The sequence of events by which
primary hyperoxaluria type 1 (PH1) causes
renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because
oxalate secretion raises
calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term (2) or longer term (2) dialysis. In these patients, and another five PH1 patients without
renal failure, we calculated
oxalate secretion, and estimated PT CaOx SS. Plasma
oxalate was elevated in all PH1 patients and inverse to
creatinine clearance. Renal secretion of
oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed
end stage renal disease (
ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical
inflammation or
scarring by histopathology or
hyaluronan staining. PH1 with short
ESRD showed CaOx deposition and
hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer
ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and
fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with
ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.