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 NH4Cl (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). NH4Cl, 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, NH4Cl 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.