collapsing glomerulopathy

Renal biopsy shows glomerulus with global collapse of the glomerular tuft with surrounding tubules exhibiting atrophy. Interstitial fibrosis is also present (silver methenamine stain x200).

 

Collapsing glomerulopathy is a distinct morphologic variant of focal segmental glomerulosclerosis (FSGS) characterised by marked wrinkling and 'collapse' of the glomerular basement membrane and hypertrophy and hyperplasia of overlying podocytes . Compared with classic FSGS, the collapsing variant is distinguished by a more severe nephrotic syndrome, greater resistance to immunosuppressive therapy, rapid progression to end-stage renal failure and predominant occurrence in African American patients . Collapsing glomerulopathy was reported in patients with HIV-associated nephropathy . Additionally, an idiopathic variant of collapsing glomerulopathy has been defined . An increased incidence of parvovirus B19 DNA in renal biopsies of patients with non-HIV collapsing glomerulopathy was reported . Li et al.  found evidence of Simian virus 40 replication in human kidney and suggested that this virus may contribute to the pathogenesis of FSGS.

 

Recently, Markowitz et al. described seven patients with collapsing glomerulopathy and severe tubular degenerative changes in all those cases and related the disease to treatment with high-dose pamidronate. Another case report described a patient with multiple myeloma who was treated with high-dose pamidronate and developed nephrotic syndrome due to collapsing glomerulopathy, with subsequent fluctuations in proteinuria in parallel with discontinuation and reintroduction of the drug .

Studies in primary and recurrent FSGS implicate podocytes injury in the pathogenesis of segmental glomerular scarring . Evidence from the HIV-associated and non-HIV collapsing forms also supports the concept of primary podocytes injury, resulting in a loss of differentiation markers and a dysregulated podocytes phenotype . Shankland et al.  have demonstrated that human podocytes differentiation and proliferation depends on the levels of specific cyclin-dependent kinase inhibitors. An important consequence of podocytes dysregulation is the induction of apoptotic cell death. Apoptosis may constitute a direct pathogenic mechanism for loss of podocytes in FSGS  or, alternatively, it may represent a physiological process for the elimination of sublethally injured or excessively proliferating podocytes .

Our case of pamidronate-induced collapsing glomerulopathy showed well preserved tubules and interstitium. The biopsies of patients with HIV-related glomerulopathy and previously reported cases of pamidronate-induced collapsing glomerulopathy  displayed diffuse severe degenerative changes in tubules and tubular microcyst formation. Banerjee et al. described a patient with biopsy-proven acute tubular necrosis from pamidronate with a reversible renal failure due to solely tubular damage. The mechanism of tubular toxicity of pamidronate is probably similar to that of glomerular lesions: induction of apoptosis in tubular cells. An alternative explanation for tubular injury may be tubular epithelial cell damage by transdifferentiated podocytes having acquired macrophagic epitopes and migrating from the tuft to Bowman's space or drifting within the tubular lumens as was described in progressive glomerulonephritides and collapsing glomerulopathy .

In the previously reported and our cases of pamidronate-induced glomerulopathy, the total dose of the drug administrated ranged from 1.3 to 8.6 g. This wide range indicates that additional factors may influence the patient susceptibility to renal injury, such as the duration of intravenous infusion of the drug or underlying diseases like malignancy.

In conclusion, pamidronate-induced glomerulopathy can occur at recommended doses although long-term treatment is needed. Therefore, pamidronate-treated patients should be monitored for changes in renal function and proteinuria. The development of nephrotic syndrome and renal failure during remission of multiple myeloma should raise the possibility of collapsing glomerulopathy due to pamidronate.

Thus, pamidronate represents a new, toxic cause in the aetiology of collapsing glomerulopathy in human. Apoptosis is a possible mechanism for podocyte injury in this entity.

^{aiims nov 07}