and outcome.

Results. There were 22 biopsies with ISN/RPS class IV-S. ISN/RPS class IV-G comprises two morphologically discrete classes of renal biopsies: 39 biopsies originally classified as WHO class IV (WHO-IV) and 22 that switched from WHO III ≥50% to ISN/RPS class IV-G (IV-Q). We will analyze IV-S, IV-Q and WHO-IV separately. WHO-IV had significantly more immune aggregate deposition than IV-S and IV-Q. WHO-IV had lower serum complements C3 (P = 0.05) and C4 (P = 0.05) than patients with IV-Q. Patients with WHO-IV had more remissions (56%) than IV-Q (23%) (P = 0.01), and stable renal function at the last follow-up was less frequent in patients with IV-Q (18%) than IV-S (50%, P = 0.05) and WHO-IV (62%, P = 0.001). Renal survival and renal survival without end-stage renal disease were different when the patients were diagnosed as WHO classes III ≥50% and IV, but the outcomes for ISN/RPS class IV-S and IV-G (WHO-IV plus IV-Q) were not different.

Conclusions. WHO III ≥50% and WHO-IV lupus GN are not congruent with ISN/RPS IV-S and IV-G. The ISN/RPS minimizes pathological and outcome differences between classes IV-S and IV-G which results in the loss of informational content from the renal biopsies. ISN/RPS does not detect pathogenetic or clinical differences among patients with severe lupus GN.

Keywords: diffuse global glomerulonephritis; hyaline thrombi; pathology; patient survival; remissions; renal survival; wire loops; subendothelial deposits; IV-S; IV-G



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Appendix
 References
 
Focal segmental glomerulonephritis (GN) is a discrete pattern of glomerular involvement seen in patients with systemic lupus erythematosus (SLE) that is defined by lesions that affect only a portion of the glomerulus, while other glomeruli in the biopsy may not be involved [1–6]. The proportion of glomeruli involved in focal segmental lupus GN is variable, but the glomerular pathology is similar whether the involvement is in a few glomeruli or in all the glomeruli in the biopsy. In an insightful comment, Jacob Churg noted,

It is uncertain whether focal lupus nephritis as defined is produced by the same immunological mechanisms as mesangial and diffuse forms, because in some instances immune deposits are absent from the focal lesion though present elsewhere in the glomerulus. The segmental lesion may or may not contain deposits, but the mesangium almost invariably does. [6]

Thus, the pathogenesis of focal segmental SLE GN appears to be different from the immune complex mechanism of diffuse SLE GN and may have a causative mechanism analogous to the pauci-immune lesion of systemic vasculitis [7,8].

In the Collaborative Study Group clinical trial [5,9], which utilized the 1982 World Health Organization (WHO) classification [6], lupus patients with severe segmental GN with involvement of 50% or more of the glomeruli (WHO class III ≥50%) had a significantly worse clinical outcome compared to clinically similar patients with diffuse global GN (WHO class IV) [7]. The classification of lupus nephritis proposed by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) places all lupus biopsies with ≥50% involvement in the class of diffuse lupus nephritis (class IV) and divides class IV into those with predominantly segmental lesions (class IV-S) and predominantly diffuse global lesions (class IV-G) [10]. Several studies of the ISN/RPS classification [8,11,12] have not shown different outcomes between patients with IV-S and IV-G glomerular lesions, implying that morphological differences between severe segmental and diffuse global SLE GN are clinically irrelevant and of neither prognostic nor therapeutic import.

We are concerned that the definitions and assumptions inherent in the ISN/RPS classification may mask the prognostic and pathogenetic implications of the diagnosis of segmental lupus GN by including the most extensive and widely distributed cases in the category of diffuse global lupus GN (IV-G). In the present study we reclassified the renal biopsies of well-characterized SLE patients [5,9] using the ISN/RPS classification [10] and determined the outcomes for ISN/RPS classes IV-S and IV-G to test whether previously demonstrated pathological and outcome differences between severe segmental and diffuse GN persist.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Appendix
 References
 
Patients
The adult patients who participated in the prospective, controlled trial of plasmapheresis in severe lupus nephritis of the Lupus Nephritis Collaborative Study Group (LNCSG) comprised the study patients [9]. At the completion of the formal trial in October 1986, 14 patients had died. In the remaining 72 patients, we extended the overall mean follow-up to 120 months. Because there were no outcome differences between the treatment groups, the patient data were pooled for this study. The entry criteria, therapeutic and medical management protocols, and results of the initial study have been reported [9,13]. In brief, patients were eligible if they were ≥16 years of age, had SLE as defined by the American Rheumatism Association [14] and had the histologic diagnosis of severe lupus GN by the Pathology Reading Committee of the LNCSG (see the appendix). Patients with a serum creatinine >6 mg/dL (>528 µmol/L), previous plasmapheresis or pregnancy were excluded from the study.

