Preconditioning of the distal tubular epithelium of the human kidney precedes nephrocalcinosis

Abstract

Background: Preterm neonates and renal transplant patients frequently develop nephrocalcinosis. Experimental studies revealed that crystal retention in the distal nephron, a process that may lead to nephrocalcinosis, is limited to proliferating/regenerating tubular cells expressing hyaluronan and osteopontin at their luminal surface. Fetal and transplant kidneys contain proliferating and/or regenerating cells since nephrogenesis is not completed until 36 weeks of gestation, while ischemia and nephrotoxic immunosuppressants may lead to injury and repair in renal transplants. This prompted us to investigate the expression of hyaluronan and osteopontin and to correlate this to the appearance of tubular calcifications both in fetal/preterm and transplanted kidneys.

Methods: Sections of fetal/preterm kidneys and protocol biopsies of transplanted kidneys (12 and 24 weeks posttransplantation from the same patients) were stained for osteopontin, hyaluronan, and calcifications (von Kossa).

Results: Hyaluronan and osteopontin were expressed at the luminal surface of the epithelial cells lining the distal tubules of all fetal kidneys at birth and in all kidney graft protocol biopsies 12 and 24 weeks posttransplantation. In 7 out of 18 surviving (at least 4 days) preterm neonates crystal retention developed. In renal allografts a striking increase (from 2/10 to 6/10) in tubular crystal retention between 12 and 24 weeks posttransplantation was observed. In addition, crystals were selectively retained in distal renal tubules containing cells with hyaluronan and osteopontin at their luminal surface.

Conclusion: The results of this study show that luminal expression of hyaluronan and osteopontin preceded renal distal tubular retention of crystals in preterm neonates and renal transplant patients. We propose that the presence of this crystal binding phenotype may play a general role in renal calcification processes.