Bladder function impairment in aquaporin-2 defective nephrogenic diabetes insipidus
Hanna Shalev1,
Igor Romanovsky2,
Nine V. Knoers3,
Salomon Lupa4 and
Daniel Landau1
1Department of Pediatrics and 2Department of Urology, Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel, 3Department of Human Genetics, University Medical Center Nijmegen, the Netherlands and 4Alyn Pediatric and Adolescent Rehabilitation Center, Jerusalem, Israel
Correspondence and offprint requests to: Daniel Landau, MD, Pediatric Nephrology, Department of Pediatrics, Soroka Medical Center, P.O. Box 151, Beer Sheva 84101, Israel. Email: ldaniel{at}bgumail.bgu.ac.il
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Abstract
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Background. The aim of this study was to describe the urological complications associated with nephrogenic diabetes insipidus (NDI) due to a mutation in aquaporin-2 (AQP2), a collecting-duct protein activated by ADH signalling.
Methods. We provide a case series description of a group of seven patients with autosomal recessive NDI due to AQP2 gene mutation, receiving routine medical management since diagnosis in the first months of life.
Results. Mean urine osmolarity at diagnosis and last follow-up was 89±25 and 83±18 mosm/l, respectively. Hydroureteronephrosis was observed in all children, beginning at age 3 years. Two children have daytime enuresis at ages 7 and 10 years and all children older than 6 years continue to have nocturnal enuresis. Markedly enlarged bladders were observed as early as age 4 years in all patients. Trabeculated bladder walls were found in three children. Urodynamic studies performed in two daytime incontinent children revealed a hypotonic-large-capacity type of neurogenic bladder. No impairment in kidney function is currently observed.
Conclusions. The severe renal concentrating defect in this type of NDI is associated with the development of hydroureteronephrosis followed by bladder enlargement and dysfunction. Careful follow-up is needed in order to assure that no bladder outlet obstruction and/or renal insufficiency develop.
Keywords: bladder dysfunction; hydroureteronephrosis
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Introduction
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Congenital nephrogenic diabetes insipidus (NDI) is characterized by insensitivity of the distal nephron to arginine vasopressin. The most common genetic type of NDI is X-linked, due to mutations in the V2 type of vasopressin receptor in the renal collecting duct [1]. However, autosomal forms are also described. The identified defected gene in these forms has been aquaporin-2 (AQP2), which encodes a water channel affected by V2 receptor stimulation and causes both recessive and dominant forms of NDI [2,3]. The AQP2 gene is located in the chromosome region 12q13 [4].
Urinary tract dilatation develops in children affected with NDI, as well as other polyuric syndromes [5], probably due to the large volume of urine produced [6]. This correlation between NDI and severe urinary tract dilatation is well known [7], although usually considered a rare complication, mainly due to proper medical care. The usual therapeutic measures include salt and solute load restriction as well as thiazide diuretics and prostaglandin inhibitors. This therapeutic approach causes a significant reduction in urine volume, in both the X-linked [8] and the AQP2 recessive forms [9]. The usual therapy in these diseases is not directed specifically at the defective pathway, but improves very much the quality of life in these children, to an extent that a normal life expectancy can be envisioned. However, in spite of these measures, polyuria continues to be a common symptom in these patients. Usually, it causes no more than a mild to moderate hydronephrosis. However, more rare cases of severe distension of the urinary collecting system have been described in persistent polyuric syndromes. In these cases the upper urinary tract, and not the bladder, is usually involved [10]. In this report, this complication is much more prevalent and is, therefore, described.
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Subjects and methods
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Medical records of all children affected by autosomal recessive NDI treated in our centre were reviewed. Nine children were identified. All belonged to an extended Bedouin family with a high rate of consanguinity. The laboratory findings and age of diagnosis were recorded. Two of the patients died at an early age (1.5 years). Therefore, clinical data and urinary tract imaging results from the remaining seven children were analysed. All patients were evaluated annually, including imaging of their urinary tract by renal sonograms and voiding cystourethrograms. Hydronephrosis grading (mild, moderate and severe) was done according to Hricak et al. [11]. Mild hydronephrosis is characterized by fluid-filled intrarenal collecting structures that are not significantly distorted, but are slightly separated from the sinus fat. In moderate hydronephrosis there is obvious distension and rounding of the intrarenal collecting structures with well-preserved cortical thickness. The diagnosis of severe hydronephrosis is made in cases in which the sinus fat is virtually replaced by a rounded and dilated infundibulae and calyces in a kidney in which there is significant cortical thinning.
NDI was diagnosed clinically during the first months of life, based on hyposthenuric urine during events of hypernatraemic dehydration, which did not respond to exogenous desmopressin. Conventional therapy, including hydrochlorothiazide, indomethacin and low-salt diet, was initiated at diagnosis.