Pathology studies
Eighty-three of the 86 LNCSG patients were included and 3 were excluded (one biopsy was unclassified, and in two cases the slides were no longer available). The Pathology Reading Committee determined the diagnoses of severe lupus GN and lupus membranous GN (MGN), the classification of the pathology according to a modification of the 1982 WHO classification, the presence of histological features of activity and chronicity, and the activity and chronicity indices [15]. An adequate biopsy contained ≥10 nonsclerotic glomeruli. The diagnosis of severe lupus nephritis, using a modification of the 1982 WHO classification, required proliferation and/or necrosis in ≥50% of the nonsclerotic glomeruli with or without concomitant MGN [5,16]. We focused on the nonsclerotic glomeruli because we reasoned that glomerular scars would not respond to therapy. Thus, severe lupus GN comprised three discrete glomerular lesions: (1) severe segmental GN: characteristically, segmental GN was a focal lesion with a heterogeneity of inflammatory changes within glomeruli. Some glomeruli were uninvolved or had small segmental lesions involving <50% of the glomerulus (Figure 1) and the most extensively involved glomeruli had at least one uninvolved lobule (Figure 2). Severe segmental GN was defined by active lesions in ≥50% of the nonsclerotic glomeruli (class III ≥50%). The diagnosis was a consensus reached by four experienced renal pathologists who were able to identify the segmental nature of this lesion even in cases with involvement of most of the tuft. (2) Diffuse global GN is class IV in the 1982 WHO classification [6]. The glomerular lesions involved all or nearly all of the nonhyalinized glomeruli with cellular proliferation and infiltration in a global endocapillary, mesangiocapillary, or crescentic pattern or prominent, extensive subendothelial deposits seen by light (wire loops) or fluorescence microscopy (Figure 4) and (3) MGN with concomitant severe segmental (III ≥50%) or diffuse global GN was the third form of severe lupus GN. Because we have shown that the prognosis of the combined membranous and proliferative lesions is determined by the distribution of the proliferative component (segmental versus global inflammation) [7], we combined the cases into class III ≥50% ± MGN and class IV ± MGN. These two classes of severe lupus GN will be called severe segmental (WHO III ≥50%) and diffuse global GN (WHO-IV), respectively.


Figure 1
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  		Fig. 1. The 22 patients who transfer from WHO III ≥50% to class IV-G when the ISN/RPS criteria are applied are represented in this Venn diagram as class IV-Q. ISN/RPS class IV-S are biopsies (n = 22) with active and chronic lesions involving <50% of the glomerular surface area ≥50% of the glomeruli. WHO class IV are biopsies (n = 39) with global involvement of all or nearly all the non-sclerosed glomeruli, and they would be included in ISN/RPS class IV-G. Note that ISN/RPS class IV-G comprises classes IV-Q plus WHO-IV.

 

Figure 2
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  		Fig. 2. ISN/RPS class IV-S. The left side of the glomerulus shows endocapillary proliferation and a small cellular adhesion. Endocapillary proliferation involves ~50% of the surface area of the glomerulus. The biopsy contains 13 glomeruli: nine glomeruli have <50% involvement and four have >50% involvement. Methenamine silver periodic acid Schiff stain (Jones), x400.

 

Figure 4
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  		Fig. 4. ISN/RPS class IV-G. There is global endocapillary proliferation involving virtually every capillary in the glomerulus. The biopsy contains 37 glomeruli, and two are hyalinized. Thirty-five have global endocapillary proliferation with crescents in three. Methenamine silver periodic acid Schiff stain (Jones), x400.

 

Figure 3
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  		Fig. 3. ISN/RPS class IV-Q. The glomerulus shows endocapillary proliferation at the hilum that involves >50% of its surface area, and the uninvolved capillaries are patent. The biopsy contains 23 glomeruli: 15 glomeruli have endocapillary proliferation involving >50% of the glomerular surface area. Three glomeruli have <50% involvement and five glomeruli have no significant proliferation. Methenamine silver periodic acid Schiff stain (Jones), x400.

