Riding the waves: evidence for a beneficial effect of increased water intake in autosomal dominant polycystic kidney disease patients?

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) can lead to end-stage kidney disease and accounts for ∼10% of people receiving renal replacement therapy. Until recently, no treatment had been proven to effectively postpone kidney failure. Interestingly, experimental studies that have been published over the past decades have suggested a detrimental role for the antidiuretic hormone arginine vasopressin (AVP) in ADPKD. V2 receptor activation by AVP was discovered to result in an increase of 30,50-cyclic adenosine monophosphate (cAMP) [1]. In turn, cAMP stimulates cell proliferation and fluid secretion, leading to cyst formation and cyst growth [2–4]. ADPKD patients appeared to have high serum levels of AVP, and AVP levels were, in cross-sectional studies, associated with disease severity [5] and, in longitudinal studies, with disease progression [6, 7]. These observations formed the rationale to study interventions that block this cAMP-mediated pathway using V2 receptor antagonists. In various animal models for cystic kidney disease, these interventions were successful to reduce cyst growth [8–10]. Subsequently, the selective AVP V2 receptor antagonist tolvaptan was tested for its efficacy in ADPKD patients in the TEMPO 3:4 trial. For the first time, a medical treatment proved to be beneficial with respect to kidney outcomes. In 1445 ADPKD patients, relatively early in the disease, treatment with tolvaptan slowed the rate of growth in total kidney volume by ∼50% and the rate of estimated glomerular filtration rate (eGFR) loss by ∼30% compared with placebo. In 2013, however, the US Food and Drug Administration (FDA) decided against approval of tolvaptan for the indication of slowing disease progression in ADPKD (http:// www.fda.gov/downloads/advisorycommittees/committeesmeeting materials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ ucm373520.pdf). This decision was based, amongst others, upon questions relating to the effectiveness of the drug and to tolvaptan’s risk of drug-induced liver injury. This decision felt surprising for some, because the effect on eGFR loss with tolvaptan is comparable with that of, for instance, angiotensin-II receptor blockers that are registered for diabetic nephropathy [11], a disease for which other treatments are available, whereas for ADPKD there is no renoprotective alternative. In addition, all liver function abnormalities that occurred in the TEMPO 3:4 trial were reversible after drug withdrawal. The FDA, however, extrapolated from these data that 1 per 3.000 treated ADPKD patients may develop hepatic failure for which a liver transplant would be needed (http://www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/Cardiovascular andRenalDrugsAdvisoryCommittee/UCM364582.pdf ). This should be weighed against the need for liver transplantation due to the cystic disease which occurs in a number of ADPKD patients anyway [12, 13]. Notwithstanding these considerations, the FDA decided not to register tolvaptan for the indication ADPKD, but to ask for additional evidence. The decision of the European Medicines Agency is expected late in 2014. With tolvaptan at present not being available for clinical care, other options that lower AVP activity should be considered. An alternative might be to lower AVP concentration by increasing water intake [14]. In a rat model for polycystic kidney disease, a 3.5-fold increased water intake reduced urinary osmolality, renal expression of the AVP V2 receptor and reduced kidney weight compared with normal water intake [15] (Figure 1). Given the theoretical background and the promising animal data, Higashihara et al. investigated the effects of increased water intake on disease progression in ADPKD, a clinically important and very timely topic. In their study, published in this issue of NDT, 34 ADPKD patients with a relatively preserved kidney function were divided based upon their preference into a high and a free water intake group.