Hydronephrosis, defined as dilatation of renal collecting system, is commonly encountered in clinical practice, and it is crucial to differentiate true mechanical obstruction from nonobstructive causes. Bilateral nonobstructive hydronephrosis is an uncommon presentation in both children and adults alike [1], etiologies include increased urine production, postobstructive dilation, vesicoureteral reflux, papillary necrosis, congenital megacalyces and overdistended bladder [2]. Whilst it is widely known that hydronephrosis can disturb the concentration ability of the urine, it is less recognized in nephrogenic diabetes insipidus (NDI) and central diabetes insipidus [3], where it manifests as bilateral dilatation of the urinary tract, even in the absence of anatomic urinary tract obstruction [4] when urinary output exceeds the capacity of the genitourinary system. We report a case of a 29-year-old man with bilateral nonobstructive hydronephrosis and hydroureter from hereditary NDI with a novel c.328delG mutation of arginine vasopressin receptor 2 (AVPR2) gene, as well as a literature review of adult nonobstructive hydronephrosis in an attempt to determine the clinical importance of its association with NDI.

A 29-year-old Asian man without prior medical history was presented to the hospital with an abnormal serum creatinine detected during a health screening. He noticed massive amount of urine in the past five years. The urine output was > 4 L/day and frequently interrupted his sleep, with incomplete voiding sensation for the past three years. He denied dysuria, incontinence, pitting edema, shortness of breath, alcohol or illicit drug abuse, psychological history nor excessive fluid intake. At the same time, no blurred vision, diplopia, nausea, vomiting nor head injuries were mentioned. On recall, he remembered having polydipsia since primary school (> 4 L/day). To his knowledge, there was no relevant family history. On physical examination, the patient was alert, oriented, athletic, and well-nourished, with a BMI of 22.6 and absence of growth retardation. His temperature was 36.9°C, blood pressure 128/89 mm Hg, pulse rate 100 beats per minute, respiratory rate 18 breaths per minute, and the oxygen saturation 100% under ambient air. Knocking tenderness over the left costophrenic angle was present, while the remainder were unremarkable. Laboratory data disclosed white blood cell count (14700 /uL), C-reactive protein (2.1 mg/dL), blood urea nitrogen (17 mg/dL), creatinine (1.6 mg/dL), random glucose (105 mg/dL), potassium (4.4 mEq/L), and sodium (143 mEq/L). Urinalysis showed urine specific gravity (1.003), hematuria, and pyuria. Random urine osmolality was 101 mOsm/kg. Renal sonography portrayed bilateral enlarged kidney size, hydronephrosis, increased cortical echogenicity and cortical atrophy, suggesting sequelae of long-term hydronephrosis. Additionally, abdominal computed tomography with contrast enhancement unveiled hydroureter and cystitis without obvious obstruction site (Figure 1). Urological examination includes transrectal sonography, cystometry, fluorescent cystoscopy and ureteroscopy. Prostate hypertrophy and intraluminal obstruction were absent with normal detrusor pressure.

Figure 1: Contrast-enhanced abdominal and pelvic computed tomography showing (a): Thickening of bladder wall, indicating cystitis (arrowhead). (b): Dilatation of pelvis and ureter, indicating bilateral hydronephrosis with hydroureter (arrow).

Once admitted, urine output of 13L per day was recorded. Investigation went underway for the potential cause of polyuria, and a fasting blood test showed normokalemia (4.4 mEq/L), normocalcemia (9.9 mg/dL), and hypernatremia (151 mEq/L), with normal thyroid and adrenal function tests. A 24-hour urine sample were analyzed (Table 1).

Table 1: Urine output 14.322 L, 24 hours data.

As shown above, calculated urine osmolarity was 97 mOsm/L and urine glucose < 10 mg/dL; hence osmotic diuresis was believed to be less conceivable and water diuresis more plausible. As polyuria persisted a week after urinary catheter insertion, we deemed postobstructive diuresis and recovery phase of acute kidney injury to be unlikely, thereby making diabetes insipidus the tentative diagnosis. After obtaining consent from the patient, fluid deprivation test was initiated with the protocol as follows.

• Nothing by mouth initiated at 8AM
• Starting from 8AM, Q1H recording of weight, urine quantity, blood pressure and pulse rate
• Starting from 8AM, Q2H recording of urine specific gravity, urine osmolality, serum sodium and serum osmolality
• If any of the following condition occurs, it is up to the clinician’s discretion whether to terminate the test or give a desmopressin stimulation test.

(A) Weight loss 5%, (B) urine specific gravity > 1.025, (C) urine osmolality > 600 to 700 mOsm/kg, (D) urine osmolality rises < 30 mOsm/kg or urine specific gravity rises < 0.001 for 3 consecutive tests, and (E) vital signs change such as hypotension or severe hypertension.

• After giving nasal desmopressin 10 mcg (1 puff), record urine specific gravity, urine osmolality, serum sodium and serum osmolality after 1st and 2nd hour respectively.

Results were as follows (Table 2).

Table 2: Fluid deprivation test and desmopressin stimulation test.

