Modification of disease progression in rats with inherited polycystic kidney disease

The most common inherited form of human polycystic kidney disease (PKD), autosomal dominant PKD (ADPKD), is a leading cause of chronic renal failure, but has a variable clinical presentation, with end-stage renal disease occurring in only 25% to 75%. Several findings are consistent with the idea that factors in addition to the primary mutation can affect the progression of cystic change and chronic renal failure in PKD. Epithelial cell proliferation is a central element in the pathogenesis of renal cysts. We postulated that the superimposition of a growth- promoting stimulus might promote more intense proliferation of cystic epithelial cells in inherited cystic disease. To study this, we subjected Han:SPRD rats, with a form of ADPKD that resembles human ADPKD, from 4 until 10 weeks of age to diets designed to promote tubule cell growth. The diets included supplemental NH 4CI (280 mmol/ L in drinking water), limited dietary K + (0.016% of diet; control diet was 1.1% K +), and increased dietary protein (50%; control diet was 23% protein). Treatments designed to promote cell growth caused more aggressive PKD in males and females, worsened azotemia in males, and resulted in azotemia in females (which normally develop PKD but not azotemia at the ages studied). NH 4CI, K + restriction, and increased dietary protein each caused greater kidney enlargement in males (kidney weight/body weight ratios increased by 35%, 78%, and 105%, respectively) and worsened azotemia in males (serum urea nitrogen values increased by 63%, 514%, and 224%, respectively); in contrast, decreased dietary protein (4%) caused less severe PKD in males (kidney weight/body weight ratios decreased by 43%) and lessened azotemia in males (serum urea nitrogen values decreased by 49%). Similarly, NH 4CI and K + restriction caused greater kidney enlargement in females (kidney weight/body weight ratios increased by 206% and 203%, respectively) and caused azotemia in females (serum urea nitrogen values increased by 177% and 430%, respectively). On the basis of these results, we conclude that growth-promoting stimuli can alter the expression of hereditary renal cystic disease. These findings demonstrate that the progression of hereditary renal cystic disease can be altered by factors in addition to the primary genetic defect.