Urinary concentration: different ways to open and close the tap

Abstract

Nephrogenic diabetes insipidus (NDI) provides an excellent model for the benefits and insights that can be gained from studying rare diseases. The discovery of underlying genes identified key molecules involved in urinary concentration, including the type 2 vasopressin receptor AVPR2 and the water channel AQP2, which constitute obvious pharmacologic targets. Subsequently developed drugs targeting AVPR2 not only provide potential benefit to some patients with NDI, but are now used for much more common clinical applications as diverse as nocturnal enuresis and heart failure. Yet, the story is still evolving:clinical observations and animal experiments continue to discover new ways to affect urinary concentration. These novel pathways can potentially be exploited for therapeutic gain. Here we review the (patho)physiology of water homoeostasis, the current status of clinical management and potential new treatments.3

The Trafficking of the Water Channel Aquaporin-2 in Renal Principal Cells—a Potential Target for Pharmacological Intervention in Cardiovascular Diseases

“…They decrease urine volume, but the mechanism by which they exhibit their paradoxical antidiuretic effect is poorly understood (Kim et al, 2004a ). It was proposed that thiazides inhibit reabsorption of sodium and chloride in the distal collecting duct and thus increase the osmolality of the urine (Bockenhauer and Bichet, 2014 ).…”

“…EP 2 agonists are already used in the treatment of dysmenorrhea (Moeller et al, 2013 ). Moreover, selective EP 4 agonists relieved NDI symptoms developed in V2R gene-deficient mice (Bockenhauer and Bichet, 2014 ). In a mouse model for X-linked NDI, an EP 4 receptor agonist, [ONO-AE-329 (ONO)] efficiently increased urine osmolality and reduced polyuria.…”

“…Both strategies with antagonists or agonists are not applicable if V2R is not at least partially functional or if it is insensitive to such agents (Moeller et al, 2013 ; Bockenhauer and Bichet, 2014 ).…”

Tolvaptan is successful in treating inappropriate antidiuretic hormone secretion in infants

“…The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterised by euvolaemic or hypervolaemic hyponatraemia with inappropriately concentrated urine. The excess secretion of the antidiuretic hormone (ADH) leads to activation of the type 2 vasopressin receptor (AVPR2) in the kidney, which mediates urinary concentration . Excess ADH secretion can be triggered by pain, stress, numerous medications, brain injury or be associated with brain malformations .…”

Vasopressin receptors and pharmacological chaperones: From functional rescue to promising therapeutic strategies

“…The main strategy for treating cNDI patients consists of a sufficient water supply to replace the urinary water loss, but this can seriously impact on the quality of life due to excessive drinking and urine voiding. Some diuretics, like hydrochlorothiazide, amiloride or the cyclooxygenase inhibitor indomethacin, have been proven effective to reduce urine output by up to 50% [8]. However, diuretics may affect the sodium and potassium balance in patients and therefore these treatments require tight monitoring of serum electrolytes and osmolality.…”