Under fluid deprivation test, the presence of serum hyperosmolality (306 mOsm/kg) and suboptimal urine concentration (< 800 mOsm/kg) excludes the possibility of primary polydipsia, thereby making the diagnosis of diabetes insipidus. Desmopressin stimulation test was therefore prompted, with results showing insignificant increase in urine osmolality (< 10%), hence the diagnosis of NDI was confirmed. We sent exon-wide sequencing analyses for AVPR2 and aquaporin 2 (AQP2) genes, with results demonstrating a c.328delG mutation of AVPR2 gene, which give rise to a mutated p.Ala110fs and truncated AVPR2 protein in our patient (Figure 2).

Figure 2: Gene analyses for AVPR 2 2 (patient) and AVPR2 2-2 (patient’s mother). Male was affected as the AVPR2 is an X-linked gene.

Figure 3: Truncated AVPR2 protein was produced in our patient.

With treatment of trichlormethiazide 2mg QD and indomethacin 25mg TID, the patient had a decreased urine output of 6 to 7 L/day and stable serum creatinine at around 1.6 mg/dL. We follow-up with a literature search through PubMed with the keywords of nonobstructive hydronephrosis for case reports, with 272 articles found. After excluding non-adult patients, unilateral hydronephrosis and non-English articles, a total of nine case reports were listed (Table 3), including two cases of central diabetes insipidus, six of NDI, and one of primary polydipsia. 

Table 3: Results from search of adult bilateral nonobstructive hydronephrosis through PubMed Abbreviations: CBC, complete blood count; Cr, creatinine; CT, computed tomography; IVP, intravenous pyelogram; NA, not available; VCUG, voiding cystoureterography; U Sp.G: urine specific gravity; UA, urinalysis; UO, urine output.

Bilateral nonobstructive hydronephrosis is an uncommon presentation in adults, of which NDI is an important differential diagnosis. NDI is a disorder characterized by the loss of the ability to concentrate urine and the insensitivity to arginine vasopressin (AVP) [7]. NDI can be acquired, such as drug induced, with lithium being the most common culprit agent or hereditary due to genetic defects. In majority of the cases, hereditary NDI (> 90%) have X-linked mutation in the AVPR2 gene, while less than 10% are caused by autosomal recessive or dominant mutation in the AQP2 water channel gene [6]. Differentiation between hereditary NDI with hydronephrosis and acquired NDI of postobstructive uropathy can be challenging; however, gene mutation analysis can be a useful diagnostic tool to delineate between the two [7]. Our patient and his mother carried a c.328delG mutation of AVPR2 gene, resulting in a truncated AVPR2 protein in our patient. To our knowledge, the genetic mutation c.328delG has not been reported on the Human Gene Mutation Database (HGMD®), a well-known genetic browser, and is therefore a novel finding.Although severe hydronephrosis is a rare complication in patients with NDI [3], it has been reported that dilatation of the urinary tract was present in up to 67% of the reported cases [9]. Dilatation of the urinary tract is more likely to occur in hereditary NDI, presenting with persistent massive polyuria from an early stage of development, when the urinary tract is more adaptive. In contrast, the bilateral hydronephrosis occurring in the setting of acquired form of pituitary diabetes insipidus occurs relatively short in duration, and thus less likely to undergo dilatation [4]. This appears to be consistent with our patient’s finding as well as our literature review, that among 9 adult patients with bilateral nonobstructive hydronephrosis, 6 (66.7%) were accounted for by NDI, and all of the cases of NDI were hereditary. Chronically, massive urine volumes can lead to distension and hypertrophy of the urinary bladder, with reported subsequent intramural obstruction of the distal ureters [3]. However, in the review conducted by Jin [9], only one out of thirty cases showed unilateral vesicoureteral reflux, rendering their association speculative. Contractility of the bladder is usually compromised along with diminishing ureteric peristalsis, which worsens this functional obstructive uropathy [3]. Moreover, these patient often self-cause urine retention due to social embarrassment, which only acts to aggravate the uropathy even further [9]. Although treatment response in our patient is less than satisfactory with limited reduction in urine output, sodium restriction and thiazide diuretic alone[10] or in combination with a prostaglandin synthetase inhibitor or amiloride[11-13] remain to be the only practical form of treatment. On the contrary, central diabetes insipidus shows excellent response to desmopressin, as presented in the two cases in our review. Although chronic kidney disease is an infrequent finding in hereditary NDI, it can occur due to recurrent dehydration, long-term hydronephrosis, or ureteral dilatation [14].As majority cases of the nonobstructive hydronephrosis arises in the setting of hereditary NDI, timely management of massive polyuria through medication and frequent voiding could improve quality of life, and at the same time minimize the likelihood of postrenal kidney injury. 

We report here a case of hereditary NDI with bilateral nonobstructive hydronephrosis that was diagnosed by fluid deprivation and desmopressin stimulation tests, which was later confirmed by genetic analysis and revealed a novel c.328delG mutation of AVPR2 gene. In the presence of bilateral nonobstructive hydronephrosis, it is vital to consider NDI, especially the hereditary form, as an important differential diagnosis, as if unabated early on, kidney injury could ensue.

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