Significance of segmental glomerulosclerosis in IgA nephropathy: What is the evidence?

*Corresponding author: Prof. Muhammed Mubarak, Department of Histopathology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan. E-mail: [email protected] P IgA nephropathy (IgAN) is the commonest primary glomerular disease worldwide (1,2). The disease is notorious for a wide variation in the epidemiology, clinical presentation, histology, and the prognosis (3,4). The only unifying feature is the presence of dominant or codominant IgA deposits in the mesangium and occasionally in the peripheral capillary loops on immunofluorescence (IF) microscopy (5-9). The reported frequency ranges from 2 to 52% of all renal diseases in renal biopsy series from different parts of the world (1,2). The clinical presentation ranges from asymptomatic to acute renal failure to endstage renal disease (ESRD). The typical pathological lesion is the mesangial proliferative glomerulonephritis (MesPGN), but the spectrum of pathological lesions is broad and the morphological lesions of segmental glomerulosclerosis are common on renal biopsies in patients with primary IgAN (10-16). Hill et al. noted in their preliminary analysis the presence of such lesions in 66% of cases (17). In a subsequent detailed study, some form of segmental glomerulosclerosis was found in 78.9% of biopsies (18,19). The original study cohort of the Oxford classification showed such lesions in 76% of the biopsies (10). We also found the lesions of segmental glomerulosclerosis in 63.2% in a cohort of consecutive cases of primary IgAN (unpublished data). The exact origin and pathogenesis of these lesions is still enigmatic. It is possible that, there are at least three ways by which segmental glomerulosclerosis may occur in patients with IgAN. First; by post-inflammatory scarring of segmental proliferative or necrotizing lesions, commonly observed in this disease, second; due to compensatory hemodynamic changes following nephron loss, and finally by primary podocyte damage, perhaps due to mediators released from mesangial cells (18,19) or perhaps due to direct cytotoxic action of IgA1 deposits. This schema of events is shown schematically in Figure 1. We and some other investigators are of the view that it is possible to identify two types of segmental sclerosing lesions on renal biopsy examination in these patients (17,18). First is the focal segmental glomerulosclerosis (FSGS), which is classified as a separate category in the Hass classification of IgAN and more recently defined more elaborately in Columbia classification (20,21). This lesion may be considered as “definite FSGS” lesion or the FSGS of Columbia classification and is the result of podocyte injury. How the podocyte injury is induced by IgA deposits is not known at preset. The second mechanism involves fibrosis or healing process arising on the background of segmental proliferative and necrotizing lesions. This may be considered the “indeterminate form” of segmental glomerulosclerosis Implication for health policy/practice/research/medical education: Primary IgA nephropathy (IgAN) is the commonest glomerulopathy worldwide. Its clinical presentation, histology and prognosis vary widely. The lesions of segmental glomerulosclerosis are common in IgAN and represent participation of at least three pathogenetic mechanisms. It is important to identify the different subtypes of segmental sclerosing lesions as these are of prognostic value. A R T I C L E I N F O