NDT Advance Access originally published online on July 29, 2007
Nephrology Dialysis Transplantation 2007 22(12):3495-3500; doi:10.1093/ndt/gfm491
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Clinical presentation and outcome in a cohort of paediatric patients with membranous lupus nephritis*
1Pediatric Nephrology, Pediatric and Adolescent Medicine Department, Mayo Clinic, Rochester, MN 55905, 2Pediatric Nephrology, C.S. Mott Children's Hospital, Ann Arbor, MI 48109, 3Pediatric Nephrology, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI 48201 and 4Pediatric Rheumatology Department of Pediatrics, C.S. Mott Children's Hospital, Ann Arbor, MI 48109, USA
Correspondence to: C. H. Cramer II, Pediatric Nephrology, 200 First Street SW, Rochester, MN 55095, USA. Email: cramer.carl{at}mayo.edu
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Abstract |
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Background. Membranous glomerulopathy accounts for 28% of the biopsy-proven systemic lupus erythematosus nephritis in paediatric patients at the time of first biopsy, yet minimal data are available regarding outcomes in this population.
Methods. We present a retrospective analysis of 26 paediatric patients with World Health Organization class V lupus nephritis. Patients were subdivided based on renal biopsy findings into the following subclasses: 16 (63%) Va, 2 (9%) Vb, 7 (26%) Vc and 1 (4%) Vd. We evaluated outcomes of renal function and urine protein to creatinine ratio (UPr/UCr).
Results. Mean follow-up time was 38.6 (±22) months. Eight patients at presentation had a glomerular filtration rate (GFR) <90 ml/min/1.73 m2, six with Va and two with Vc. The initial presenting serum creatinine was predictive of renal function at last follow-up in class Va and Vb patients (P = 0.002). Twenty-one of the 26 patients had GFR 
90 ml/min/1.73 m2 at last follow-up; the five patients with GFR <90 ml/min/1.73 m2 were all lupus class Va. Cyclophosphamide (CTX) therapy did not demonstrate a significant improvement in outcome. The following parameters failed to predict GFR at last follow-up visit: blood pressure, C3, C4 and UPr/UCr.
Conclusions. The initial creatinine in patients with classes Va and Vb lupus nephritis predicted follow-up renal function. We found no correlation with outcome based on therapy with CTX and/or mycophenolate mofetil.
Keywords: membranous nephropathy; paediatrics; systemic lupus erythematosus
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Introduction |
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Systemic lupus erythematosus (SLE)-associated membranous glomerulopathy (MGN) accounts for 0–28% of cases of membranous nephropathy in the paediatric population [1–8]. The treatment of World Health Organization (WHO) class V lupus nephritis in children is unclear, with therapy guidelines extrapolated primarily from adult treatment publications. Currently patients with membranous nephropathy type Va (pure), Vb (mild mesangial expansion), non-nephrotic range proteinuria and normal renal function are treated conservatively with therapy aimed primarily at treating extra-renal manifestations of the SLE. In contrast, membranous lupus nephritis with nephrotic range proteinuria Vc (focal segmental glomerulonephritis) or Vd (diffuse proliferative glomerulonephritis) on renal biopsy are treated more aggressively with steroids and cyclosporine, chlorambucil or cyclophosphamide (CTX) [9–12]. Most adult studies have reported a correlation between renal outcome and patient mortality based on the type of lupus nephritis WHO classification, with classes Va and Vb patients having better outcomes than patients with classes III, IV, Vc and Vd [13]. However, Donadio et al. [14] retrospectively studied 439 patients with biopsy-proven lupus nephritis and failed to find the WHO classification as an individual predictor of renal failure. We present our experience regarding presentation, treatment and outcome of paediatric patients with WHO class V lupus nephropathy.
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Subjects and methods |
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Patient criteria
We conducted a retrospective chart review of 26 patients with biopsy-proven lupus associated MGN from July 1991 to December 2003. The review included all patients from the University of Michigan (Ann Arbor, MI) and Children's Hospital of Michigan (Detroit, MI) with class V lupus nephritis. Institutional Review Board committees from each centre approved the study. All patients met the 1982 American Rheumatism Association revised criteria for SLE.