During the current re-evaluation, a repeated standard desmopressin test was performed, based on the protocol by Monnens et al. [12]. Briefly, children were given 2040 µg desmopressin (Minirin, Ferring) intranasally. They were then asked to decrease their regular fluid intake by 50%. Urine and serum osmolarity were measured hourly during the 4 h since DDAVP administration.
Children with daytime enuresis underwent a urodynamic study, using standard methods. The investigation comprised full pressure-flow recordings, on an outpatient basis, using a Urolab Spectrum (Life Tech) instrument. Intravesical and intra-abdominal pressure were measured during both bladder filling and emptying, the former using a dual lumen 6 Fr. transurethral catheter and the latter with the use of a rectal catheter. Room temperature normal saline solution was used to fill the bladder at a rate of {(age (years) + 2) x 30}/10 ml/min, with the patient standing. The bladder capacity relates to maximum cystometric capacity and was expressed as a percentage of the mean bladder capacity expected for the child's age [13], calculated as (age (years) + 3.16) x 24.8 ml [14]. The proportion of intravesical pressure that is due to detrusor activity was obtained by subtracting abdominal pressure from intravesical pressure. Instability was defined as a phasic detrusor contraction of >15 cm H2O from baseline that the patient did not suppress during provocative cystometry [15]. The end-filling detrusor pressure (pre-micturition pressure) was measured after filling had stopped and the detrusor pressure recording remained at a stable level for several seconds. End-filling pressure is related to the normal cystometric bladder capacity predicted for age. The bladder compliance was calculated as bladder capacity/end-filling detrusor pressure. Four of the seven patients refused to perform a urodynamic study. Therefore, bladder volume was assessed by the radiologist to be normal, large or huge.
Urine ß-2 microglobulin was determined by an enzyme-linked immunosorbent assay using a standard commercial kit (Abbott Diagnostics, Illinois, USA). Urine was alkalinized before analysis with 0.1 N NaOH to prevent protein precipitation.
Six non-affected siblings (three males, three females) aged 12±7 years (range: 322 years), were recently assessed by first morning urine specimen analysis for volume and urine osmolarity, in addition to a renal ultrasound.
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Results
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The patient group includes nine children and adolescents (seven males and two females) with autosomal recessive NDI who belong to a highly consanguineous extended Bedouin family (Figure 1). A novel T83C mutation in the AQP2 exon 1 gene, resulting in a L28P amino-acid substitution in the first transmembrane region of the AQP2 protein, was identified in the DNA analysed in five affected children (patients 2, 4, 5, 6 and 8 in Figure 1), who represent each of the nuclear families. Given the high level of consanguinity between families, a similar mutation is expected in all other affected patients. Functional analysis using Xenopus oocytes revealed that this mutant was non-functional [16].
None of the affected children was the product of a pregnancy complicated with polyhydramnios. All patients were diagnosed during the first 4 months of life with hypernatraemic dehydration. Two children died during their second year of life, one of them due to severe hypernatraemic dehydration and the second one due to measles complications. Neither of them received regular medical attention. Mean urine osmolarity at diagnosis was 89±25 mosm/l. This value is lower than that described in a series of NDI children (n = 30) with V2 receptor mutations (175±119 mosm/l) [10]. Mean urine osmolarity after DDAVP challenge remained very low at the time of the last evaluation at age 11±4.5 years (83±18 mosm/l) (Table 1). In comparison, the mean urine osmolarity on first morning urine samples among six non-affected siblings was 600±170 mosm/l.
The patients mean current age is 11±4.5 years. All children grew poorly during the first decade of life. This affected both longitudinal growth and weight gain. Weight standard deviation scores (SDS) showed catch up towards the end of the first decade, changing from -2.9±0.36 at age 2 years to -1.2±0.2 and 0.37±0.19 at age 6 and 10 years, respectively. However, height SDS remained low (-3.02±0.54, -1.85±0.34 and -1.37±0.43 at ages 2, 6 and 10 years, respectively; Figure 2). In comparison, weight and height SDS among six non-affected siblings (age: 418 years) were -0.57±0.95 and -0.54±1.1, respectively.
