Nephrogenic Diabetes Insipidus - A Rare Differential Diagnosis of Bilateral Hydronephrosis in Adults: A Case Report and Literature Review

Chang G, Chen W, Hong Z and Rong L

Published on: 2021-03-18

Abstract

Objective: Nonobstructive hydronephrosis can be a key manifestation of nephrogenic diabetes insipidus (NDI), more commonly in hereditary rather than the acquired form.

Presentation of case: We report a case of a 29-year-old adult presented with elevated kidney function and bilateral hydronephrosis. After meticulous investigation, the diagnosis of hereditary NDI was made. Exon-wide sequencing analysis demonstrated a novel c.328delG mutation of arginine vasopressin receptor 2 (AVPR2) gene, resulting in a truncated AVPR2 protein. Treatment with thiazide and prostaglandin synthetase inhibitor resulted in limited response. We also performed a review of case reports through PubMed indexing bilateral nonobstructive hydronephrosis in adults. The most common etiology is NDI, with all of them hereditary in origin.

Conclusion: Bilateral nonobstructive hydronephrosis is an uncommon finding among adults and NDI should be at the top of the list among the differential diagnosis, as if diagnosed and managed early on, the risk of kidney injury could be reduced, as well as improvements in quality of life.   

Keywords

Nonobstructive hydronephrosis; Nephrogenic diabetes insipidus

Introduction

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.

Case Presentation

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.

Urine glucose

<10 mg/dL

Urine potassium

5 mEq/L

Urine sodium

25 mEq/L

Urine chloride

22 mEq/L

Urine nitrogen

103 mg/dL

Urine creatinine

13 mg/dL

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.

Time

Weight (kg)

Urine output (ml/hr)

Blood pressure (mm Hg)

Pulse rate (/min)

Urine specific gravity

Urine osmolality

Serum sodium

Serum osmolality (mOsm/kg)

(mOsm/kg)

(mEq/L)

800

64.9

160

143/92

108

1.003

93

141

306

900

65.5

500

127/71

91

 

 

 

 

1000

64.8

700

129/85

111

1.002

76

144

296

1100

64

740

125/83

92

 

 

 

 

1200

63.6

560

123/83

94

1.003

80

147

300

1300

62.8

840

135/96

101

 

 

 

 

1400

62.3

500

126/86

104

1.003

96

149

307

1500

61.9

500

130/87

118

 

 

 

 

1600

61.7

290

123/80

109

1.004

116

152

322

1700

Nasal desmopressin 10 ug given

1800

61

310

118/81

100

1.004

120

152

313

1900

62.2

210

137/86

104

1.004

123

151

322

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.

 

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.

Case

Age

/Sex

Key clinical history

Associated laboratory/imaging studies

Diagnosis

Treatment and Outcome

[5]

21M

Ataxia, polydipsia and polyuria

Chronic heavy water drinker since early childhood

No relevant family history

Cr 1.3 mg/dL, U Sp.G 1.002

CBC, UA, and electrolytes normal

UO 6-8 L/day

IVP: dilatation of bladder and urinary tract

VCUG: no bladder neck or urethral obstruction

Cystoscopy: trabeculated bladder

Flow-EMG study: no dysnergia

Central diabetes insipidus

Desmopressin 15 mcg BID

àSubstantial decrease in urine, able to go through the night without getting up.

à A month later, IVP showed improved hydronephrosis; Cr 0.8 mg/dL

[3]

40M

Mild chronic renal failure Cr 1.4 mg/dL

Compulsive water drinking from the age of 18

Serum Osmolality 300 mOsm/kg

Urine osmolality 100 mOsm/kg

UO 7-8 L/day

Voiding cystography: no reflux

Renal ultrasound: Bilateral hydronephrosis

Brain MRI: no pituitary stalk or infundibulum enlargement

Central diabetes insipidus

Oral desmopressin 150 mcg QD

à UO 3 L/day; stable Cr 1.5 mg/dL

[4]

21M

 

Polyuria and polydipsia since childhood.

Mild hypertension, elevated Cr

Family history of an X-linked genetic condition

 

Serum osmolality 286 mOsm/kg

Urine osmolality 99 mOsm/kg

UO 9 L/day

Renal ultrasound: severe bilateral hydronephrosis and enlarged bladder

IVP: no obstruction

Cystoscopy: trabeculated bladder

Hereditary

NDI

 

NA

[4]

24M

Marked polyuria and polydipsia since early childhood.

