Crystal Deposition Triggers Tubule Dilation That Accelerates Cystogenesis in Polycystic Kidney Disease

J Clin Invest. 2019 Jul 30;129(10):4506-4522. doi: 10.1172/JCI128503.

Abstract

The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of "flushing out" crystals by purposefully dilating renal tubules has not previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.

Keywords: Fibrosis; Genetic diseases; Nephrology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium Oxalate / metabolism*
  • Citric Acid / urine
  • Dilatation, Pathologic / metabolism
  • Dilatation, Pathologic / pathology
  • Female
  • Humans
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Polycystic Kidney, Autosomal Dominant / metabolism*
  • Polycystic Kidney, Autosomal Dominant / pathology
  • Protein Kinase C / metabolism
  • Rats

Substances

  • Calcium Oxalate
  • Citric Acid
  • protein kinase D
  • Protein Kinase C