A renal pathologist interpreted all biopsies performed at the University of Michigan. A renal pathologist at a neighbouring institution read renal biopsies processed by the pathology department at Children's Hospital of Michigan. The diagnoses of MGN met the criteria outlined by the WHO 1995 classification for lupus nephritis. Light microscopy showed evidence of glomerular membrane abnormalities described as basement membrane thickening, ‘spikes’, or rarefraction zones. Immunofluorescence microscopy demonstrated beading of IgG along the capillary loops. Electron microscopy showed diffuse subepithelial deposits. We stratified patients further based on the renal biopsy into the following four categories: (i) pure MGN without proliferation (WHO class Va), (ii) MGN with mesangial hypercellularity (WHO class Vb), (iii) MGN with segmental and focal proliferative glomerulonephritis (WHO class Vc) and (iv) MGN with diffuse proliferative glomerulonephritis (WHO class Vd).
Clinical parameters and treatment
The clinical data obtained at baseline (time first diagnosed with SLE) included renal biopsy, age at biopsy, blood pressure, serum creatinine (mg/dl), serum C3 (mg/dl), serum C4 (mg/dl) and urine protein to creatinine ratio (UPr/UCr) or urine dipstick albumin analysis. All patients had greater than 10 red blood cells per highpower field on urine microscopy. The glomerular filtration rate (GFR) was calculated using the Schwartz formula. Follow-up data consisting of serum creatinine (mg/dl), UPr/UCr and calculated GFR were collected at 2 months, 6 months, and then yearly.
Hypertension was defined by the criteria outlined in the Report of the Second Task Force on Blood Pressure Control in Children. All patients were treated with an angiotensin-converting enzyme inhibitor (n = 25) or angiotensin receptor blocker (n = 4) for ‘anti-proteinuric effects’ and blood pressure control. Patients received a combination of therapies from the following agents: pulse intravenous (IV) steroids followed by oral prednisone and IV CTX, azathioprine or mycophenolate mofetil (MMF). Prednisone starting dose was 1–2 mg/kg/day and then tapered at the discretion of the treating medical team. The IV CTX was given in bolus therapy per previous published protocols at monthly intervals for 6 months and then every 3 months for an additional 24 months [15]. The doses varied between 500 and 1000 mg/m2. The patient's 2-week nadir white blood cell counts were used to determine the follow-up doses. The lack of uniformity in the treatment regimen for each patient is because of the multiple treating paediatric nephrologists and the current lack of consensus as to what treatment options are best.
Statistical analyses
All statistical analyses were performed using the JMP 6.0.0 Statistical Package from SAS Institute Inc. Standard descriptive parameters were used. Where appropriate, the non-parametric tests of Wilcoxon rank sum test or Fischer exact test were used for comparison between groups. Spearman rank correlation was used to evaluate the relationship between the presenting features and GFR and UPr/Cr at last follow-up. Statistical analysis of subclassification was performed after classes Va and Vb were combined into study group 1 and classes Vc and Vd were combined into study group 2. These patients were combined into groups because of the small number of patients in class Vb (two patients) and class Vd (one patient). Results were considered significant at P < 0.05.
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Results |
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This retrospective data collection study consisted of 26 children (Table 1) with WHO class V lupus nephritis. The median age was 15 years (7–18 years), with 22 patients (85%) older than 12 years of age at the time of the renal biopsy. Nineteen percent were male and 81% were female. African Americans made up 62% (n = 16) of the cohort. The renal biopsy results revealed 16 (62%) with class Va, two (8%) with class Vb, seven (26%) with class Vc and one (4%) with class Vd. Blood pressure, serum C3, serum C4, UPr/UCr and GFR were assessed at the time of renal biopsy (Table 1). UPr/UCr was measured in 22 patients and four patients had urine albumin dipsticks performed with values of +2–3. Eighteen (69%) children had GFR
90 ml/min/1.73 m2 and 8 (31%) children had GFR <90 ml/min/1.73 m2. No statistical differences were detected between study group 1 (classes Va and Vb) and study group 2 (classes Vc and Vd) based on the above presenting parameters except the UPr/UCr being greater in study group 2 (P = 0.016) (Table 2). The median patient follow-up time was 38 months (6–84 months).
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A variety of oral agents were used in combination with steroids to treat membranous lupus nephritis. All patients received daily steroids for a median of 27.8 months (2–66 months). Ten patients (nine Va and one Vc) were transitioned to alternate day prednisone because of side effects and/or improvement in UPr/UCr during follow-up visits. Five (19%) patients (three Va, one Vb and one Vc) were treated with azathioprine. Indications for treatment with MMF in 12 patients (eight Va and four Vc) included weaning of steroids because of side effects or additive immunosuppressive therapy. MMF treatment started with 500 mg/m2 divided BID and increased to 1000 mg/m2 divided BID if there were no contraindications. There was no statistically significant difference in renal function (P = 0.898) or UPr/Cr (P = 0.937) at last visit based on the addition of MMF to the patients treatment regimen.
