A Case for Water in the Treatment of Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic disease (ADPKD) is an inherited disorder characterized by the development within renal tubules of innumerable cysts that progressively expand to cause renal insufficiency. Tubule cell proliferation and transepithelial fluid secretion combine to enlarge renal cysts, and 3-5-cyclic adenosine monophosphate (cAMP) stimulates that growth. The antidiuretic hormone, arginine vasopressin (AVP), operates continuously in ADPKD patients to stimulate the formation of cAMP, thereby contributing to cyst and kidney enlargement and renal dysfunction. Studies in animal models of ADPKD provide convincing evidence that blocking the action of AVP dramatically ameliorates the disease process. In the current analysis, the authors reason that increasing the amount of solute-free water drunk evenly throughout the day in patients with ADPKD and normal renal function will decrease plasma AVP concentrations and mitigate the action of cAMP on the renal cysts. Potential pitfalls of increasing fluid intake in ADPKD patients are considered, and suggestions for how physicians may prudently implement this therapy are offered.Clin J Am Soc Nephrol 4: 1140 -1150, 2009. doi: 10.2215/CJN.00790209 C onvergent findings in the last decade have established that 3Ј-5Ј-cyclic adenosine monophosphate (cAMP) stimulates mural epithelial cell proliferation and secretion of fluid into cysts of patients with autosomal dominant polycystic kidney disease (ADPKD), contributing to massive renal enlargement and dysfunction (1). AVP promotes cAMP production in the distal nephron and collecting ducts (CDs) by acting on AVP-V2 receptors (V2R). Preclinical evidence has shown in four different genetic models of polycystic kidney disease (PKD) that blocking the effect of AVP, thereby decreasing cAMP levels, slows cyst and renal enlargement and improves renal function (2-4).A novel treatment for ADPKD that targets AVP/cAMP is currently being evaluated in an international clinical trial (TEMPO NCT00428948). An inhibitor of V2R (tolvaptan) is administered to patients with the intent to diminish intracellular cAMP levels in cyst epithelial cells. V2R inhibition also diminishes the reabsorption of solute-free water in CDs, thereby causing partial nephrogenic diabetes insipidus and thirst. Daily urine volumes 5 d after starting different split doses of tolvaptan (15/15, 30/0, 30/15, 30/30 mg) in a preliminary phase 2 study were 4 to 6 L (5). This polyuria requires ingestion of enough water to maintain normal fluid balance, and TEMPO trial participants are instructed to drink enough to prevent or minimize thirst.Another way to decrease the effect of AVP on the kidney is to suppress its secretion by increasing fluid ingestion above what normal thirst would command. This strategy is hardly new, as a high fluid intake to dilute the urine likely is the oldest existing treatment in nephrology. Up to 3000 cc of water per day, drunk relatively evenly throughout waking hours and before going to bed, is frequently recommended to prevent urine supersaturatio...

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

“…167 This strategy has been tested directly in the PCK rat, where high fluid intake sufficient to achieve a 3.5-fold increase in urine output by adding 5% glucose to drinking water reduced AVP excretion, renal expression of V2R, cAMP-dependent activation of the B-Raf/MEK/ERK, and attenuation of PKD. 168 It must be noted that the effects of increased water intake and V2R antagonists are not equivalent, even if they both reduce cAMP in the distal nephron and collecting ducts.…”

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

“…These cysts progressively expand and compress viable renal tissue, thereby causing renal insufficiency (1)(2)(3). For a long time there was no proven renoprotective treatment for this disease.…”

Novel Treatments of Autosomal Dominant Polycystic Kidney Disease

“…Even forced-water ingestion sufficient to naturally suppress secreted vasopressin can slow cyst formation and enlargement (10). These observations led to emphatic recommendations that patients with ADPKD aim to ingest .3 liters of noncaffeinated fluid per day, with the hope that natural vasopressin suppression would attenuate cyst growth (11,12). In addition to vasopressin-mediated fluid transport into cysts, other studies have demonstrated that the disordered nephron epithelial cell proliferation is related to activation of mammalian target of rapamycin (mTOR), a protein kinase that regulates polycystin pathways, cell proliferation, and protein synthesis (13,14).…”