Sugar linked to polycystic KD development with implications for treatment

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A new study in Nature Communications has associated sugar with the development of the cysts that characterise polycystic kidney disease (PKD), with implications for how the condition should be treated. Co-lead authors Sienna Li and Ramila Gulieva (University of Washington School of Medicine, Seattle, USA) performed the experiments, which concluded that glucose absorption “can mediate PKD cyst growth in human organoids”, which may influence the development of treatments. 

PKD is an inherited disorder, usually through “heterozygous, loss-of-function mutation” in either of the genes PKD1 or PKD2. It results in the growth of cysts from the kidney, while the recently approved therapeutic for the condition, Tolvaptan, iss described by the study authors as having efficacy and safety limitations. Li, Gulieva et al have developed kidney organoids as part of an in vitro human model in order to explore other treatments. In this study, the organoids were gene-edited to “strikingly recapitulate the genotype-phenotype correlation in PKD”. 

To do this, they exposed such organoids “to fluid shear stress in a PKD-on-a-chip microphysiological system”, allowing for measurement of fluid flow, “which is difficult to assess in vivo” but is commonly associated with cystic expansion. This study examined how flow of glucose-rich fluid can modulate such development. While they describe kidneys as “highly reabsorptive organs”, the authors note that it is in fact unclear whether PKD cysts absorb glucose in particular. Flow of fluid rich in glucose, which the authors call “an abundant renal solute and transport cargo”, was measured using time-lapse imaging of “a fluorescent glucose analogue, NBD glucose”. 

While the authors anticipated that fluid flow generally would exacerbate cyst development, they unexpectedly discovered that the cysts formed by absorbing glucose-rich fluid, rather than releasing fluid as was anticipated. In their discussion, they state that their findings “indicate that flow, volume, and solute concentrations are positive regulators of cyst expansion,” noting that it can be accelerated via “glucose transport”. They describe glucose and “its transport into cyst structures” as “a driver of cystic expansion in proximal nephron-like structures”. Finally, they offer the suggestion that therapeutic treatments that may limit reabsorption of glucose could be “beneficial in reducing cyst growth in specific nephron segments”. Future studies into the mechanics of PKD, they say, may build on these findings. 

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