MECHANISMS OF PROGRESSION IN AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Autosomal dominant polycystic kidney disease (ADPKD) progresses to end -stage renal insufficiency before the age of 73 in approximately 48% o f affected individuals. Why the disease, characterized by innumerable cysts arising in proximal and distal tubules, eliminates functioning n on-cystic parenchyma in some patients and spares others is a mystery. The cysts initiate in early childhood in fewer than 1% of renal tubule s as a consequence of the focal expression of mutated DNA. Tubule cell s proliferate, causing segmental dilation, in association with the abn ormal deposition of extracellular matrix proteins. Most of the cysts s eparate from the parent tubules and fill with fluid by cAMP-mediated c hloride secretion. Risk factors associated with accelerated loss of re nal function include: genotype (PKD Type 1 progresses more rapidly tha n PKD Type 2); gender (males progress more rapidly than females); race (black patients progress more rapidly than whiles); hypertension; pro teinuria. The relation between kidney size and progression to renal fa ilure is debated. Progressive PKD is associated with the cellular expr ession of proto-oncogenes (fos, myc, ras, erb), growth factors (EGF, H GF, acid and basic FGF), chemokines (MCP-1, osteopontin), metalloprote inases, and apoptotic markers, and the interstitial accumulation of Ty pes I and IV collagen, laminin, fibronectin, macrophages and fibroblas ts, the magnitudes of which increase with age. Cyst activating factor (CAF), a neutral lipid identified in cyst fluid that stimulates fluid secretion and proliferation of renal epithelial cells and monocyte che motaxis, has recently been identified as a potential progression facto r. In those patients destined to develop renal failure there is loss o f non-cystic parenchyma in association with mass replacement by fluid- filled cysts in a network of interstitial fibrosis. The decline in ren al function is probably the consequence of processes leading to inters titial fibrosis, as in other nephropathies, rather than due to simple mechanical displacement of parenchyma by cysts.