Inherited Disorders of Water Handling

Under normal circumstances, about 90% of the 180 L/day glomerular filtrate is constitutively reabsorbed in the proximal tubule and descending limb of Henle’s loop. According to the needs, the remaining 10% of the fluid is reabsorbed in the collecting duct by a tightly regulated process under control of arginine vasopressin (AVP). After binding of AVP to arginine vasopressin type 2 receptors (AVPR2) in the basolateral membrane of collecting duct cells, aquaporin-2 (AQP2) water channels are inserted into the luminal membrane of these cells, allowing water reabsorption and urine concentration. Disorders of water handling are characterized by disturbances of this AVP-regulated system. In congenital nephrogenic diabetes insipidus (NDI), the kidney cannot concentrate urine in response to AVP, as a result of loss-of-function mutations in genes encoding AVPR2 and AQP2, resulting in polyuria and polydipsia. In recent years, extensive research has led to increased understanding of the cellular defects in NDI, with important implications for future development of targeted treatment of the disorder, with hope for better outcomes in comparison to the conventional symptomatic therapy. The very rare nephrogenic syndrome of inappropriate antidiuresis (NSIAD), caused by gain-of-function mutations in the gene encoding AVPR2, is the mirror image of NDI. In this disorder, urinary dilution is impaired, independent of the presence or absence of AVP. In this chapter, the focus will be on the physiology of water handling in the collecting duct and on its disturbances in congenital NDI. The clinical details, differential diagnosis, genetics, and conventional and possible future therapies of NDI will be discussed in detail.