Recurrence of membranoproliferative glomerulonephritis after renal transplantation in Denys–Drash

Abstract

Denys-Drash syndrome (DDS) consists of the triad of nephropathy, male pseudohermaphroditism, and Wilms tumor caused by mutations within exons 8 or 9 of the Wilms tumor suppressor gene 1. Early onset nephrotic syndrome progresses to end-stage renal failure. The characteristic histological lesion is diffuse mesangial sclerosis. Here, we report on a boy with DDS who presented early with diffuse mesangial sclerosis, but subsequently also developed immune complex glomerulonephritis with a membranoproliferative pattern (MPGN-pattern GN) in his native kidneys. Four years after renal transplantation, immune complex glomerulonephritis with an MPGN pattern recurred in the renal graft resulting in proteinuria and progressive renal insufficiency.

Immune-complex glomerulonephritis with a membranoproliferative pattern in Frasier syndrome: a case report and review of the literature

“…Second, dysfunctional WT1 might be associated with aberrant immune responses, leading to IC formation [22], based on its role in the transcriptional regulation of multiple genes implicated in the differentiation of hematopoietic stem cells and apoptosis [24]. Consistent with our case, clinical studies report the effectiveness of cyclosporin in WT1 glomerulopathy [25], with no report of MPGN recurrence after renal transplant in patients bearing WT1 mutations, except for one DDS patient [4], which represents an unusual case of MPGN recurrence in the allografted kidney, even after WT resection and subsequent thorough immunosuppressive therapy.…”

“…Mutational survey of WT1 in steroid-resistant nephrotic syndrome cohorts [2,3] revealed that an intron 9 splice mutation typically causes FSGS with a gonadal tumor, whereas missense and truncating mutations result in DMS with nephroblastoma. However, morphologic abnormalities considerably vary in histologic appearance among individuals with DDS/FS [3][4][5][6][7][8][9]. Detailed analysis of the renal histology of DDS individuals revealed complex glomerular changes, including endotheliosis-like endothelial injuries, foot-process fusion, and GBM alterations [6].…”

“…Previous studies report a significant fraction of DDS/FS individuals, including original and some familial cases, display MPGN with IC deposition in addition to FSGS or DMS, a histopathology commonly seen in WT1-related glomerulopathy [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] (Tables 1 and 2). Out of six DDS cases, four patients harbored a p.Arg467Trp (NM_024426.6:c.1399C > T) variant [4][5][6], the most common substitution (present in 40% of DDS patients), and two harbored a nonsense p.Arg463Ter (NM_024426.6:c.1387C > T) variant [3,7] manifesting in an MPGN pattern. Moreover, nine FS cases have been reported, including two monozygous twins harboring a donor splice site mutation in intron 9 and initially presenting with MPGN [8,9].…”

“…In this context, it is plausible that ICs might form through aberrant immune responses against oncofetal and/or non-autologous tumor antigens and trigger endothelial injuries of glomerular capillaries in WT patients [23]. Clinically, in most DDS cases, glomerulonephritis precedes or manifests simultaneously with WT diagnosis [3][4][5][6][7][12][13][14][15][16] (Tables 1 and 2). Moreover, nephrotic syndrome can persist, even after complete excision of tumors with no evidence of recurrence and metastasis [4,7].…”

“…WT1-related nephropathy is generally ascribed to developmental defects in glomerular podocytes [2,3]. Several patients with DDS or FS display membranoproliferative glomerulonephritis (MPGN) that is mainly characterized by subendothelial immune deposits [3][4][5][6][7][8][9], suggesting that renal pathologies resulting from WT1 mutations are complex and affected by multiple factors. Possible pathogenic mechanisms are discussed by reviewing the current literature.…”