Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

Enhancement of renal function by a long-acting somatostatin analogue in patients with decompensated cirrhosis.

The effect of the long-acting somatostatin analogue SMS 201-995 on renal function was investigated in nine cirrhotic patients with ascites, low urine output, low serum sodium, and normal serum creatinine. SMS 201-995, infused at 40 micrograms/h for 2 h, produced a significant increase in urine volume, a significant decrease in urine osmolality, and a significant increase in creatinine clearance. These changes, although less pronounced, persisted 24 h after the infusion of the analogue. No significant changes in free water clearance, urinary sodium excretion or serum sodium were noted. The effects of SMS 201-995 might be attributed to an improvement of renal haemodynamics through inhibition of vasoconstrictor systems acting in cirrhosis. It is concluded that SMS 201-995 may have a role in the treatment of the renal abnormalities complicating liver disease.