Abstract
Background and Aims
The vasopressin V2 receptor antagonist tolvaptan is the first drug that was proven to ameliorate kidney function decline in ADPKD. Blockade of the vasopressin V2 receptor, however, also results in nephrogenic diabetes insipidus (NDI), with an associated polyuria of on average 6 to 8 L/24h, limiting its clinical use. Hydrochlorothiazide (HCT) is an established treatment in NDI of other origins, but is unclear whether it is also efficacious in tolvaptan-caused NDI. Importantly, the combination of HCT and tolvaptan could cause electrolyte disturbances, and HCT treatment could theoretically increase vasopressin, which might accelerate ADPKD disease progression. Recently, metformin has been shown to ameliorate aquaresis in an animal model of NDI, but has never been investigated for this indication in humans. We aimed to investigate efficacy and safety of hydrochlorothiazide and metformin treatment to ameliorate the aquaretic side-effects of tolvaptan.
Method
This is an investigator driven, double-blind, randomized, controlled cross-over trial. ADPKD patients (Ravine criteria) were eligible for inclusion if they were 18-55 years of age, had an eGFR ≥ 30 mL/min/1.73m2 and were treated with a stable dose of tolvaptan. Patients were treated for three 2 week-periods with hydrochlorothiazide (HCT) 25 mg (12.5 mg in the first week), metformin 2000 mg (1000 mg in the first week) or placebo (half dose in the first week), in random order. Primary outcome was change in 24-hour urine volume (average of 2 collections) compared to baseline. Key secondary outcomes were measured GFR (mGFR), plasma copeptin (the stable precursor of vasopressin), quality of life and electrolytes.
Results
All 13 patients that were included were able to complete every treatment period in the trial. Their mean age was 45±8 years, 54% was female and mGFR was 55±11 mL/min/1.73m2 (Table). 85% of participants used the maximum tolvaptan dose (90/30 mg). At baseline urine volume was 6.9±1.4 L/24h. On HCT treatment urine volume decreased with -25±13% (p<0.001) and on metformin with -22±10% (p<0.001). Metformin treatment induced no change in mGFR and copeptin compared to baseline. During HCT treatment however, both mGFR and copeptin were lower (p=0.002 and p=0.001, respectively). There were no adverse events that required dose reductions. Quality of life was found to be equal on metformin and borderline better (p=0.06) on HCT treatment when compared to tolvaptan only. Plasma sodium was similar during all three treatment periods. Plasma potassium was significantly lower during HCT treatment (p=0.01), but in only three cases mild hypokalemia was noted (plasma potassium 3.0-3.5 mmol/L).
Conclusion
This is the first study to show that metformin can ameliorate aquaresis in NDI, and that HCT improves tolvaptan-caused NDI. Both treatments were well tolerated and safe during short-term use. The fact that copeptin is not increased by metformin, and even decreased by HCT suggests that these treatments will not negatively impact renoprotection by tolvaptan. These data provide an evidence base to test metformin and especially HCT in a real life setting to improve aquaresis and tolerability in patients with tolvaptan induced NDI. BaselineHCTPlaceboMetforminAbsolute urine volume (L/24h)6.95.1**6.35.4**Change in urine volume (%)0-25**-8-22**Creatinine excretion (mmol/24h)15.815.416.115.7Osmolar excretion (mOsm/24h)104410201013947*mGFR (mL/min/1.73m2)5551**5554SBP (mmHg)125117**122120Plasma copeptin (pmol/L)2520**2628Plasma sodium (mmol/L)141139141140Plasma potassium (mmol/L)3.83.6*3.94.0Plasma urea (mmol/L)7.08.6**6.97.2QoL ImprovedN/A7 (58%)2 (17%)1 (8%)Results in n=13 ADPKD patients on highest tolerated tolvaptan dose*P<0.05 compared to placebo ** p<0.01 compared to placeboFigure:
Effects of a 24-h naproxen dose on hydration and electrolyte measures during moderate-intensity cycling in the heat