Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus

Abstract

Background: Congenital nephrogenic diabetes insipidus (NDI) is characterized by massive polyuria and polydipsia due to defects in the vasopressin-sensitive signaling system expression of the acuaporin-2 (AQP2) water channel of the kidney collecting duct principal cells. Current conventional treatment regimen including hydration, diuretics and non-steroidal anti-inflammatory drugs can only partially reduce polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP)-mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital NDI. Patient and Methods: A 4-year old boy with X-linked NDI resistant to conventional therapy was treated with sildenafil for 10 days after a 2-day washout period between the 2 treatment regimens. Aliquots of the 24-hour urine collections before and after treatment were analyzed for urine volume, osmolality, cGMP and AQP2 determinations. Blood samples were also obtained for sodium and osmolality measurements. The primary endpoint was 24-hour urine volume after 10 days of sildenafil and conventional treatments. Results: Compared to conventional therapy, treatment with sildenafil resulted in substantial reduction in 24-hour urine volume (1,764 vs. 950 ml) and serum sodium (148 vs. 139) mEq/l, and increased urine osmolality (104 vs. 215 mOsm/l), and AQP2 excretion (5 vs. 26 fmol/mg creatinine). The patient tolerated sildenafil well and experienced no adverse effects. Conclusions: Sildenafil citrate should be considered an alternative agent in the treatment of X-linked NDI resistant to conventional therapy.

Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus

“…Sildenafil was also shown to increase AQP2 membrane accumulation in vitro and in vivo by enhancing cGMP levels in Brattleboro rats (20). Assadi and Sharbaf reported a case of X-linked NDI treated with sildenafil; treatment decreased urine volume and enhanced urine osmolality compared with the combination of HTCZ, amiloride, and indomethacin (21). Rosiglitazone was shown to upregulate AQP2 and NKCC2 in MCD4 cells by a Ca-dependent/cAMP-independent pathway (22).…”

Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update

“…Sildenafil was also shown to reduce polyuria and increase urine osmolality in rats with lithium-induced NDI [ 152 ]. Recently, Assadi and Sharbaf described a case of a young male patient with X-NDI treated with sildenafil and showing a substantial decrease in urine output and increased urine osmolality compared with conventional treatment [ 153 ]. Strikingly, they also detected an increase of urinary excretion of AQP2, suggesting that cGMP can also increase AQP2 expression.…”

“…This finding is inconsistent with those reported by Boone et al in mice [ 151 ]. The minimal activity of the AVPR2 mutation in this patient may also play a role in the beneficial effect of sildenafil [ 153 ].…”

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

“…In line, mice deficient in NO synthase isoforms developed NDI (Morishita et al, 2005a ). PDE5 inhibitors and ANP combined cause natriuresis and decreased urine output (Bouley et al, 2005 ; Assadi and Ghane Sharbaf, 2015 ). Therefore, the activation of AVP-independent cGMP signaling with sildenafil could be an option in the treatment of X-linked NDI as it bypasses the defective V2R/cAMP axis (Sanches et al, 2012 ).…”