Two children have daytime enuresis at age 7 and 10 years and six of the seven continue to have nocturnal enuresis beyond the age of 6 years. In comparison, none of the non-affected siblings had nocturnal enuresis beyond age 6 years. Hydroureteronephrosis was observed in all children, beginning at age 3 years. Sonography also revealed markedly enlarged bladders (all defined as huge by different radiologists) as early as age 4 years. Mean bladder volume was 1233±628 ml (equivalent to 250±83% of expected bladder volume for age) in six of the seven affected children and all of them had a significant post-voiding residuum (
1000 ml). Maximum bladder capacity was assessed by ultrasound in six healthy asymptomatic siblings of these patients and found to be 206±105 ml (55±20% of normal value for age) (P < 0.005 by t-test). None of the healthy siblings had urinary tract dilatation or significant post-voiding bladder residuum. Voiding cystourethrography revealed trabeculated bladder walls in three of six children tested (Figure 3, bottom). The two children with daytime incontinence underwent urodynamic studies, which revealed a hypotonic-large-capacity, high compliant (as high as 74 ml/cm H2O in the older 14-year-old child tested) type of neurogenic bladder. Bladder residuum was as high as 1000 ml (Figure 3). These two children initiated a clean intermittent catheterization regimen, which improved the bladder appearance but could not solve the daytime enuresis. No impairment in kidney function, including serum creatinine and low molecular weight proteinuria (as measured by ß-2 microglobulin excretion), is currently observed.

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Fig. 3. Renal ultrasound and voiding cystogram of one of the patients. (Top) Longitudinal view of right kidney shows marked hydronephrosis and hydrocalicosis, with thin cortex (arrow). A similar pattern was seen in the left kidney. (Middle) Longitudinal view of the bladder shows a marked distal hydroureter (arrow). (Bottom) The cystogram shows a markedly enlarged bladder, with trabeculated walls. No vesicoureteric reflux is seen.
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Discussion
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We describe a family with a mutation in the AQP2 gene, whose affected members have consistently developed massive dilatation of the urinary tract. This has occurred in spite of standard medical therapy, supported by the fact that any of the patients were hospitalized due to dehydration after age 12 years. All affected patients presented at an early age (2.7±1.1 months), earlier than a group of children with V2 receptorX-linked NDI (Table 1). In previous reports on X-linked NDI, this urinary tract dilatation complication is rare [10]. The massive distension of the urinary tract occurred at a relatively young age in all our patients. Previous reports on such complications in the paediatric age were made more than 3 decades ago [17]. This complication has also been described in several adult patients with long-standing polyuria [5,18,19], some of whom were left untreated for several years [6]. In some cases, induction of standard medical treatment with thiazide diuretics and salt restriction caused some regression of the urinary tract dilatation [17]. However, Zender et al. [20] described one case and summarized four additional previously published cases of NDI associated with chronic renal failure and bilateral hydronephrosis. Therefore, this potential severe late complication needs to be taken into consideration when planning follow-up and therapy for these patients.
The variable manifestation of urinary tract dilatation in NDI could also be due to a heterogenous genotype in previous series, which included mutations in different sites along the V2R gene [10], whereas our patients belong to a more homogenous group. To the best of our knowledge this is the largest group of patients from one family with mutations in this gene. The variability in genotypes described for V2R is also associated with a high variability in maximal urine concentrating ability, which may be as high as 315 mosm/l [10]. In our series, maximal urine concentrating ability remained very low in most patients (<100 mosm/l). This finding has been affirmed with a repeated test, performed years after the original diagnosis. Canfield et al. [21] described a patient with a mild type of NDI (able to concentrate his urine to an osmolarity as high as 442 mosm/l), who was found to be a compound heterozygote in the AQP2 gene. This is in contrast with the mutation in our patients (L28P), which has major inhibitory effects on water permeability in the collecting duct, contrary to other AQP2 mutations, where some function of the channel is retained [16].
AQP2 is located downstream of V2R in the ADH signalling pathway. The AQP2 gene is known to be highly regulated. Different stimuli can up- and down-regulate its expression, irrespective of the ADH status, such as fasting [22], hypokalaemia [23] and lithium [24]. Therefore, it is possible that mutations in a more proximal gene in the ADH signal transduction (such as the V2 receptor) can be compensated by a higher expression of AQP2. However, mutations in the more distal gene (AQP2 itself) may result in a more significant and recalcitrant polyuria. An analogous condition exists for pseudohypoaldosteronism, where two genes located along the aldosterone signalling pathway cause a different phenotype: a milder condition in proximal mineralocorticoid receptor mutation [25], but a more severe disease when the more distal epithelial sodium channel (ENaC) gene is mutated [26].
In summary, we describe a family with a novel mutation in the AQP2 gene, who become homogeneously affected by massive urinary tract dilatation, up to a level of bladder dysfunction, in spite of proper medical care. Given previous reports on potential deterioration of kidney function due to a relative obstructive uropathy in similar conditions, a judicious long-term follow-up is recommended in these patients.
Conflict of interest statement. None declared.
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Received for publication: 24. 7.02
Accepted in revised form: 24. 9.03