Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy. II. Light microscopic and clinical studies

Abstract

It is well known that lesions morphologically identical with focal segmental glomerulosclerosis (FSGS) may appear in IgA nephropathy (IgAN). Capsular adhesions without underlying abnormalities in the tuft, often the first sign of FSGS, are frequent in IgAN. In this retrospective study, a new cohort of 128 adult patients with IgAN was used to validate the new Oxford classification system of IgAN, and shown to have highly significant associations with clinical and outcome parameters. We then used these patients to determine the extent to which IgAN could be accounted for in terms of FSGS. Some form of lesion consistent with FSGS, notably hyalinosis and collapsing glomerulopathy, was found in 101 of these patients. No glomerular lesions were found in 16 patients, and 11 had mild lesions not definable as FSGS. Those with FSGS had significantly worse renal survival at 80 months than those without. Comparison of pure forms of FSGS (excluding collapsing glomerulopathy) with cases of FSGS having other glomerular lesions (mesangial hyperplasia, endocapillary hypercellularity, glomerular necroses, extracapillary proliferation) revealed that those with FSGS and other superimposed lesions did significantly worse than cases of pure FSGS at 80 months following diagnosis. Importantly, patients with pure FSGS had relatively poor survival even without other superimposed glomerular abnormalities. Thus, the majority of cases of IgAN can be interpreted as representing one or another variant of FSGS. Hence, interpreting IgAN in terms of FSGS emphasizes the role that podocyte lesions may play in the pathogenesis and progression of this disease.

IgA Nephropathy with Minimal Change Disease

“…Mesangial cells may respond to immune deposits and release inflammatory cytokines that cause mild alterations of the glomerular filtration barrier, but this typically results in only mild, subnephrotic proteinuria (26). Hill and colleagues (27,28) have suggested that aberrantly glycosylated IgA1 can cause mesangial cells to release cytokines that cause podocyte injury, resulting in some of the segmental sclerosis often seen in IgAN (although predominantly absent in this series). In the analogous example of lupus nephritis (LN), patients with mesangial proliferative LN (class II) who present with full NS and extensive foot process effacement in the absence of endocapillary involvement are interpreted as having LN II with superimposed MCD (29) or lupus podocytopathy (30,31).…”

Relationships between Levels of Urinary Podocalyxin, Number of Urinary Podocytes, and Histologic Injury in Adult Patients with IgA Nephropathy

“…Recently, IgAN patients with FSGS have been reported to have a relatively poor renal outcome than those without FSGS (30,31). Preventing the development of glomerulosclerosis as soon as possible is extremely important, particularly if the renal outcome can be improved by some treatments.…”

Collapsing Glomerulopathy in 19 Patients with Systemic Lupus Erythematosus or Lupus-Like Disease

“…In a recent report by El Karoui et al (38), IgA nephropathy was associated with podocyte injury representing all variants of FSGS, including the collapsing variant. The work by El Karoui et al (38) concluded that immunologic injury may be responsible for the epithelial injury seen in immune complex-mediated glomerular disease. Development of antiphospholipid antibodies and subsequent thrombotic microangiopathy may also play a role in some lupus patients by causing podocyte ischemia to contribute to epithelial injury (particularly case #16 in our study).…”

“…A circulating factor has been postulated to play a role in podocyte injury in FSGS not otherwise specified in the form of high soluble urokinase receptor (37). In a recent report by El Karoui et al (38), IgA nephropathy was associated with podocyte injury representing all variants of FSGS, including the collapsing variant. The work by El Karoui et al (38) concluded that immunologic injury may be responsible for the epithelial injury seen in immune complex-mediated glomerular disease.…”