Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models.

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were two aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight, and cyst index. Mechanisms of increased cyst growth that were investigated were proinflammatory cytokines, the inflammasome, and crystal deposition in the kidney. Oxonic acid resulted in an increase in proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.NEW & NOTEWORTHY This is the first reported study of uric acid measurements and xanthine oxidase inhibition in polycystic kidney disease (PKD) rodents. Raising serum uric acid with a uricase inhibitor resulted in increased kidney weight and cyst index in Pkd1RC/RC mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.

Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease.

Metformin (MET) has the potential to activate p-AMPK and block mTORC1-induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene mutation model of human autosomal recessive polycystic kidney disease (ARPKD). MET 300 mg/kg/day IP from days 28 to 84 of age resulted in a mean serum metformin level that was 10 times the upper limit of therapeutic, no effect on cyst indices, nephrotoxicity, and increased serum lactate. MET 150 mg/kg resulted in a therapeutic serum metformin level but had no effect on kidney weight, cyst indices, kidney function, or mTOR and autophagy proteins. In summary, a standard dose of MET was ineffective in reducing PKD, did not activate p-AMPK or suppress mTOR and the higher dose resulted in increased lactate levels and nephrotoxicity. In conclusion, the study dampens enthusiasm for human studies of MET in PKD. Doubling the metformin dose resulted in a 10-fold increase in mean blood levels and toxicity suggesting that the dosage range between therapeutic and toxic is narrow.

The Pathophysiology of Left Ventricular Hypertrophy, beyond Hypertension, in Autosomal Dominant Polycystic Kidney Disease.

Heart disease is one of the leading causes of death in autosomal dominant polycystic kidney disease (ADPKD) patients. Left ventricular hypertrophy (LVH) is an early and severe complication in ADPKD patients. Two decades ago, the prevalence of LVH on echocardiography in hypertensive ADPKD patients was shown to be as high as 46%. Recent studies using cardiac magnetic resonance imaging have shown that the prevalence of LVH in ADPKD patients may be lower. The true prevalence of LVH in ADPKD patients is controversial. There is evidence that factors other than hypertension contribute to LVH in ADPKD patients. Studies have shown that young normotensive ADPKD adults and children have a higher left ventricular mass index compared to controls and that the prevalence of LVH is high in patients with ADPKD whose blood pressure is well controlled. Polycystin-1 (PC-1) and polycystin-2 (PC-2) control intracellular signaling pathways that can influence cardiac function. Perturbations of PC-1 or PC-2 in the heart can lead to profound changes in cardiac structure and function independently of kidney function or blood pressure. PC-1 can influence mammalian target of rapamycin and mitophagy and PC-2 can influence autophagy, processes that play a role in LVH. Polymorphisms in the angiotensin-converting enzyme gene may play a role in LVH in ADPKD. This review will detail the pathophysiology of LVH, beyond hypertension, in ADPKD.