Emerging treatments


Tolvaptan, a vasopressin V2 receptor antagonist, lowers cAMP concentrations in the distal nephron and collecting duct, the major site of cyst development in autosomal-dominant PKD (ADPKD), and inhibits the development of PKD in animal models orthologous to the human disease. [93] In a large randomized trial, tolvaptan slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in individuals with ADPKD compared with placebo, but was associated with a higher discontinuation rate owing to adverse events. [94] Tolvaptan has not been approved for the treatment of ADPKD by the FDA but has been approved for use in several countries, including Japan and Canada, and the European Medicines Agency has recommended granting a marketing authorization for the drug with an indication for slowing the progression of cyst development and failing kidney function in adults with normal to moderately reduced kidney function who have rapidly progressing ADPKD. High water intake alone may be protective through suppression of vasopressin and should be encouraged in individuals with preserved renal function. These drugs have no effect on liver cysts.

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 analog therapy (e.g., octreotide, lanreotide) has been shown in 3 clinical trials to be effective in decreasing liver cyst volume. [95] [96] [97] 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. [98] The drugs are administered intramuscularly on a monthly basis. Safety and efficacy data are limited by the short study duration (6-36 months) and the small patient numbers. Longer and larger trials will be necessary to establish long-term safety and efficacy. [95] [96] [97] [98]

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. [99] In the everolimus study, 2 years of treatment slowed the increase in total kidney volume, but did not slow the decline in renal function. [100] In another study, sirolimus halted cyst growth and increased parenchymal volume (compared with no appreciable changes in kidney parenchyma in the control group), [101] 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 GFR. [102] Another study combining everolimus with octreotide failed to show an augmentation of positive effects on liver volume reduction. [103] 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. [104] [105] Therefore, despite the conflicting evidence and negative trials, mTOR inhibitors continue not to be recommended as an effective treatment for ADPKD. [106]

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. Preclinical trials are in progress with these agents and clinical trials are in progress with Src kinase inhibitors. [107] [108]


Roscovitine is a cyclin-dependent kinase inhibitor shown to be effective in animal models of PKD. [109]

ACE inhibitors/angiotensin-II receptor antagonist combinations

The HALT-PKD study (an ongoing NIH-funded prospective study) is designed to determine whether treatment with an ACE inhibitor versus an ACE inhibitor/angiotensin-II receptor antagonist combination is superior in slowing the progression of renal cystic disease in patients with stage 1 or 2 chronic kidney disease, or is effective in slowing the GFR decline in patients with stage 3 disease. The study will also address whether lowering the BP to a target <110/75 mmHg is better than the current standard target of <130/80 mmHg.

Use of this content is subject to our disclaimer