Inherited secondary nephrogenic diabetes insipidus: concentrating on humans

Abstract

The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models.

Long-term outcome in inherited nephrogenic diabetes insipidus

“…There are primary and secondary forms of inherited NDI [2]. In primary inherited NDI, we distinguish between an Xlinked form, due to mutations in the gene encoding the vasopressin type 2 receptor, namely arginine vasopressin receptor-2 (AVPR2) and an autosomal form, due to mutations in the gene encoding the water channel aquaporin2 (AQP2).…”

Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus

“…110 were found, whereas in others, the phenotype was not detailed enough to clearly establish a diagnosis of NDI. 56 In a Japanese study no mutations were identified in 7 of 62 (11%) families with clinical NDI, 34 suggesting that genes other than AQP2 and AVPR2 might be involved. However the phenotypes of these patients were poorly described and not further investigated by the referring physicians.…”

“…55,56 These patients have Mendelian diseases that affect tubular function with NDI as a secondary complication. In some such patients the NDI symptoms dominate the clinical picture, leading to an initial misdiagnosis, with the true underlying cause of disease subsequently identified.…”

Urinary concentration: different ways to open and close the tap

“…Moreover, this pathway may be involved in some of the secondary forms of NDI, seen in disorders with hypercalciuria, such as Bartter syndrome [21,22]. However, luminal calcium concentrations in concentrated urine are typically much higher than those seen in the dilute urine of patients with secondary NDI, raising questions about the clinical relevance of this pathway [23,24].…”

“…Indeed, potassium deprivation in rats is associated with polyuria and decreased Aqp2 expression, through yet unidentified mechanisms [28]. But yet again, the clinical relevance in man is unclear, considering that patients with Gitelman syndrome have hypokalemia, but an apparent normal urinary concentrating ability [23].…”