The management of lupus nephritis has undergone a major revolution since the introduction of percutaneous renal biopsy (1), which resulted in the recognition that certain histologic subtypes are associated with very different natural histories and responses to therapy (2). Renal lesions due to systemic lupus erythematosus (SLE) initially were classified into 3 subtypes (focal, diffuse, and membranous glomerulonephritis) (3). This classification gave way to the World Health Organization's (WHO) more elaborate scheme using 6 different types and multiple subtypes (4). After more than a decade of use, the WHO system was revised, and the more recent WHO classification (4) reflects the prevailing view that the presence of cellular proliferation on renal biopsy relegates the renal specimen with coincident membranous pathology to either the focal proliferative or diffuse proliferative categories. Unfortunately, much of the currently available literature uses the 1982 WHO classification system.
The use of the 1982 WHO classification system has been supplemented by activity and chronicity indices that quantify reversible and irreversible lesions (5). Generally in lupus nephritis, the WHO classification parallels these indices with regard to outcome (6). However, the activity and chronicity indices may not independently predict outcome, in part because there is inconsistency in scoring from one center to another (7). In general, very inflammatory biopsy specimens have a high activity index and a poor prognosis if left untreated. However, these lesions are thought to be relatively responsive to immunosuppressive therapy with corticosteroids and cytotoxic agents, particularly cyclophosphamide (8). Biopsy specimens with little inflammation and a lower activity index can be associated with good outcomes with more modest intervention, as long as the kidneys are not scarred. Finally, patients with scarred kidneys with a high chronicity index do poorly no matter what intervention is chosen (6, 9).
Diffuse subepithelial deposits of immune complexes histologically characterize the membranous lesion of lupus nephritis. It is similar to idiopathic membranous nephritis (10), but has several distinct pathologic characteristics, including mesangial and subendothelial electron dense deposits and intense C1q deposition (11). The pure membranous lesion in both the idiopathic and lupus forms has little cellular proliferation and usually results in the nephrotic syndrome.
In an effort to elucidate the prognosis and optimal management of lupus membranous nephropathy (LMN), we analyzed the literature on natural history and treatment.
Materials and methods
We identified references that provided information about outcome, either related to natural history or to treatment, of biopsy-proven LMN. To accomplish this, we performed a MEDLINE search using the keywords “membranous nephropathy” and “nephrotic syndrome” with date limits of 1965–1998. Once reviewed, articles were chosen for inclusion in this analysis if they provided information that was specific to patients with biopsy-proven LMN for at least 2 points in time.
Aggregation of data across studies is necessary to apply meta-analytic techniques (12). We have utilized quantitative analysis to the extent permissible by the study designs and the data included. Furthermore, several large studies (10, 13–16) that provide important information about LMN were not included in the analysis because the data were not in a form that could be aggregated with those outlined in the results section.
Proteinuria. Six studies provided information concerning the degree of proteinuria at presentation and followup in 117 biopsy-proven LMN patients (Table 1). Reported followup periods ranged from less than 1 year to 23 years. The majority (64.1%) of patients with LMN presented with nephrotic-range proteinuria. Only 23.1% had complete resolution of proteinuria at followup. Another 12% remained nephrotic. These data suggest that the remaining 65% had some level of persistent proteinuria.
