While membranous nephropathy (MN) is one of the most common forms of nephrotic syndrome in adults, it is rarely associated with the pathologic finding of crescents on kidney biopsy. Most reported cases are in the context of concomitant anti-neutrophil cytoplasmic antibody (ANCA) or anti-glomerular basement membrane (anti-GBM) antibody disease, or were documented prior to the association between ANCA and crescentic glomerulonephritis. Crescentic MN without ANCA or anti-GBM has only been rarely described. In a recent AJKD article, Rodriguez and colleagues present a retrospective case series of 19 patients with ANCA- and anti-GBM negative crescentic MN whose kidney biopsies were reviewed at the Mayo Clinic between 1994 and 2013. All patients presented with nephrotic range proteinuria (3.3 to 29 g/day), 12 had nephrotic syndrome, and most had evidence of hematuria. None of the patients had clinical evidence of vasculitis or systemic lupus erythematosus (SLE) during the follow-up period after the biopsy. Four patients tested positive for anti-nuclear antibody (ANA), but none were positive for anti-double-stranded DNA antibody, hepatitis B or C virus, or HIV. The authors provide representative light, immunofluorescence, and electron microscopic images of these biopsies, demonstrating the presence of thickened GBMs with focal cellular crescents (on average, crescents were seen in 25% of glomeruli), granular staining for IgG (C3, κ, and λ were also positive but not shown), and diffuse foot process effacement. Interestingly, PLA2R immunostaining was positive in 6 of 16 biopsy specimens (38%), including 3 that showed mesangial or endocapillary proliferation, findings typically characteristic of secondary MN. Patient prognosis was variable, with some patients responding to treatment and others progressing to CKD or ESRD.
The findings of this study raise a number of questions. Does the presence of crescents in the context of MN suggest a different pathophysiologic mechanism of disease in these patients? Is crescentic MN a distinct variant of MN, or could it represent MN with superimposed ANCA-negative crescentic glomerulonephritis, considering that 10-30% of patients with pauci-immune crescentic glomerulonephritis are negative for serum ANCA? One of the patients in the study subsequently was found to have a positive MPO titer 8 months after kidney biopsy, highlighting the importance of repeat ANCA testing in these patients. The majority of the cases described in this report were negative for anti-PLA2R antibodies, suggesting either that most crescentic MN involves a pathogenic antibody against a different antigen than PLA2R. Alternatively, the occult secondary causes for MN, other than vasculitis or autoimmune disease, could be associated with crescentic MN.
Do patients with crescentic MN need to be treated more aggressively than patients with MN without crescents? Given the relative rarity of crescentic MN, many of these questions may be challenging to study prospectively, but if answered, could provide valuable insight into our understanding of this disease process.
Albert Q. Lam, MD