Eight patients (five Va and three Vc) completed IV CTX using the protocol outlined in Subjects and methods section. These five patients with class Va lupus nephritis were followed for a median 48 months (36–84 months). Four patients had normal GFR and improved UPr/UCr at the time of last follow-up (Figures 1 and 2). The fifth patient had a GFR of 74 ml/min/1.73 m2 and UPr/UCr of 1.00 at presentation and a GFR of 62 ml/min/1.73 m2 and UPr/UCr of 2.73 at time of last follow-up. The three patients with class Vc lupus nephritis were followed for a median 48 months (37–58 months). All three class Vc patients had normal GFR and UPr/UCr less than 0.7 at time of last follow-up (Figures 3 and 4).
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Nine patients received a partial protocol treatment of IV CTX. Two of these patients presented with class Va and a GFR of 21 ml/min/1.73 m2 and 36 ml/min/1.73 m2. Subsequent doses of IV CTX were discontinued in these two patients because of continued decline in renal function. Of the remaining seven patients with partial administration of the IV CTX protocol (minimum four doses), three patients had class Va, two class Vc and one patient each had class Vb and Vd. After combining all patients treated with IV CTX, no benefit was demonstrated on follow-up GFR (P > 0.253) or UPr/UCr (P > 0.698), even after removing the two patients who presented with a GFR less than 36 ml/min/1.73 m2.
Proteinuria and renal function at time of renal biopsy and last follow-up were recorded based on the WHO class V subtypes (Figures 1–4
). Twelve patients had nephrotic range proteinuria (UPr/UCr >3.5) at time of renal biopsy. Subsequent UPr/UCr were >1.0 at the last clinic visit in nine patients, seven of whom had class Va. All six class Vc patients with initial nephrotic range proteinuria had UPr/UCr values <1.0 at last follow-up visit. Even though there was a difference in presenting proteinuria between study groups 1 and 2 (P = 0.016), there was no correlation with follow-up proteinuria (Figures 2 and 4, P = 0.641 and P = 0.471, respectively) or at time of last follow-up between groups (P = 0.949).
Six class Va and two class Vc patients had GFR <90 ml/min/1.73 m2 at the time of presentation. Four out of six patients with class Va who presented in acute renal failure remained with chronic renal insufficiency during the study period. Two class Vc and two class Va patients had recovery of their renal function. The GFR at the time of renal biopsy was not different between study groups 1 and 2; however, the GFR between the two groups at time of last follow-up trended towards a significant difference (Table 2, P = 0.374, P = 0.095, respectively). The presenting GFR was significant in predicting GFR at follow-up in study group 1, (classes Va/Vb, P = 0.002, r2 = 0.457), but not in study group 2 (classes Vc/Vd, P = 0.118, r2 = 0.356) (Figures 1 and 3). Correlation coefficients were calculated on the remaining presenting features to assess predictors of GFR at last visit in study groups 1 and 2. None of the following was a significant predictor of GFR at follow-up: C3 at presentation, C4 at presentation or HTN at presentation.
A total of four patients had resolution of their renal failure at last follow-up appointment. Two of these patients with resolution of renal failure had WHO class Va. One was treated with prednisone/MMF while the other received prednisone/azathioprine. The other two patients with recovery of renal function had WHO class Vc. Their individualized immunosuppressive regimens consisted of the following: prednisone plus IV CTX and prednisone, IV CTX plus MMF.
Five patients with WHO class Va on presenting renal biopsy had renal insufficiency at last follow-up. One of these patients had presented initially with a GFR of 166 ml/min/1.73 m2, but subsequently developed chronic kidney disease and at the 2-year follow-up visit had a GFR of 65 ml/min/1.73 m2. Three of these five chronic renal failure patients underwent renal transplantation. One was transplanted 1 year after biopsy, the second patient was transplanted 3 years after biopsy and the third transplanted patient had a GFR of 62 ml/min/1.73 m2 at his 3-year post-biopsy clinic visit. This patient was transferred to the adult nephrology clinic, started on haemodialysis 9 years after his renal biopsy, and subsequently underwent a renal transplant 1 year post-initiation of dialysis. The fifth class Va patient with chronic renal failure died 2 years after her initial presentation. She had an outpatient documented GFR of 49 ml/min/1.73 m2 prior to her hospitalization. She died secondary to pulmonary haemorrhage and haemorrhagic pericardial effusion unresponsive to IV CTX and plasmapheresis.
