Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria.
BACKGROUND
Primary hyperoxaluria is a rare genetic disorder of glyoxylate metabolism that results in overproduction of oxalate. The disease is characterized by severe calcium oxalate nephrolithiasis and nephrocalcinosis, resulting in end-stage renal disease (ESRD) early in life. Most patients eventually require dialysis and kidney transplantation, usually in combination with the replacement of the liver. Reduction of urinary oxalate levels can efficiently decrease calcium oxalate depositions; yet, no treatment is available that targets oxalate biosynthesis. In previous in vitro studies, we demonstrated that pyridoxamine can trap reactive carbonyl compounds, including intermediates of oxalate biosynthesis.


METHODS
The effect of PM on urinary oxalate excretion and kidney crystal formation was determined using the ethylene glycol rat model of hyperoxaluria. Animals were given 0.75% to 0.8% ethylene glycol in drinking water to establish and maintain hyperoxaluria. After 2 weeks, pyridoxamine treatment (180 mg/day/kg body weight) started and continued for an additional 2 weeks. Urinary creatinine, glycolate, oxalate, and calcium were measured along with the microscopic analysis of kidney tissues for the presence of calcium oxalate crystals.


RESULTS
Pyridoxamine treatment resulted in significantly lower (by approximately 50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals. This was accompanied by a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney.


CONCLUSIONS
These results, coupled with favorable toxicity profiles of pyridoxamine in humans, show promise for therapeutic use of pyridoxamine in primary hyperoxaluria and other kidney stone diseases.
Chetyrkin
Sergei V
SV
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2372, USA.
Kim
Daniel
D
Belmont
John M
JM
Scheinman
Jon I
JI
Hudson
Billy G
BG
Voziyan
Paul A
PA
D000818:Animals; D002129:Calcium Oxalate / Q000378:metabolism* / Q000652:urine; D003460:Crystallization; D004195:Disease Models, Animal; D006038:Glyoxylates / Q000378:metabolism; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000188:drug therapy* / Q000378:metabolism* / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011733:Pyridoxamine / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006038:Glyoxylates; D002129:Calcium Oxalate; D011733:Pyridoxamine; C031150:glyoxylic acid