 
One pathologist (MMS) reclassified the 83 study cases without knowledge of the outcomes, according to the ISN/RPS classification [10], using the set of four glass slides [hematoxylin and eosin, periodic acid Schiff, Masson's trichrome, and periodic acid Schiff methenamine silver (Jones stain)] and electron micrographs [5], which were originally analyzed by the Pathology Reading Committee. ISN/RPS class IV includes all cases with ≥50% glomerular involvement (active and chronic) as ‘diffuse lupus nephritis’, and all the study cases fall into this class. ISN/RPS Class IV is divided into diffuse segmental GN (IV-S) if ≥50% of all the glomeruli (active and chronic) have segmental lesions (segmental is defined as involvement of <50% of the surface area of each glomerulus). Diffuse global GN (class IV-G) is diagnosed if ≥50% of all the glomeruli (active and chronic) have global lesions (global is defined as involvement of >50% of the surface area of each glomerulus). In this paper, the ISN/RPS classes of diffuse segmental GN ± MGN and diffuse global GN ± MGN are referred to as IV-S and IV-G, respectively.

Application of the ISN/RPS criteria to the study cases resulted in the removal of some from the WHO severe segmental GN class (WHO III ≥50%) and inclusion in the diffuse global GN class of the ISN/RPS (IV-G.). We named this peripatetic group of biopsies IV-Q (IV-Query) to facilitate its study. Thus, ISN/RPS IV-G comprises two separate and discrete classes of renal biopsies: diffuse global GN in the WHO classification (WHO-IV) and IV-Q. We report IV-S, IV-Q and WHO-IV separately in our analysis of the ISN/RPS classification.

Laboratory analysis
Baseline serum creatinine, C3 and C4 complement components, anti-dsDNA and cryoprecipitable immune complex concentrations were determined in a central laboratory as previously described [17]. Antibodies to Ro, La, nRNP and Sm were determined in the laboratory of Dr Morris Reichlin using an ELISA with affinity-purified antibodies as previously described [18,19].

Treatment protocol
Detailed treatment protocols for this study have been published [9,13]. All patients initially received 60 mg of prednisone and 2 mg/kg of cyclophosphamide orally per day. In addition, patients were randomized to receive standard therapy plus plasmapheresis three times weekly for 4 weeks. After the initial 4 weeks of treatment, patients who improved clinically received cyclophosphamide at 1 mg/kg/day for an additional month after which it was discontinued. The dose of prednisone was gradually tapered over a 22-week period to 20 mg on alternate days. Patients whose renal symptoms had worsened at 4 weeks (see below) were continued on the initial high-dose prednisone and cyclophosphamide for an additional 4-week period, and patients in the plasmapheresis arm of the study also received an additional 12 treatments. Thereafter, renal and extrarenal flares were treated based on other standardized protocols of intensive drug therapy as previously described [13]. When the formal study ended, the patients had received standardized therapy for an average of 133 ± 10 weeks, and subsequent treatment was determined by the individual investigator.

Outcome variables
The following outcomes were evaluated from the time of entry into the study: (1) time to remission (serum creatinine of <1.4 mg/dL (<123 µmol/L) and proteinuria of <0.33 g/d) within 5 years of entering study; (2) time to end-stage renal disease (ESRD) [defined by a serum creatinine of >6 mg/dL (>528 µmol/L), or the initiation of renal replacement therapy] and (3) time to death. The definition of renal death is patients who died in ESRD with or without renal replacement therapy, and the definition of non-renal death is patients who died without ESRD or renal replacement therapy.

Statistical analysis
Comparison of the clinical and laboratory characteristics among the groups of patients used Fisher's exact test for categorical data [20] and the Wilcoxon rank-sum test for continuous data [21]. For the analysis of length of time from entry to remission, ESRD (renal survival), death (patient survival), or ESRD or death (survival without ESRD), product-limit life-table distributions were compared with the log-rank test statistic [22]. Results are reported as mean ± SD, and a P-value < 0.05 was considered significant.



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Appendix
 References
 
Baseline histological features
The ISN/RPS classification switches cases of segmental GN in which ≥50% of the glomeruli have lesions involving >50% of the glomerular surface area from the severe segmental class in the WHO classification (III ≥50%) to ISN/RPS class IV-G (Figure 1). The switched cases represent biopsies with the most extensive segmental glomerular lesions. Twenty-two biopsies are in ISN/RPS class IV-S (Figure 2) and 61 are in IV-G. Thus defined, class IV-G contains two morphologically discrete and dissimilar forms of lupus GN: 22 with widely distributed segmental glomerular lesions (IV-Q) (Figure 3) and 39 with diffuse global lesions (WHO-IV) (Figure 4). Although the signs of activity listed in Table 1 [6] were not different among the groups, the activity indices were markedly elevated, and IV-Q had a higher activity index than IV-S. The glomerular signs of chronicity were not different, and the chronicity indices, although elevated in all three groups, were not different.


