Plasmapheresis with immunosuppressive therapy vs immunosuppressive therapy alone for rapidly progressive anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis

Sir,

Rapidly progressive deterioration of kidney function is a common and usually serious feature of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis; it can lead to end-stage renal failure (ESRF) within weeks. Rapidly progressive glomerulonephritis (RPGN) is a syndrome characterized by a sudden and relentless decline in renal function associated with extensive crescent formation involving most glomeruli [1]. The European Vasculitis Study Group reported recently that the glomerular filtration rate and predominantly chronic renal lesions are potent predictors of patient outcome in ANCA-associated RPGN [2]. Intensive immunosuppressive therapy improves the outcome of patients with RPGN; RPGN progresses to ESRF in 90% of patients who do not undergo therapy [3]. There have been reports that plasmapheresis delays ESRF in patients with ANCA-associated RPGN [4,5], and its limited efficacy in some patients with ANCA- positive glomerulonephritis may be explained in part by its insufficient effect on the elimination of pro-inflammatory cytokines [6].

Podocytes, which play an important role in glomerular filtration in conjunction with the glomerular basement membrane, are strategically situated on the outer surface of the glomerular capillary wall. We reported previously that urinary podocytes may be a useful laboratory marker for estimating the severity of glomerular injury [7,8]. The aim of the present study was to determine whether plasmapheresis and/or conventional immunosuppressive therapy affect urinary podocyte excretion in patients with ANCA-associated RPGN.

Twenty-two patients with biopsy-proven RPGN underwent either immunosuppression therapy with prednisolone (initial dose: 60 mg/day) and cyclophosphamide (100 mg/day) (group A: n = 10; seven men, three women; mean age 58.5 years) or plasmapheresis and immunosuppression therapy (group B: n = 12; seven men, five women; mean age 60.0 years). Seventeen patients (eight in group A and nine in group B) were perinuclear-ANCA (P-ANCA) [myeloperoxidase (MPO)-ANCA]-positive, and five patients (two in group A and three in group B) were cytoplasmic-ANCA (C-ANCA) [proteinase-3 (PR-3)-ANCA]-positive. P-ANCA and C-ANCA were determined by enzyme-linked immunosorbent assays with Nephroscholar MPO-ANC and Nephroscholar PR3-ANC kits (Nipro Corp., Osaka, Japan). Five of the 10 patients in group A and 6 of the 12 patients in group B had interstitial pneumonitis. Plasmapheresis was performed twice weekly with the Plasmacure (Kuraray Co., Ltd, Osaka, Japan) plasma separator and Evaflux 2A (Kuraray) fractionator. The total number of plasmapheresis sessions (3000 ml each) for each patient ranged from 5 to 10 (mean 8.0). Immediately before and at 3 and 6 months after treatment, urinary podocytes were counted by means of anti-podocalyxin antibodies as described previously [7,8]. Data are expressed as mean±SD. Statistical differences between groups were determined by analysis of variance. Correlation between the number of plasma exchanges, urinary podocyte counts and serum creatinine levels were assessed by Pearson's correlation coefficient. Differences were considered significant at P<1.05.

After 6 months, patient survival was 80% in group A and 100% in group B. After 3 months, serum creatinine showed little change in group A (before treatment, 3.9±1.3 mg/dl; at 3 months, 4.1±1.5 mg/dl); however, serum creatinine decreased from 4.3±1.6 to 2.7±1.1 mg/dl (P<0.01) in group B. Urinary protein excretion showed little change during the study period in either group (group A, from 0.8±0.2 to 0.7±0.3 g/day; group B, from 0.9±0.2 to 0.8±0.2 g/day). In group A, the urinary podocyte count decreased from 5.5±1.1 to 3.9±1.0 cells/ml (P<0.05). In group B, the count decreased from 5.9±1.9 to 1.7±0.6 cells/ml (P<0.01). After treatment, the urinary podocyte count was significantly lower in group B than in group A (P<0.05). There was no correlation between serum creatinine level and urinary podocyte excretion. After 6 months, serum creatinine levels in groups A and B were 5.4±1.8 and 3.0±1.2 mg/dl, respectively (P<0.01). In addition, the urinary podocyte count was 4.8±1.2 cells/ml in group A and 1.7±0.7 cells/ml in group B (P<0.01). P-ANCA titres (normal<10 EU) were significantly decreased after treatment in both groups (group A, from 250±60 to 40±20 EU; group B, from 240±46 to 36±12 EU, P<0.01). However, the difference between the two groups was not statistically significant (Table 1). All patients in the plasmapheresis group remained in sustained remission 6 months after stopping plasmapheresis, whereas relapse occurred in 38% of patients without plasmapheresis treatment. A strong negative correlation was observed between the number of plasma exchanges and the urinary podocyte count (r = –0.984, P<0.001) and the serum creatinine level (r = –0.975, P<0.001).


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Table 1. Changes in markers of renal injury after treatment with immunosuppression therapy alone (group A) vs plasmapheresis and immunosuppression therapy (group B)

 
This is the first report that plasmapheresis with immunosuppression is more effective than immunosuppression alone in ameliorating podocyte injury in ANCA-associated RPGN. Plasmapheresis may influence the activity of vasculitis not only by removing pathogenic autoantibodies but also by lowering the serum levels of circulating cytokines [6]. However, the precise mechanisms are still unclear. Podocytes form a filtration slit structure that prevents the escape of plasma protein from the glomerular circulation. Normal function of the filter requires maintenance of the foot-process structures of the podocytes. Injury to the glomerulus is usually associated with protein leakage across the glomerular filter into the urine. Meyer et al. [9] reported that the number of podocytes per glomerulus is the strongest predictor of renal disease progression among the morphological glomerular changes. We reported previously that counting of urinary podocytes is useful in various renal diseases [7,8,10]. It is difficult to speculate about pathological changes occurring in the glomerulus on the basis of laboratory test results. Discovery of a new marker in the urine would allow estimation of the degree of glomerular injury. Traditionally, clinical measures such as proteinuria and serum creatinine have guided treatment decisions. However, these measures do not specifically identify the sites of renal injury. In contrast, the podocyte is a constituent of the glomerulus; thus, the urinary podocyte count may be a direct indicator of glomerular injury. Urinary protein did not differ significantly between our two treatment groups. We previously reported that podocytes are absent from the urine of patients with minimal-change nephrotic syndrome despite massive proteinuria [7]. Data suggest that both proteinuria and urinary podocytes are important in estimating glomerular injury, but proteinuria does not necessarily coincide with urinary podocyte excretion. We offer herein the first report of urinary podocytes detected in patients with RPGN, and suggest that early plasmapheresis might prolong renal survival.

In summary, our data suggest that plasmapheresis may ameliorate glomerular epithelial injury and delay ESRF for a short period (6 months) in ANCA-associated RPGN. We continue to monitor the long-term renal outcome in both treatment groups, and a large population study is now in progress.

Conflict of interest statement. None declared.

Tsukasa Nakamura, Takaharu Matsuda, Yasuhiro Kawagoe, Yoshihiko Ueda1, Isao Ebihara2 and Hikaru Koide2

Department of Medicine Shinmatsudo Central General Hospital Chiba1 Department of Pathology Koshigaya Hospital Dokkyo University School of Medicine Saitama2 Department of Medicine Koto Hospital Tokyo Japan Email: hkoide{at}koto-hospital.or.jp

References

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