Therapy for polycystic kidney disease? It's water, stupid!

Water, which is preeminent among all biomolecular compounds, creates more complexities than implied by simple H2O. Humans are more than 50% water and die in a few days without it. Space scientists eagerly search dry planets for traces of water. Nephrologists spend most of their time thinking and worrying about urine, which is mostly water. When the heart fails, we drown from too much water. Now we are confronted by the bizarre prospect that water is the “cure” for hereditary diseases that grotesquely bloat the kidneys with . . . water. In autosomal dominant and autosomal recessive polycystic disease (ADPKD and ARPKD, respectively, or PKD when referring to both), the kidneys often grow larger than footballs. They are composed of innumerable fluid-filled cysts varying in size from a pinhead to a grapefruit. Cysts arise in renal tubules when epithelial cells focally proliferate, leading to tiny out-pouchings, or hernias, that progressively expand. Aberrant cell differentiation and sustained proliferation initiate the formation of the cysts, and upstream fluid from glomerular filtrate fills the budding cyst cavity. Later, after they separate from the parent tubules, fluid is transported across the epithelium in conjunction with active chloride transport into the lumens of autonomous cysts. Thus, two ordinarily quiescent renal processes, epithelial cell proliferation and solute-driven fluid secretion, come storming out of hiding and push a relatively small number of cystic segments to take over eventually the parenchymal landscape, driving functional glomeruli and tubules into oblivion.1 We knew this much about PKD for more than a decade. We also knew, without the benefit of specific genetic molecular information about these hereditary disorders, that abnormal growth of cyst epithelial cells and the transepithelial transport of chloride and fluid are increased dramatically in polycystic kidneys by our old friend cAMP, the “second messenger” of a host of G-protein–linked hormone and autacoid receptors.2 cAMP stimulates cell proliferation in mural epithelial cells from polycystic kidneys but not in cells from normal kidney tubules. Renal tubules harbor receptors for a swarm of adenylyl cyclase agonists (vasopressin, parathyroid hormone, epinephrine, norepinephrine, secretin, vasointestinal polypeptide, prostaglandin E2, adenosine, and forskolin), bringing with them the potential to activate many normal and abnormal physiologic processes that could also drive the enlargement of renal cysts.3 In a seminal study, Gattone et al.4 tested in living animals the idea that endogenous vasopressin has a role in promoting cyst growth through its action to stimulate adenylyl cyclase production of cAMP. Cpk/cpk mice with a rapidly progressive form of recessive PKD were administered a vasopressin V2 receptor inhibitor (OPC-31260), and an impressive decrease in renal enlargement and preservation of renal function followed. OPC-31260 also dramatically slows renal enlargement and preserves function in three more genetically different forms of cystic diseases in rodents (Pkd2/Pkd2 , pcy/ pcy, and PCK).5,6 OPC-41061, a highly specific V2 blocker with a higher affinity for the V2 receptor, also diminishes renal enlargement and protects renal function.7 These findings suggest that in all renal cystic disorders, AVP, acting through cAMP, has a commanding role in promoting cyst growth. Nagao et al.8 further reasoned that if blockade of V2 receptors is beneficial in PKD, then reducing plasma vasopressin levels should be effective as well. PCK rats, encouraged to drink enough water to reduce urine osmolality below that of plasma, show a marked reduction in renal enlargement with preservation of renal function. Although the foregoing studies clearly implicate a central role for vasopressin and cAMP in promoting kidney enlargement and reducing renal function in PKD, a study from the Mayo laboratory in this issue of the JASN9 provides definitive proof. PCK rats with ARPKD (Pkhd1 / ) were crossed with Brattleboro rats (AVP / ) with diabetes insipidus and then backcrossed to create double-homozygous null animals. Pkhd1 / rats developed progressive renal enlargement as a result of cysts in the collecting tubules, and AVP / animals were born with diabetes insipidus and required supplemental water to survive. The AVP / /Pkhd1 / double-null rats also had diabetes insipidus and drank large amounts of water; moreover, there was a dramatic reduction of cyst formation in the kidneys. When exogenous AVP V2 agonist (dDAVP) was given to these animals by osmotic minipump, cysts developed within the kidneys, fulfilling Koch’s postulates. These are astounding results in this field of study! All of the cells in the collecting ducts of these animals carry mutated copies of Pkhd1 genes in both alleles. Thus, the cells are “primed” to Published online ahead of print. Publication date available at www.jasn.org.