The spectrum of FSGS: does pathology matter?

The spectrum of podocytopathies ranges from steroid-responsive minimal change disease (MCD) to devastating focal segmental glomerulosclerosis (FSGS), which may recur and cause end-stage renal disease in the transplant. Sclerotic lesions of glomeruli may also develop as a secondary event, both in immune complex and non-immune diseases, such as conditions with extensive loss of renal mass, diabetic nephropathy, arterionephrosclerosis or reflux nephropathy. Even amongst the group of patients with so-called ‘primary FSGS’, there is increasing recognition of a variety of contributing aetiologies, including genetic, viral, drug toxicity and others [1]. Discernment of clues to patient course and prognosis could be valuable in stratifying patients according to risk and targeting improved treatment. In addition to the traditional methods afforded by renal biopsy, novel approaches with proteomics, microarray gene expression, genetic influences and others have been used to approach this problem [2–4]. Ultimately, of course, patients do not read textbooks, and we must continue to learn from observations in our patients to further refine and improve our approaches for better understanding of these entities. In this regard, the studies of Canaud et al. are of interest [5]. They have studied retrospectively a group of 77 patients with idiopathic nephrotic syndrome and ‘FSGS’ in native kidneys who underwent renal transplantation. Of this largely paediatric cohort, 42 patients had development of nephrotic range proteinuria after transplantation. As expected, early biopsies performed in these patients with recurrent nephrotic syndrome showed no lesions by light microscopy in most patients (32/33). One of these early recurrent nephrotic syndrome biopsies showed perihilar variant FSGS. This constellation of lack of sclerosis in a setting of presumed recurrent disease clinically was a condition unfortunately designated as ‘minimal change disease’ by the authors (see below). Over the long-term follow-up, a total of 20 patients had FSGS lesions in the transplant, and of these, seven showed collapsing lesions at time points ranging from 6 to 48 months after transplant (on average 22 months). Biopsies done at month 3 in 40 of the patients showed lesions in 14 patients. Of interest, lesions observed in month 3 biopsies were the same as seen later in seven of the eight patients who had segmental lesions at both time points, with one patient showing transition from a tip lesion to a perihilar lesion. Patients who showed the same segmental lesions present at both time points included collapsing (n = 2), cellular (n = 3) and perihilar (n = 2) variants. It is important in analysing segmental lesions in the transplant to recognize that the transplanted kidney remains, of course, a kidney, and is subject to all injuries that may affect the native kidney. In this report, unfortunately, electron microscopy was not done to assess these lesions. This is important in light of the multiplicity of injury that may result in segmental lesions. Recent studies have demonstrated that secondary segmental sclerotic lesions have subtotal foot process effacement, often <50%, whereas primary FSGS typically has extensive foot process effacement [6,7]. Thus, to completely understand the dynamics of the collapsing and perihilar lesions observed, particularly at late time points after transplant, it would be of great interest to examine the extent of foot process effacement and other concomitant lesions that could suggest e.g. calcineurin inhibitor toxicity as a contributor to the collapsing phenotype. Our recent survey of transplant lesions demonstrated that recurrence of the disease FSGS in the transplant (diagnosed based on significant proteinuria and extensive foot process effacement, with or without overt segmental sclerosis) was very rare after 2 years, and most recurrent FSGS occurred within the first 6 months after transplantation [8]. Thus, segmental sclerotic lesions at later time points most often represented transplant glomerulopathy evidenced by duplication of glomerular basement membrane and increased lamina rara interna and subtotal foot process effacement by electron microscopy; or calcineurin inhibitor toxicity, often with collapsing features and subtotal foot process effacement, with concomitant arteriolar nodular hyalinosis [9]. New approaches to investigate the aetiology of this spectrum of MCD to FSGS lesions include immunohistochemistry, proteomic and gene array studies. Thus, the group of Kerjaschki has demonstrated that dystroglycan staining is markedly decreased in minimal change disease, while remaining intact in the non-sclerotic areas in FSGS [4]. Proteomic and gene array studies by Kretzler also point to a different pathogenesis of minimal change disease and FSGS [2]. The term ‘minimal change disease’ is typically used for a steroid-responsive