Rajeev Rohatgi, MD

Polycystic kidney disease (PKD) is a common genetic disease that is associated with a high morbidity and mortality. Autosomal dominant PKD (ADPKD) affects ~1:1,000 while autosomal recessive PKD (ARPKD) affects ~1:20,000 live births. Approximately 50 percent of patients with ADPKD develop end-stage renal disease (ESRD) by the sixth decade of life while most infants with ARPKD that survive beyond the perinatal period develop chronic renal failure by early adolescence. In PKD, cyst growth and expansion destroys normal renal parenchyma and leads to renal failure. ADPKD cysts arise from any tubular segment, "bud" off from the nephron, and no longer communicate with the tubule from which they originate. Cysts in ARPKD, however, are actually ectatic dilated collecting ducts which remain contiguous with the filtering nephron, allowing for urine to continue to flow through the dilated collecting system.

Evidence from experimental ADPKD models and human disease suggests that cyst formation and expansion arise, at least in part, from transepithelial solute and fluid secretion. In contrast to the latter observation, we have recently reported that ARPKD cystic collecting ducts, at least early in disease, reabsorb Na. Patch clamp analysis showed that apical Na channel activity in ARPKD cells is ~2 fold greater than that detected in age-matched human fetal collecting tubule (HFCT) cells. The additional observation that steady state expression levels of the and subunits of the apical epithelial Na channel (ENaC), the rate limiting step in Na absorption in the collecting duct, are higher in ARPKD than HFCT cells leads us to hypothesize that ARPKD is associated with upregulated Na absorption, presumably mediated by ENaC. We speculate that dysregulated Na transport contributes to the early onset of hypertension characteristic of this disease. Using assorted molecular (RT-PCR, Northern Blot, Western Blot) and physiologic (patch clamp, Ussing chamber) techniques on a human cell culture model, we plan to elucidate the mechanisms of Na transport in ARPKD renal cystic epithelia.