|Banfi, 1998 (25)||51–177 months||19/19 nephrotic||1/19 nephrotic||19/19 normal||3/19 doubling of creatinine|
|9/19 partial remission|
|9/19 complete remission||1/19 end-stage renal disease|
|Chan, 1998 (19)||25–123 months||0/20 nephrotic||1/20 nephrotic||18/20 normal||20/20 stable creatinine clearance|
|9/20 partial improvement||2/20 abnormal creatinine|
|10/20 complete resolution|
|Radhakrishnan, 1994 (24)||23–43 months||9/10 nephrotic||3/10 nephrotic||9/10 normal||8/10 stable creatinine|
|7/10 improved||1/10 creatinine >1.5 mg/dl||1/10 normalized creatinine|
|1/10 end-stage renal disease|
|Pasquali, 1993 (17)||6–128 months||29/42 nephrotic||9/42 nephrotic||35/42 normal||4/42 creatinine >1.5 mg/dl|
|25/42 proteinuria||7/42 creatinine >1.5 mg/dl|
|8/42 complete remission||6/42 end-stage renal disease|
|Moroni, 1992 (26)||132–276 months||4/6 nephrotic||0/6 nephrotic||6/6 normal||1/6 elevated creatinine|
|Adler, 1990 (18)||59–89 months||—||—||18/18 normal||6/18 creatinine <1.5 mg/dl|
|3/18 creatinine <1.5 mg/dl|
|Leaker, 1987 (23)||64 months||14/20 nephrotic||4/17 proteinuria >1 g/24 hour||20/20 normal||0/20 end-stage renal disease|
|13/17 proteinuria <1 g/24 hour|
|Schwartz, 1984 (13)||60 months||—||—||17/22 normal||3/22 creatinine improved by 20% (2 with Vd)|
|5/22 abnormal creatinine|
|7/22 creatinine worsened by 20% (1 Vb, 5 Vd)|
|Total||75/117 (64.1%)||14/117 (12.0%)|
|nephrotic||nephrotic||15/157 (9.6%) abnormal creatinine||23/157 (14.6%) abnormal creatinine|
|76/117 (65.0%) persistent proteinuria||8/157 (5.1%) end stage renal disease at followup|
|27/117 (23.1%) complete resolution of proteinuria|
Eight studies provided information about renal function in 157 patients with LMN (Table 1). Followup in these studies ranged from 6 months to 23 years. The vast majority (90.4%) of patients with LMN presented with normal renal function as measured by serum creatinine. Most (85.4%) continued to have normal renal function. However, 14.6% had abnormal renal function at followup, and 5.1% developed end-stage renal disease.
Renal function by WHO classification
Three studies presented data according to the 1982 WHO classification for LMN. This classification divides membranous nephropathy into 4 subclasses based on histologic features. Subclass Va includes those with only changes of membranous nephropathy; subclass Vb includes mesangial widening or mesangial hypercellularity; subclass Vc includes focal segmental changes with mild to moderate mesangial change; subclass Vd includes diffuse proliferative changes (4). The more recent WHO classification has been updated to eliminate the Vc and Vd designations. These have been subsumed under the mesangial and diffuse proliferative categories (4). The literature available for analysis, however, uses Vc and Vd.
Data on the outcome of patients with regard to proteinuria could not be abstracted from 2 of the 3 studies with information by WHO subclassification. However, Pasquali et al (17) were able to show that patients with more proliferative change on renal biopsy presented with more proteinuria, were more likely to have persistent nonnephrotic proteinuria, and were less likely to have complete resolution of their proteinuria.
Data on renal function as measured by serum creatinine were available in all 3 studies that divided patients by WHO subclassification (17–19). Patients in these studies did worse (Table 2) than patients in our analysis as a whole (Table 1). This could be due to the smaller number of patients available for analysis and to a larger proportion with proliferative changes. WHO classification does not appear to be an independent predictor of renal failure when adjusted for impaired renal function, proteinuria, anemia, or age (10).
|Reference||WHO subclasses Va and Vb||WHO subclasses Vc and Vd|
|Stable creatinine||Increased creatinine||End-stage renal disease||Stable creatinine||Increased creatinine||End-stage renal disease|
|Sloan, 1996 (16)||15/36||13/36||5/36||10/43||14/43||14/43|
|Pasquali, 1993 (17)||21/26||3/26||2/26||11/16||1/16||4/16|
|Adler, 1990 (18)||4/7||1/7||1/7||2/11||2/11||7/11|
|Total||40/69 (58.0%)||17/69 (24.6%)||8/69 (11.6%)||23/70 (32.9%)||17/70 (24.3%)||25/70 (35.7%)|
Most of the studies reviewed provided information about mortality by WHO class. The number of deaths among patients with LMN and the reported causes of mortality are listed in Table 3. Deaths directly attributable to end-stage renal disease are in the minority. However, the causes of many of the deaths were not reported.
