Severe bladder dysfunction in a family with ADH receptor gene mutation responsible for X-linked nephrogenic diabetes insipidus

Sir,

We read with great interest the article by Shalev et al. [1] who reported a family affected by nephrogenic diabetes insipidus (DI) associated with hydroureteronephrosis and bladder dysfunction. The authors found a mutation of the aquaporin 2 gene (AQP2) to be responsible for the underlying concentration defect. As the authors indicate, the hyperdiuresis is thought to be responsible for the hypotonic large capacity-type bladders. We regularly see several patients affected by different forms of nephrogenic DI. We want to draw attention to one particular family with three boys affected by X-linked DI due to an R106C mutation in the AVPR2 gene coding for the antidiuretic hormone (ADH) receptor. The maximal urine concentration capacity in these three patients is extremely reduced (140–215 mosm/kg) and diuresis ranges between 6 and 8 l/day. Ultrasound investigations revealed bilateral hydroureteronephrosis. Voiding cystography (VCUG) did not show any pathological reflux or outlet obstruction, but revealed an enlarged bladder (Table 1). Urinary flowmetry revealed a hypotonic large capacity-type neurogenic bladder similar to that described by Shalev et al. Clean intermittent catheterizations (CICs) are necessary in all three boys (Table 1). Undoubtedly the development of severe bladder distension in situations of extremely high amounts of hypo-osmotic urine remains rare. Nevertheless, our three patients presented with a bladder dysfunction of severity comparable with the cases reported by Shalev et al. Other authors have reported similar cases of bladder dysfunction in patients with nephrogenic DI [2,3]. In vivo studies in rats with hyperdiuresis evidenced a decrease in total bladder collagen content, but showed a normal contractile function [4]. It has not yet been elucidated if the large urine flow is the only contributing factor to the development of such urinary tract dilatation in DI. It is thought to exceed the capacity of the urinary tract, causing a functional obstruction and residual urine volume. One could hypothesize that severe distension of the bladder induces stretching of actin and myosin filaments responsible for the contractile defect in patients with severe bladder dysfunction. More complicated mechanisms might be involved in its pathogenesis, such as an independent associated urinary tract dysfunction. One could hypothesize that some gene mutations could be responsible for both the concentration defect and the bladder dysfunction in certain patients. These cases provide evidence that a similar phenotype is caused by two different gene mutations, which is a strong argument against a separate genetically mediated bladder dysfunction.


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Table 1. Major clinical symptoms and results of radiological investigations in three male patients with a mutation of the ADH receptor gene responsible for nephrogenic DI

 
In conclusion, a mutation of the ADH receptor gene can be responsible for DI with severe bladder dysfunction, as well as a mutation of the AQP2 gene.

Conflict of interest statement. None declared.

Tim Ulinski1, Christine Grapin2, Veronique Forin2, Rosa Vargas-Poussou3, Georges Deschênes1 and Albert Bensman1

1 Pediatric Nephrology2 Pediatric Surgery Hôpital Trousseau3 Physiology Hôpital Européen Georges Pompidou Paris France Email: tim.ulinski{at}trs.ap-hop-paris.fr

References

  1. Shalev H, Romanovsky I, Knoers NV et al. Bladder function impairment in aquaporin-2 defective nephrogenic diabetes insipidus. Nephrol Dial Transplant 2004; 19: 608–613[Abstract/Free Full Text]
  2. Ramsey EW, Morrin PA, Bruce AW. Nephrogenic diabetes insipidus associated with massive hydronephrosis and bladder neck obstruction. J Urol 1974; 111: 225–228[ISI][Medline]
  3. Tank ES, Alexander SR, Craven RM. Polyuric megalocystis. J Urol 1980; 124: 692–694[ISI][Medline]
  4. Eika B, Levin RM, Longhurst PA. Comparison of urinary bladder function in rats with hereditary diabetes insipidus, streptozotocin-induced diabetes mellitus, and nondiabetic osmotic diuresis. J Urol 1994; 151: 496–502[ISI][Medline]
  5. Zerin JM, Chen E, Ritchey ML et al. Bladder capacity as measured at voiding cystourethrography in children: relationship to toilet training and frequency of micturition. Radiology 1993; 187: 803–806[Abstract]