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  		Table 1. Baseline histologic features

 
In accord with our purpose of determining whether segmental and global glomerular inflammations are caused by separate and distinct pathogenetic mechanisms, the histologic and ultrastructural features of massive immune aggregate deposition were examined. Wire loops (P < 0.01), hyaline thrombi (P < 0.05) and massive subendothelial electron-dense deposits (P < 0.001) were more frequent in WHO-IV compared to IV-S (Table 1). Although IV-Q is classified as diffuse global GN (IV-G) in ISN/RPS classification, IV-Q has a profile of immune complex deposition that is different from the other cases in IV-G (WHO-IV) (wire loops—P < 0.05; hyaline thrombi—P < 0.01 and massive subendothelial deposits–-P < 0.01) and is similar to the IV-S cases.

Baseline clinical characteristics and serology
The baseline clinical characteristics of sex, systolic and diastolic blood pressure, serum creatinine, protein excretion and treatment randomization were not different, and the differences in age and race are presented in Table 2. As noted in the Materials and methods section, the treatment groups in the original clinical trial did not differ in the study outcomes, and the distribution of randomized patients among the three histological classes of lupus GN was not different.


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  		Table 2. Baseline clinical characteristics

 
The baseline lupus serological studies are presented in Table 3. The serum complements C3 and C4 were depressed in all three groups, but both C3 (P < 0.05) and C4 (P < 0.05) were significantly higher in class IV-Q compared to WHO-IV. The complement levels in IV-Q were similar to IV-S. The baseline serologies including double-stranded DNA, cryoglobulins, and anti-Ro, anti-La, anti-nRNP and anti-SM antibodies were markedly abnormal but not different among the three groups of patients.


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  		Table 3. Baseline serology

 
Follow-up
Table 4 lists the follow-up data. The length of follow-up and the median follow-up were not different among the three groups of patients. Achievement of a remission following treatment was significantly different: the rate of remission in IV-Q was significantly lower (P = 0.01) than that in WHO-IV (23% versus 56%). The rate of remission in IV-S was intermediate between IV-Q and Class-IV (41%), but it was not significantly different from either. The overall status at the last follow-up was also significantly different. IV-Q had the lowest prevalence of stable renal function (18%), WHO-IV had the highest prevalence (62%), and IV-S had an intermediate prevalence of stable renal function (50%). The differences between IV-Q and both IV-S (P = 0.05) and WHO-IV (P = 0.001) were significant. Additionally, IV-Q had the highest prevalence of ESRD and renal death and WHO-IV had the highest prevalence of non-renal death.


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  		Table 4. Follow-up

 
Cumulative survival outcomes
Figures 5A and 6 represent renal survival and patient survival without ESRD, respectively. For both, the best survival was for patients with WHO-IV and the worst was for patients with IV-Q. Patients with IV-S either had intermediate survival or were similar to WHO-IV. Renal survival was different among the three groups (P = 0.0009), and it (Figure 5A) was worse for IV-Q than for WHO-IV (33% versus 77% at 10 years, P = 0.001). Renal survival after 10 years was almost twice as high in IV-S compared to IV-Q (62% versus 33%), but the difference was not statistically significant (P = 0.057).


Figure 5
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  		Fig. 5. Renal survival. A. Renal survival for patients with IV-Q was significantly worse than for WHO-IV (P = 0.001). After 10 years, more than twice as many patients with IV-S had renal survival than did patients with IV-Q, and although IV-Q was not statistically different from IV-S, the continued dropout of renal survivors from IV-Q over the course of the study is clinically important. B. Analysis of renal survival without patients with membranous GN. The survival curves are similar to those for the entire study group that included cases of membranous GN plus severe segmental or diffuse global GN. Renal survival for patients with IV-Q was significantly worse than for IV-G (P = 0.008).

 

Figure 6
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  		Fig. 6. Patient survival without ESRD. Survival for patients with IV-Q was significantly worse than for WHO-IV (P = 0.0038). Although survival for IV-S and IV-Q were not statistically different, it seems that survival of twice as many patients with IV-S than IV-Q after 10 years is clinically significant.

