Alport Syndrome is a Partial Tubulointerstitial Disease of the Kidney

Recent genetic studies have shown that Alport syndrome (AS) is much more prevalent than clinically recognized, suggesting that atypical cases may phenocopy other kidney diseases. To date, pathomechanistic studies of AS have focused exclusively on the glomerular membrane, yet equally strong expression of collagen α(IV) chains is found along the distal renal tubule. We hypothesized that genetically determined abnormality of the tubular collagen IV (α345) molecule contributes to kidney failure and may drive atypical phenotypes.

Histology and primary tubular cells (PTCs) of 8 patients with AS were investigated alongside controls.

Collagen α5 (IV) was detected within the tubular basement membrane (BM) (TBM) of the distal segments of renal tubules by immunohistochemistry. In situ hybridization on human tissues and protein detection of collagen α5 (IV) in PTC cultures clearly showed that the distal tubular apparatus predominantly produces collagen IV for the TBM. Electron microscopy of biopsies from patients with AS demonstrated irregularities of the TBM, somewhat similar as described for the glomerular BM (GBM). Finally, computer-assisted analyses showed that in biopsies of patients with AS, interstitial fibrosis preferentially occurs in spatial vicinity of the affected distal tubules.

Our study demonstrates that the collagen IV (α345) molecule within the TBM is largely produced by the distal tubule itself. In AS, the TBM shows ultrastructural changes, which may induce fibrotic molecular signatures, as tubulointerstitial fibrosis appears to start in the vicinity of the distal tubule. Therefore, we postulate that the progression of kidney disease in AS may in part stem from the (distal) tubular apparatus.