Targeting kidney inflammation as a new therapy for primary hyperoxaluria?

Nephrol Dial Transplant. 2019 Jun 1;34(6):908-914. doi: 10.1093/ndt/gfy239.


The primary hyperoxalurias (PHs) are inborn errors of glyoxylate metabolism characterized by endogenous oxalate overproduction in the liver, and thus elevated urinary oxalate excretion. The urinary calcium-oxalate (CaOx) supersaturation and the continuous renal accumulation of insoluble CaOx crystals yield a progressive decline in renal function that often ends with renal failure. In PH Type 1 (AGXT mutated), the most frequent and severe condition, patients typically progress to end-stage renal disease (ESRD); in PH Type 2 (GRHPR mutated), 20% of patients develop ESRD, while only one patient with PH Type 3 (HOGA1 mutated) has been reported with ESRD so far. Patients with ESRD undergo frequent maintenance (haemo)dialysis treatment, and finally must receive a combined liver-kidney transplantation as the only curative treatment option available in PH Type 1. In experimental models using oxalate-enriched chow, CaOx crystals were bound to renal tubular cells, promoting a pro-inflammatory environment that led to fibrogenesis in the renal parenchyma by activation of a NACHT, LRR and PYD domains-containing protein 3 (NALP3)-dependent inflammasome in renal dendritic cells and macrophages. Chronic fibrogenesis progressively impaired renal function. Targeting the inflammatory response has recently been suggested as a therapeutic strategy to treat not only oxalate-induced crystalline nephropathies, but also those characterized by accumulation of cystine and urate in other organs. Herein, we summarize the pathogenesis of PH, revising the current knowledge of the CaOx-mediated inflammatory response in animal models of endogenous oxalate overproduction. Furthermore, we highlight the possibility of modifying the NLRP3-dependent inflammasome as a new and complementary therapeutic strategy to treat this severe and devastating kidney disease.

Keywords: NLRP3-inflammasome; calcium-oxalate; immune response; primary hyperoxaluria; renal failure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Calcium Oxalate / metabolism*
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Humans
  • Hyperoxaluria, Primary / therapy*
  • Infant
  • Inflammasomes / metabolism
  • Kidney / pathology
  • Kidney Failure, Chronic / complications*
  • Kidney Transplantation / adverse effects
  • Macrophages / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Nephritis / metabolism
  • Nephritis / therapy*
  • Oxalates / metabolism
  • RNA Interference
  • Renal Dialysis / adverse effects
  • Renal Insufficiency / complications
  • Uric Acid / metabolism
  • Young Adult


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Oxalates
  • Calcium Oxalate
  • Uric Acid