 
Patient survival without ESRD was different among the three groups (Figure 6) (P = 0.013), and it was worse for IV-Q than for WHO-IV (32% versus 66% at 10 years, P = 0.0038). Although patient survival without ESRD after 10 years was almost twice as high in IV-S compared to IV-Q (58% versus 32%) and was similar to that in WHO-IV, IV-S was not significantly different from IV-Q (P = 0.078).

We combined IV-Q and WHO class IV to form one class (IV-G) as indicated by the definitions and criteria of the ISN/RPS classification [10] and compared its outcomes to those of ISN/RPS IV-S. The survival curves for renal survival (Figure 7A) and patient survival without ESRD (Figure 8A) were not different. When the same biopsies were diagnosed as severe segmental and diffuse GN using the 1992 WHO classification [6] (in this classification, III ≥50% includes IV-Q and IV-S), the outcomes were significantly different for renal survival (Figure 7B) and patient survival without ESRD (Figure 8B).


Figure 7
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  		Fig. 7. Renal survival comparing outcome in patients with severe lupus GN. A. Patients classified by the ISN/RPS classification. There is no difference in outcome between patients with diffuse segmental (IV-S) and diffuse global GN (IV-G), P = 0.97. B. The same patients classified by the WHO classification. The renal survival was significantly worse for patients with severe segmental GN (WHO class III ≥50%) than for patients with WHO class IV (WHO-IV), P = 0.0028.

 

Figure 8
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  		Fig. 8. Patient survival without ESRD in patients with severe lupus GN. A Patients classified by the ISN/RPS classification. There is no difference in outcome between patients with diffuse segmental (IV-S) and diffuse global GN (IV-G), P = 0.86. B. The same patients classified by the WHO classification. Patient survival without ESRD was significantly worse for patients with severe segmental GN (class III ≥50%), than for patients with diffuse global GN (WHO-IV), P = 0.025.

 
Analysis without MGN
Removing the biopsies showing MGN plus severe segmental or diffuse GN from the analysis resulted in no or minor changes in the histologic evidence of immune aggregate deposition, baseline clinical characteristics and baseline serologies. Patients with IV-Q lesions had the worst clinical status at the last follow-up. They had the highest prevalence of patients progressing to ESRD (i.e. ESRD plus renal death) [IV-S 5/13 (38%) versus IV-Q 8/11 (72%) versus WHO-IV 8/33 (24%), P = 0.01], and the lowest prevalence of stable renal function [IV-S 6/13 (46%) versus IV-Q 3/11 (27%) versus WHO-IV 21/33 (64%), P = 0.09]. Patients with IV-Q lesions had the poorest renal survival (P = 0.03) (Figure 5B).



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Appendix
 References
 
The diagnosis of severe lupus GN is established in renal biopsies with the involvement of equal to or greater than 50% of the glomeruli [5]. This diagnostic rubric is associated with two discrete forms of acute glomerular inflammation [5,23]: one that is segmental in nature, affecting only a portion of the glomerulus, while the other involves the entire tuft of virtually every glomerulus. The ISN/RPS classification [10] divides biopsies with severe lupus GN into two categories: diffuse segmental (IV-S) and diffuse global (IV-G) GN. Although these categories were created to be analogous to severe segmental and diffuse GN in the WHO classification [5] and are considered to be congruent by some pathologists [24], they clearly are not. The important clinical and pathogenetic differences noted with the WHO classification are lost when the same cases are reclassified using the ISN/RPS definitions and criteria.

The WHO (1982) [6] and the ISN/RPS (2004) [10,25] classifications reflect radically different diagnostic approaches. In the WHO classification, the diagnosis is an interpretation based upon the pathologist's observations, informed by knowledge of the pathogenesis of inflammation in general and GN in particular. In contrast, the ISN/RPS classification reflects the belief [26] that the severity and prognosis of lupus GN are a function of the proportion of cross-sectional glomerular involvement and that there is a pathologic continuum from focal segmental to diffuse global GN. However, if the latter were true, the prognosis of WHO-IV should be worse than widely distributed segmental GN (IV-Q), which should be worse than less widely distributed segmental GN (IV-S). In fact, we report that IV-Q had the worst prognosis, followed by IV-S, and WHO-IV had the best outcome. The arbitrary definitions of the ISN/RPS classification result in the transfer of the most extensively involved cases from WHO III ≥50% that accurately describes their pathology and in which they are associated with other cases that have similar but less extensive glomerular lesions. These cases ‘migrate’ to class IV-G in which they form a substantial, morphologically discrete minority (22/61 cases in the present study) grouped with a majority of cases of diffuse global GN.