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Discussion |
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Our retrospective study demonstrates children with pure membranous nephropathy (class Va) trend towards a more aggressive decline in renal function compared with those diagnosed with lupus class Vc. The patient's GFR at presentation predicted renal disease progression in class Va and should play a key role when determining the type and duration of therapy. These patients require close follow-up. If renal function continues to deteriorate despite aggressive immunosuppressive therapy, then the risk/benefit of immunosuppressive agents and long term prednisone treatment should be addressed.
Five patients in our cohort at last follow-up had either renal insufficiency, underwent renal transplantation or died, all of them with class Va. These findings are contrary to other studies which suggest classes III, IV, Vc and Vd portend a similar or worse outcome then class Va [5–7,9,11,12,16].
Our limited data set of patients presenting with renal failure does not corroborate with Sloan's study which demonstrated class Vc and Vd patients who presented with an elevated creatinine predicted progression of renal failure [9]. Other studies involving paediatric patients have demonstrated prognostic indicators of renal outcome including the following risk factors: (i) persistent hypertension, (ii) prolonged elevation of serum creatinine >1 mg/dl, (iii) proteinuria and haematuria on urinalysis, (iv) low C3 in setting of elevated serum creatinine and (v) anaemia [4–6]. In the current study we assessed blood pressure, serum C3, serum C4 and UPr/UCr at the time of renal biopsy. Although none of these was clinically significant to predict future renal function, the initial serum creatinine was predictive of follow-up GFR in the subclass of class Va. These findings are in contrast to the above paediatric cohorts which involved all classes of WHO lupus nephritis and were limited in the number of class V lupus patients.
WHO class Va lupus nephritis patient outcome being worse than the class Vc group may be related to transformation from class Va to a proliferative form of lupus nephritis (class III, IV, Vc and Vd) [17,18]. We did not repeat any renal biopsies in our patients. However, Sorof's study did not demonstrate any transformation from class V to class III or IV lupus nephritis in a group of paediatric patients. Instead, five patients progressed from class III or IV to class V on repeat renal biopsies [2]. Our conclusion must also be taken in context of the relatively short follow-up period. This may account for the better outcome seen in our study group 2 (Vc and Vd) compared to other studies.
Our data does not support or refute the efficacy of IV CTX in patients with class V lupus nephritis. We believe IV CTX therapy in the setting of classes Vc and Vd should still be considered because of the proliferative elements seen on renal biopsy and benefits of IV CTX demonstrated in other proliferative forms of lupus nephritis [15]. Currently, the final results of a NIH trial in membranous lupus nephropathy are anticipated. The preliminary data favours the use of IV CTX over cyclosporine A to maintain partial or complete remission at 5 years. Partial remission, defined by proteinuria <3.5 g/day and a 50% reduction from highest value, is associated with improved renal survival [19]. In our patients who received MMF, no significant statistical effects were identified on the limited follow-up of renal function or UPr/UCr. However, this analysis is limited and should not negate the other study which implicates this drug to be an effective antiproteinuric agent [20].
We used the 1995 version of the WHO classification for SLE nephritis. We present our data using this classification system because the treating physician's medical decision was based on this classification. The 2003 International Society of Nephrology and Renal Pathology Society (ISN/RPS) is a new classification for renal pathology in patients with SLE. Based on the new ISN/RPS classification, our study group 1 (WHO Va and Vb) corresponds to ISN/RPS class V, whereas our study group 2 (WHO Vc and Vd) corresponds to the class V with separate classification of either class III or class IV, respectively. We combined WHO Vc and Vd into study group 2 because of the single Vd patient. Therefore, based on our combining of groups, our results would not be different based on the WHO vs ISN/RPS classification system.
The small number of patients in our cohort limits the statistical power of our study. Unfortunately, the number of class V lupus nephritis patients is a small portion of the lupus nephritis population, representing only 10–20% of renal biopsies in adults and paediatrics [3]. Ideally, this could be addressed through retrospective analyses of multi-centre data bases which could provide further insight into prognostic indicators, clinical course and treatment options. Despite limitations of retrospective studies, such studies allow for identifying background information and provide guidelines to establish prospective studies.
We found patients with class Va lupus nephritis were at higher risk than class Vc and Vd for progression to ESRD. These patients should be followed closely and frank discussion with patient and family members regarding anticipated course of disease. Our findings do not support or dismiss the effects of any particular drug therapy on renal function or proteinuria in the treatment of class V lupus nephritis. A large multi-centre trial would offer the best chance to clarify an optimal treatment strategy for patients with class V lupus nephritis.
Conflict of interest statement. None declared.
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Notes |
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*This manuscript was presented in abstract form at the 2005 Pediatric Academic Societies’ Meeting in Washington D.C.
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References |
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Accepted in revised form: 28. 6.07
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