A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD.

Methods: This Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function.

Results: Eighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24-2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of -3.5% (95% CI -8.4-1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio.

Conclusions: In this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Keywords: MRI; PPARγ; agonists; anti-hypertensive; crossover design; total kidney volume.

FIGURE 1:

Study schema. The study was a crossover trial where patients were randomized to either pioglitazone or placebo for 1 year, followed by a 2- to 4-week washout and then the other treatment. Study visits (white lines in purple bar) were done throughout the study. MRI to assess TKV was done at the beginning of Period 1, the end of Period 1 and the end of Period 2. The end of Period 1 served as the initial TKV for Period 2.

FIGURE 2:

Consort diagram of patient participation.

FIGURE 3:

Average resistance during treatment by bioelectric impedance analyses for each period. The plot illustrates the mean ± SD for resistance at 10 kHz during either the pioglitazone (open circles: mean ± SD = 45.8 ± 11.7 Ω) or placebo treatment (open squares: 44.2 ± 11.1 Ω) period. Bars represent mean ± SD (n = 15). The lower the resistance, the more interstitial fluid is present. Thus pioglitazone significantly reduced interstitial fluid compared with placebo.

FIGURE 4:

Change in TKV. Mean percent change in TKV in response to each treatment. The plot illustrates the change in TKV of subjects treated with pioglitazone (open circles) and placebo (open squares). Dark bars represent the mean and lighter bars the SD (n = 15).

FIGURE 5:

Average BP during treatment. The data represent systolic (left panel), diastolic (middle panel) and mean arterial BP (right panel) changes during treatment with pioglitazone (open circles) or placebo (open squares). Dark bars represent the mean and lighter bars the SD (n = 15).