Variability in the rate of disease progression among patients with autosomal dominant polycystic kidney disease (PKD) suggests an environmental component in disease pathogenesis. New findings show that deposition of calcium oxalate (CaOx) crystals activates PKD-associated signalling pathways to flush out lodged crystals but also triggers cyst formation in PKD. “Our first major finding is the discovery of a fundamental, renoprotective mechanism whereby renal tubules dilate deliberately in response to lodged micro-crystals in an effort to flush them out,” says Thomas Weimbs. “The second is that the same renoprotective mechanism inadvertently triggers cyst growth in PKD and accelerates progression of the disease.”

Weimbs explains that the basis for this study was prior work that culminated in the ‘third-hit model’, which posits that a form of kidney injury is needed, in addition to the gene mutation, to generate cysts in PKD. “I thought that there must be a common form of insult that human kidneys experience on a regular basis in order for the third-hit model to make sense. Furthermore, if this form of insult was under the influence of external factors, such as dietary intake of ‘something’, it could possibly explain the high variability of disease progression in PKD,” says Weimbs. “I realised that micro-crystals fit these criteria.”

The researchers show that CaOx crystal deposition induces activation of mTOR and STAT3 signalling pathways along with tubule dilation and hypertrophy. Blocking mTOR signalling attenuated the cellular response and led to an accumulation of CaOx crystals in tubules, suggesting that tubule dilation is a mechanism to clear lodged crystals. Deposition of CaOx or calcium phosphate crystals exacerbated cystogenesis and accelerated disease progression in rat models of PKD. Moreover, in patients with PKD, urinary levels of citrate, an inhibitor of calcium crystal formation, were inversely correlated with disease severity. “In PKD, tubule dilation is the first step towards cyst formation and this step is exacerbated by micro-crystals” explains Weimbs. “Therefore, any increase in ‘crystal burden’, such as through dietary means, could worsen PKD progression in patients. The good news is that we can try to do something about that by reducing the renal crystal burden.”