|Reference||Number of deaths||Followup||Causes of death|
|Banfi, 1998 (25)||0/19||51–177 months||—|
|Chan, 1998 (19)||0/20||25–123 months||—|
|Sloan, 1996 (16)||8/79||32–133 months||Not reported|
|Radhakrishnan, 1994 (24)||0/10||22–43 months||—|
|Pasquali, 1993 (17)||2/26||6–128 months||Cerebrovascular accidents|
|Moroni, 1992 (26)||0/6||132–276 months||—|
|Adler, 1990 (18)||4/18||59–89 months||Not reported (3 with end-stage renal disease)|
|Leaker, 1987 (23)||2/20||64 months||Pulmonary embolus Ischemic heart disease|
|Schwartz, 1984 (13)||2/22||60 months||Aspiration during seizure Fungal pneumonia|
|Total deaths 18/220 (8.2%)|
From 25%–50% of lupus patients with renal involvement will switch histologic classification on second or subsequent renal biopsies (2, 9). In one study (20), 5 of 42 patients had class V histology on initial biopsy. This number increased to 14 of 42 on repeat biopsy. Nine patients with class IV and one with class II lesions on initial biopsy subsequently converted to class V. One of the original class V patients converted to class III. Thus, the conversions to a different histologic class were predominantly to class V. It is unclear whether patients who convert to class V are similar in natural history to those who present initially with class V. It may be that this does not represent conversion to a more benign lesion, but the residua that aggressive therapy is unable to reverse (21).
A number of the reports included in our analysis assessed whether or not clinical variables correlated with outcome measures. Others have previously shown that renal morphology does not always correlate with clinical features of patients with renal disease (22). Several of the studies we analyzed drew similar conclusions. In general, for patients with LMN, no significant correlation with renal outcome could be demonstrated for age (16, 23), sex (23), the presence of hypertension (16, 18, 23), complement levels (16, 18, 19), anti–double-stranded DNA antibody levels (18, 19), or serum albumin levels (16, 19). However, 2 studies did suggest that serum creatinine on presentation was a significant clinical marker for worse outcome (16, 23), as previously reported for lupus nephritis patients as a whole (6, 10).
Moroni and colleagues (14) presented considerable information on cardiovascular and cerebrovascular complications in their series of patients who had lupus nephritis for at least 10 years. They point out that although most patients with lupus nephritis may expect kidney survival, they are at increased risk of subsequent vascular complications such as angina, myocardial infarction, cerebral thrombosis, and cerebral hemorrhage. Unfortunately, they did not present control data on vascular complications in lupus patients without nephritis for comparison. In their publication detailing outcomes by WHO classification in a group of patients with shorter followup (17), these same authors note that, in addition to 2 deaths due to cerebrovascular accidents, a number of nonfatal vascular events were seen, 75% of which were associated with antiphospholipid antibodies. These included 1 inferior vena cava thrombosis, 3 renal vein thromboses, 2 superficial iliac artery thromboses, and 1 axillary vein thrombosis.
No prospective, randomized, double-blind placebo-controlled trials exist of treatment options for LMN. Reports that address treatment have been retrospective reviews, usually from a single institution. Treatment protocols have varied widely. All of the studies included in this analysis report using corticosteroids either intravenously or orally, with and without pulse dosing (14, 16, 17, 19, 23–25). Additional reported treatments, usually used in combination with corticosteroids, have included azathioprine (14, 16–19, 23, 24), chlorambucil (14, 17, 25, 26), cyclophosphamide (14, 16–19, 23, 24), cyclosporine (24), and plasmapheresis (15, 16, 18). Dosing and duration of immunosuppressive therapy have generally not been reported. Outcome measures have generally not been reported by choice of treatment. Because of the variability in treatment regimens and the lack of prospective data, no conclusions can be made regarding the optimal treatment for LMN from the studies analyzed here.
One study included in our analysis (24) presents the only prospective data on treatment of LMN. This pilot trial was not randomized, double-blinded, or placebo-controlled and included only 10 patients, 9 of whom had nephrotic-range proteinuria. Cyclosporine (4–6 mg/kg/day) was given alone or with steroids for up to 43 months. Although no patient had a complete resolution of proteinuria, all patients had an initial decline in proteinuria, most out of the nephrotic range. Three patients subsequently experienced a flare and had increasing proteinuria while still taking cyclosporine. Interestingly, given the known nephrotoxicity of cyclosporine, no patient had a significant increase in creatinine during the study. One patient went on to develop renal failure after cyclosporine was discontinued. The role of cyclosporine remains unclear (27, 28).