Polycystic kidney disease - Emerging treatments

Lixivaptan

A selective vasopressin V2-receptor antagonist that lowers cyclic adenosine monophosphate (cAMP) concentrations in the distal nephron and collecting duct, the major site of cyst development in autosomal-dominant PKD (ADPKD). Results from the first clinical trial are as yet unpublished.[98] The US Food and Drug Administration (FDA) has granted orphan-drug designation to lixivaptan for the treatment of ADPKD.

Somatostatin SST2 inhibitors

A small prospective clinical trial demonstrated that octreotide attenuated the increase in kidney volume in patients with ADPKD. Somatostatin acts on the SST2 receptors to inhibit cAMP accumulation in both the kidneys and liver. Somatostatin analogue therapy (e.g., octreotide, lanreotide) has been shown in 3 clinical trials to be effective in decreasing liver cyst volume.[99][100][101] It was also shown to be effective in decreasing mean total kidney volumes at 1- and 3-year intervals in a study that evaluated the effects of octreotide on kidney disease.[102] However, one trial of lanreotide did not slow the decline in kidney function over 2.5 years of follow-up, despite a beneficial effect on kidney growth.[103]

Therapeutic microRNAs

MicroRNA-regulated signalling has emerged as a new mechanism to explain imbalance in proliferation and apoptosis of cyst epithelial cells.[104] RGLS4326 is a specific anti-miR-17 inhibitor, which preferentially targets the kidney and inhibits the pathological functions of the miR-17 family of miRNAs in ADPKD.[105] The FDA has granted orphan-drug designation to RGLS4326 for the treatment of patients with ADPKD and the first clinical trial is in progress.[106]

mTOR inhibitors

These agents inhibit the mTOR pathway, which is involved in PKD pathogenesis. In early chronic kidney disease, 18 months of sirolimus therapy failed to halt kidney growth.[107] In the everolimus study, 2 years of treatment slowed the increase in total kidney volume, but did not slow the decline in renal function.[108] In another study, sirolimus halted cyst growth and increased parenchymal volume (compared with no appreciable changes in kidney parenchyma in the control group),[109] although only 15 of 21 patients managed to complete the study, owing to side effects and losses to follow up. Sirolimus therapy was also associated with a marginal increase in proteinuria and also appeared to reduce native kidney and liver volumes in patients with ADPKD following renal transplant. However, it does not seem to slow down the decrease of glomerular filtration rate.[110] Another study combining everolimus with octreotide failed to show an augmentation of positive effects on liver volume reduction.[111] The EXIST 1 and 2 studies in individuals with tuberous sclerosis, which is associated with constitutive activation of mTOR, showed that everolimus was effective in achieving a 50% reduction in total volume of target renal angiomyolipomas relative to baseline in 42% of individuals, and also induced regression in growth of subependymal giant cell astrocytomas.[112][113] Therefore, despite the conflicting evidence and negative trials, mTOR inhibitors continue not to be recommended as an effective treatment for ADPKD.[114]

Inhibitors of Erb-B1, Erb-B2 tyrosine kinase, Src kinase or MEK

Clinical data are encouraging, but no human data are available in ADPKD yet. Pre-clinical trials are in progress with these agents and clinical trials are in progress with Src kinase inhibitors.[115][116]