Carmine Zoccali

This week we have two nice presentations on rare, hereditary nephropathies now deciphered at molecular level and a presentation that highlights the entering of APKD in the Clinical Trials arena.
In the first lecture Dr. Matthias Wolf (Dallas) describes recent progress on Uromodulin associated kidney diseases. Uromodulin is the most abundant protein in human urine implicated in nephrolithiasis, urinary tract infection and interstitial nephritis. Beyond these common conditions, mutations in the uromodulin gene are now solidly linked to three autosomal dominant nephropathies, namely familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2 and glomerulocystic kidney disease. These mutations result in a misfolded protein which accumulates in the endoplasmatic reticulum wherein it may trigger apoptosis. On the other hand, basolateral excretion of mutated uromodulin may activate an immune response in the renal interstitium. In vitro studies have shown that chaperones and colchicine can alleviate the intracellular damage that is caused by uromodulin mutations. However, no data in humans testing these interventions have been produced so far.
In the second lecture Dr. Emmanuelle Plaisier (Paris) focuses on type IV collagen inherited diseases. Type IV collagen is the main component of basement membranes and 6 different a-chains sharing a large collagenous domain, a small 7S domain and a non-collagenous (NC) domain at the aminoterminal have been described. The collagen IV,a1 mutation (Col4a1) mutation is associated with brain or eye restricted disease or with a systemic phenotype, hereditary angiopathy, nephropathy, aneurysm and cramps syndrome (HANAC). Collagen IV hereditary nephropathies should be suspected in cases of familial hematuria with normal GBM thickness and no deafness and in cases of multicystic kidney disease with bilateral large cysts but normal kidney size. A systematic search for a muscular, brain and eye (retinal arteriolar tortuosities) disease should always be performed in patients and in their relatives. The issue is clinically relevant because, renal disease apart, cerebral aneurysms expose affected patients to the risk of vessel rupture.
In the final lecture Dr. Piero Ruggenenti (Bergamo) summarises mechanisms of cystogenesis in APKD and pinpoints molecular alterations that are potentially modifiable by pharmacological interventions. Among emerging therapies for APKD somatostatin appears particularly promising. This compound is a cyclopeptide that inhibits the secretion of growth hormone, insulin and glucagon by binding to specific receptors which inhibit adenylate cyclase. One of these receptors, Sst2, is represented in the human kidney. Adenyl cyclase inhibition in the kidney suppresses cell proliferation and chloride secretion thereby reducing cystogenesis. Dr. Ruggenenti provides preliminary information on an ongoing 3-year, phase II-III study in 66 patients randomised to somatostatin or placebo. This and other trials focusing on additional pathways whereby cystogenesis can be modified (e.g. mTOR pathway inhibition) bring new hope for patients with this until now untreatable disease.

Enjoy your NDTe!

Carmine Zoccali – Editor in Chief NDT-Educational