Because the distinction between IV-S and IV-G is dependent upon the proportion of glomerular surface area involvement, the ISN-RPS classification becomes subject to statistical rules. An estimate of the prevalence of abnormal glomeruli in the whole kidney implied by the renal biopsy findings can be obtained by calculating a confidence interval based on a binomial distribution [27]. This demonstrates that the number of involved glomeruli in the biopsy will be variable, and when classification of biopsies is based upon the proportion of glomerular involvement in the biopsy, this variability will lead to misclassifications that will be increased in biopsies with few glomeruli. These statistical considerations also apply to the intraglomerular distribution of inflammation. Severe segmental GN has heterogeneous glomerular involvement with a mixture of normal glomeruli and glomeruli with less than and greater than 50% surface area involvement. The average biopsy in the LNCSG trial had 19.1 glomeruli [5]. Because a minimum of 50% of the glomeruli had to be involved to be included in the study, a biopsy could qualify for ISN/RPS class IV-G if only 5 of 10 involved glomeruli showed >50% involvement. Thus, the distinction between a biopsy that remains in diffuse segmental (IV-S) or migrates to diffuse global GN (IV-G) may be based upon very few glomeruli. These considerations suggest that the semiquantitative definitions developed for the ISN/RPS classification to ensure diagnostic reproducibility lead to overlap of the categories of diffuse segmental (IV-S) and diffuse global (IV-G) GN, because of the small sample size, the heterogeneity of glomerular involvement and the statistical rules that govern sampling.

Application of the ISN/RPS classification to biopsies showing severe lupus GN leads to stage migration [28,29], a term which is used in the cancer literature where it is reported that more sensitive diagnostic techniques result in reassignment of patients from a good prognostic stage to a bad one. Because the prognosis of those who migrate is worse than for the other members of the good-stage group and better than that for other members of the bad-stage group, the survival rates rise in each newly constituted group without any change in individual outcomes. This is also known as the ‘Will Rogers phenomenon’ after the famous American humorist who in referring to the movement of farmers from Oklahoma to California during the depression said, ‘This migration raised the average IQ in both states’. Regarding the classification of lupus GN, it appears doubtful that the ISN/RPS division of diffuse global GN into classes IV-S and IV-G produces clinically relevant groups of patients because it appears to have changed the outcome of both groups and minimized differences between them without changing the biology of the disease or the individual outcomes.

WHO III ≥50% and WHO-IV [6] have different morphologic characteristics and serologic abnormalities indicating that they may be mediated by different mechanisms [7]. WHO-IV is associated with evidence of glomerular immune aggregate deposition and depressed levels of serum complements C3 and C4 that indicate an immune complex mechanism. In contrast, biopsies showing WHO III ≥50% have glomerular lesions that are similar to those seen with vasculitis, have less evidence of immune aggregate deposition and have relatively higher levels of serum complement. These findings suggest a mechanism of glomerular injury analogous to that occurring in the systemic vasculitides. The ISN/RPS classification separates the most widely distributed cases of segmental GN (IV-Q) from cases with similar pathology, reduced immune aggregate deposition and serum complements, and includes them in class IV-G along with cases that have a different distribution of glomerular pathology, significantly more evidence of immune aggregate deposition and more serologic evidence of complement activation. The ISN/RPS classes IV-S and IV-G do not make the same pathogenetic distinction seen between WHO class III ≥50% and class-IV, and migration of the IV-Q cases to class IV-G appears to minimize the pathogenetic differences between ISN/RPS classes IV-S and IVG.

Patients with WHO III ≥50% [5] have worse clinical outcomes than those with WHO-IV [7], and the ISN/RPS classes IV-S and IV-G were developed to allow testing of the significance of this distinction in patients with severe lupus GN. However, the studies that have used the ISN/RPS classification to determine the outcomes of classes IV-S and IV-G have not found significant outcome differences [8,11,12]. Because ISN/RPS class IV-G is morphologically heterogeneous, the relevance of these studies is questionable. In fact, the IV-Q patients who migrate from WHO class III ≥50% to ISN/RPS class IV-G have a lower prevalence of remissions, renal survival and patient survival without ESRD than the patients in ISN/RPS class IV-S and the other patients in class IV-G. Removal of these patients with the worse outcomes from the ‘bad’ prognosis class WHO III ≥50% improves the outcomes of those remaining (ISN/RPS IV-S), and adding these patients to the ‘good’ prognosis patients with diffuse global GN (WHO-IV) worsens the prognosis of patients in class IV-G. The ISN/RPS classes IV-S and IV-G do not make the clear distinction in clinical outcomes seen between the WHO III ≥50% and WHO-IV. Migration of the IV-Q cases to class IV-G results in no differences in outcomes between ISN/RPS classes IV-S and IV-G and is in accord with the observations of others [8,11,12].

