Bully renal cysts knock down urine-concentrating capacity in the early rounds.

The commonly accepted manifestations of renal insufficiency are usually not recognized in patients with autosomal dominant polycystic kidney disease (ADPKD) until the fourth decade of life (1).However,manyADPKD patients with GFRs indistinguishable from normal are unable to increase the osmolality of urine above 800 mosm/kg H2O after overnight dehydration or after the parenteral administration of supplementary vasopressin. This “concentrating defect” can be detected in some young children and young adults decades before the GFR noticeably declines, indicating that parenchymalmalfunction begins very early in the course of renal cystic disease (2). In an excellent study reported in this issue of CJASN, Zittema et al. (3) confirm that maximal urine concentration capacity is lost in ADPKD patients comparedwithnormal controls. Still at issue is themechanism(s) by which ADPKD impairs the maximal concentration of the urine. The baseline urine volumes, osmolar excretion rates, and plasma arginine vasopressin (AVP) and copeptin concentrations were not appreciably different between ADPKD patients and controls in this study; however, after overnight dehydration, the plasma levels of AVP and copeptinwere significantly andpersistentlyhigher in the ADPKD subjects, and the urine osmolality was persistently lower than in the controls. The authors found evidence of an intact hypothalamic mechanism for the osmotic release of vasopressin, meaning that the defect must lie in the kidneys. Interestingly, ADPKD patients had higher plasma and lower urine concentrations of urea after achieving the highest elevation of urine osmolality, suggesting that urea clearance was decreased in the ADPKD patients even though eGFR was not different between study patients and control subjects. The urea excretion rate after dehydration was not reported; however, the similar baseline osmolar excretion rates make it unlikely that the urea excretion rates in the ADPKD patients were different from normal. The plasma urea levels were elevated in the ADPKD patients, possibly reflecting a decreased renal urea clearance. Because plasma sodium levels were equal in patients and control subjects, the increased urea concentration probably accounts for the consistent elevation of plasma osmolality in ADPKD patients compared with control subjects. Because urea distributes relatively freely in body water, it is unlikely that the small increase in plasmaosmolality causedby increasedurea concentration wasresponsible for the increasedplasmaconcentrations of AVP and copeptin in the ADPKD patients. On the other hand, the restriction of water intake unquestionably increased plasma levels of vasopressin and copeptin and the reabsorption of free water in the patients, although to a lesser degree than in control subjects. A nonosmotic vasopressin releasing mechanism, e.g., extracellular fluid volume contraction, is a reasonable possibility and, in this regard, careful measurements of changes in body weight and urine volume before and after water restriction would probably have confirmed that body water content had decreased overnight. The 24-hour urine volume did not differ between ADPKD and normal subjects in the baseline collection, indicating that overallwater balanceof thepatientswas appropriately regulated despite the inability to maximally concentrate the urine to normal maximal levels. In other words, the ADPKD subjects did not manifest any outward signs of a urine concentration defect. The baseline osmolar loads excreted by ADPKD (1096 mosm/d) and normal (1039 mosm/kg H2O) subjects were also similar and typical of most individuals at large (4). Consequently, polyuria and polydipsia would not be expected in these ADPKD subjects with excellent estimated GFR (eGFR) unless the solute load was increased by dietary excesses of salt and protein. Interesting in this regard, in much larger cohorts of patients, daily solute loads tended to be higher and urine volumes greater owing to increased dietary intake of protein and salt (5,6). The cause of the limited concentrating capacity of the “early”-stage polycystic kidneys reported in this study appears to reside within the kidneys and, more specifically, within the medulla. There, the prime candidates to account for the reduction in maximal Uosm are (1) a decreased responsiveness of the collecting ducts to vasopressin and (2) the failure to generate andmaintain a hyperosmotic interstitial milieu. A decreased expression of AVP-V2 receptors has been reported at the end stage of the 5/6 nephrectomy model of ESRD in rats (7); consequently, renal insufficiency from any cause could underlie reduced collecting duct responses to AVP. Contrary to that possibility, however, is the finding that AVP-V2 receptor RNA was increased in the kidneys of amurinePkd2model, and aquaporin 2 RNA was elevated and the protein expressed in the apical plasma membranes of mice with Pkd1 (8). It seems The Kidney Institute, Department of Internal Medicine, Kansas University Medical Center, Kansas City, Kansas