Caspase-4 may play a role in loss of proximal tubules and renal injury in nephropathic cystinosis.

Nephropathic cystinosis is characterized clinically by generalized proximal renal tubular dysfunction, renal Fanconi Syndrome and progressive renal failure. Glomerular-proximal tubule disconnection has been noted in renal biopsies from patients with nephropathic cystinosis. In vitro studies performed in cystinotic fibroblasts and renal proximal tubular cells support a role for apoptosis of the glomerulotubular junction, and we have further extended these studies to human native cystinotic kidney specimens. We performed semi-quantitative analysis of tubular density in kidney biopsies from patients with nephropathic cystinosis and demonstrated a significant reduction (p=0.0003) in the number of proximal tubules in the kidney tissue of patients with cystinosis compared to normal kidneys and kidneys with other causes of renal injury; this reduction appears to be associated with the over-expression of caspase-4. This study provides the first quantitative evidence of a loss of proximal tubules in nephropathic cystinosis and suggests a possible role of caspase-4 in the apoptotic loss of proximal tubular cells. Further work is needed to elucidate if this injury mechanism may be causative for the progression of renal functional decline in nephropathic cystinosis.