The ISN/RPS classification assigns many of the most severe cases of segmental GN into the IV-G category. These cases have significant morphological, serological and prognostic differences from the WHO-IV cases that make up the majority of class IV-G. The end result is that important pathogenetic and prognostic implications of the segmental lesion of SLE are lost by the ISN/RPS classification. The prognostic differences between severe segmental and diffuse global GN seen with the 1982 WHO classification suggest that the treatment protocols did not adequately address the vasculitis-like lesions of severe segmental GN, and the poor outcomes experienced by patients in this group were possibly due to undertreatment. We conclude that the ISN/RPS classification, applied to biopsies showing severe lupus GN, results in a significant loss of informational content, and the ISN/RPS classification cannot be expected to detect differences in outcome between biopsies showing diffuse segmental (IV-S) and diffuse global GN (IV-G).

Conflict of interest statement. None of the authors, Dr Schwartz, Dr Korbet or Dr Lewis, has a conflict of interest. The results presented in this paper have not been published previously in whole or part, except in abstract format.



   Appendix
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix
References
 
The Lupus Nephritis Collaborative Study Group included the following: Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL—E.J. Lewis, J.L. Roberts, M.M. Schwartz, R.A. Rodby and H.L. Corwin; George Washington University, Washington, DC—J.M. Lachin, S-P. Lan and P. Cleary; William Beaumont Hospital, Royal Oak, MI—J. Bernstein, H. Shapiro and B.F. Rosenberg; Cleveland Clinic, Cleveland, OH—M.A. Pohl, J. Clough and G. Gephardt; University of Colorado, Denver, CO—T. Berl; Henry Ford Hospital, Detroit, MI—N. Levin; University of Iowa, Iowa City—L.G. Hunsicker and S. Bonsib; Evanston Hospital, Evanston, IL—N. Simon and H. Friederici; Northwestern University, Chicago, IL—F. del Greco and F.A. Carone (deceased); Ohio State University, Columbus, OH—L. Hebert and H.M. Sharma; University of Pennsylvania, Philadelphia, PA—E. Nielson and J. Tomazewski; Tufts—New England Medical Center, Boston, MA—A. Levey and A. Ucci; Medical College of Wisconsin, Milwaukee, WI—J. Lemann, S.S. Blumenthal and J. Garancis; New York Medical College, Valhalla—K. Shapiro and P. Chander; West Virginia University, Morgantown—F. Whittier, J.W. Graves, J. Bathon and R. Riley.

Pathology Committee: M.M. Schwartz (Chairman) Rush-Presbyterian—St. Luke's Medical Center, Chicago, IL; J. Bernstein, William Beaumont Hospital, Royal Oak, MI; G.H. Hill, Francis Scott Key Medical Institution, a Johns Hopkins Medical Institution, Baltimore, MD; K. Holley, Mayo Clinic, Rochester, MI.



   Notes
 
3 See the appendix for the members of the Collaborative Study Group. Back



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix
 References
 

  1. Baldwin DS, Lowenstein J, Rothfield NF, et al. The clinical course of the proliferative and membranous forms of lupus nephritis. Ann Intern Med (1970) 73:929–942.[Abstract/Free Full Text]
  2. Grishman E, Churg J. Focal segmental lupus nephritis. Clin Nephrol (1982) 17:5–13.[Web of Science][Medline]
  3. Magil AB, Ballon HS, Rae A. Focal proliferative lupus nephritis. A clinicopathologic study using the W.H.O. classification. Am J Med (1982) 72:620–630.[CrossRef][Web of Science][Medline]
  4. Schwartz MM, Kawala KS, Corwin HL, et al. The prognosis of segmental glomerulonephritis in systemic lupus erythematosus. Kidney Int (1987) 32:274–279.[CrossRef][Web of Science][Medline]
  5. Schwartz MM, Lan SP, Bonsib SM, et al. Clinical outcome of three discrete histologic patterns of injury in severe lupus glomerulonephritis. Am J Kidney Dis (1989) 13:273–283.[Web of Science][Medline]
  6. Churg J, Sobin LH. Lupus nephritis. In: Renal Disease, Classification and Atlas of Glomerular Diseases (1982) New York: Igaku-Shoin. 127–149.
  7. Najafi CC, Korbet SM, Lewis EJ, et al. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int (2001) 59:2156–2163.[Web of Science][Medline]
  8. Hill GS, Delahousse M, Nochy D, et al. Class IV-S versus class IV-G lupus nephritis: clinical and morphologic differences suggesting different pathogenesis. Kidney Int (2005) 68:2288–2297.[CrossRef][Web of Science][Medline]
  9. Lewis EJ, Hunsicker LG, Rohde RD, et al. for the Lupus Nephritis Collaborative Study Group. A controlled trial of plasmapheresis therapy in severe lupus nephritis. N Engl J Med (1992) 326:1373–1379.[Abstract]
  10. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int (2004) 65:521–530.[CrossRef][Web of Science][Medline]
  11. Mittal B, Hurwitz S, Rennke H, et al. New subcategories of class IV lupus nephritis: are there clinical, histologic, and outcome differences? Am J Kidney Dis (2004) 44:1050–1059.[CrossRef][Web of Science][Medline]
  12. Yokoyama H, Wada T, Hara A, et al. The outcome and a new ISN/RPS 2003 classification of lupus nephritis in Japanese. Kidney Int (2004) 66:2382–2388.[CrossRef][Web of Science][Medline]
  13. Clough JD, Lewis EJ, Lachin JM. the Lupus Nephritis Collaborative Study Group. Treatment protocols of the lupus nephritis collaborative study of plasmapheresis in severe lupus nephritis. Prog Clin Biol Res (1990) 337:301–307.[Medline]
  14. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum (1982) 25:1271–1277.[Web of Science][Medline]
  15. Schwartz MM, Lan S-P, Bernstein J, et al. Role of pathology indices in the management of severe lupus glomerulonephritis. Kidney Int (1992) 42:743–748.[Web of Science][Medline]
  16. Lewis EJ, Hunsicker LG, Lan SP, et al. the Lupus Nephritis Collaborative Study Group. A controlled trial of plasmapheresis therapy in severe lupus nephritis. N Engl J Med (1992) 326:1373–1379.[Abstract]
  17. Roberts JL, Lewis EJ. Identification of antinative DNA antibodies in cryoglobulinemic states. Am J Med (1978) 65:437–445.[CrossRef][Web of Science][Medline]
  18. Harley JB, Sestak AL, Willis LG, et al. A model for disease heterogeneity in systemic lupus erythematosus. Relationships between histocompatibility antigens, autoantibodies, and lymphopenia or renal disease. Arthritis Rheum (1989) 32:826–836.[Web of Science][Medline]
  19. Reichlin M. Measurements of antibodies to Sm and nRNP by ELISA: clinical and serological correlations. In: Tissue Disease and Autoantibodies—Kasukawa R, Sharp GC, eds. (1987) Amsterdam: Elsevier. 85–97.
  20. Agresti A. Categorical Data Analysis (1990) New York: Wiley.
  21. Conover WJ. Practical Nonparametic Statistics (1980) New York: Wiley.
  22. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. (1980) New York: Wiley.
  23. Schwartz MM, Bernstein J, Hill GS, et al. Predictive value of renal pathology in diffuse proliferative lupus glomerulonephritis. Kidney Int (1989) 36:891–896.[Web of Science][Medline]
  24. Markowitz GS, D’Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years. Kidney Int (2007) 71:491–495.[CrossRef][Web of Science][Medline]
  25. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol (2004) 15:241–250.[Abstract/Free Full Text]
  26. Churg J, Bernstein J, Glassock RJ. Lupus nephritis. In: Renal Disease, Classification and Atlas of Glomerular Diseases (1995) New York: Igaku-Shoin. 151–180.
  27. Corwin HL, Schwartz MM, Lewis EJ. The importance of sample size in the interpretation of renal biopsy. Am J Nephrol (1988) 8:85–89.[Web of Science][Medline]
  28. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med (1985) 312:1604–1608.[Abstract]
  29. Feinstein AR, Sosin DA, Wells CK. The Will Rogers phenomenon: improved technologic diagnosis and stage migration as a source of nontherapeutic improvement in cancer prognosis. Trans Assoc Am Physicians (1984) 97:19–24.[Web of Science][Medline]
Received for publication: 29. 6.07
Accepted in revised form: 4.10.07


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