Family history of an X-linked genetic condition

Serum osmolality 288 mOsm/kg

Urine osmolality 81 mOsm/kg

UO 8 L/d

Renal sonography: severe bilateral hydronephrosis and enlarged bladder

IVP: no obstruction

Cystoscopy: trabeculated bladder

Hereditary

NDI

NA

[6]

47M

 

Polyuria and polydipsia since infancy

Admission for polyuria (UO 4 L/day) and elevated Cr (1.4 mg/dL)

Family history of an X-linked genetic condition

Serum osmolality 295 mOsm/kg

Urine osmolality 94 mOsm/kg

Renal sonography: bilateral hydronephrosis

Abdominal CT: dilated pelvis and urinary tract without obstruction; thickened bladder wall

Hereditary

NDI (V2R missense mutation, R104C)

NA

[7]

20M

Polyuria for several years

Serum osmolality 302 mOsm/kg

Urine osmolality 96 mOsm/kg

UO 5 L/day

IVP: bilateral dilatation of the ureter and calyceopelvic system

Hereditary

NDI (V2R missense mutation, Q225X)

NA

[7]

21M

Polyuria and nocturia

Urinated every 1 hour for several years

Serum osmolality 303 mOsm/kg

Urine osmolality 87 mOsm/kg

UO 10 L/day

Abdominal CT: markedly distended bladder with severe trabeculation

Hereditary

NDI (V2R missense mutation, S126F)

NA

[8]

34M

Polycythemia that required monthly phlebotomy

History of hereditary nephrogenic diabetes insipidus

Hemoglobin 20.2 g/dL, Cr 1.6 mg/dL

UO 12 -15 L/day

Abdominal CT: markedly distended urinary bladder; bilateral megaureter and extreme hydronephrosis with thin cortices

Hereditary NDI

Captopril and hydrochlorothiazide

à UO 7-9 L/day

Phlebotomy every 3 months

[1]

53F

Intermittent, mild, bilateral flank pain, related to fluid intake

No family history of central or nephrogenic diabetes insipidus nor malignancies.

Serum osmolality 286 mOsm/kg

Urine osmolality 334 mOsm/kg

Abdominal CT: bilateral moderate hydronephrosis and hydroureter

IVP: hydronephrosis without obstruction

Cystoscopy: no anatomical abnormality

Social polydipsia

Fluid intake decreased to 2 L/day

à 6 weeks later, renal ultrasound showed normal sized kidney with resolution of hydronephrosis

Discussion

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. 

Conclusion

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.

References

  1. Maroz N, Maroz N, Maroz U, Iqbal S, Aiyer R, Kambhampati G, et al.  Nonobstructive hydronephrosis due to social polydipsia: a case report. J Med Case Rep. 2012; 6: 376.
  2. Kamholtz RG, Cronan JJ, Dorfman GS. Obstruction and the minimally dilated renal collecting system: US evaluation. Radiology. 1989; 170: 51-53.
  3. Korzets A, Korzets A, Sachs D, Gremitsky A, Gershkovitz R, Farrage G, et al. Unexplained polyuria and non-obstructive hydronephrosis in a urological department. Nephrol Dial Transplant. 2004; 19: 2410-2412.
  4. Uribarri, J, Kaskas M. Hereditary nephrogenic diabetes insipidus and bilateral non-obstructive hydronephrosis. Nephron.1993; 65: 346-349.
  5. Boyd SD, Raz SMD, Ehrlich RMMD. Diabetes insipidus and nonobstructive dilation of urinary tract. Urology. 1980; 16: 266-269.
  6. Miyakoshi M, Kamoi K, Uchida S, Sasaki S. A case of a novel mutant vasopressin receptor-dependent nephrogenic diabetes insipidus with bilateral non-obstructive hydronephrosis in a middle aged man: differentiation from aquaporin-dependent nephrogenic diabetes insipidus by response of factor VII and von Willebrand factor to 1-diamino-8-arginine vasopressin administration. Endocr J. 2003; 50: 809-814.
  7. Yoo TH, Ryu DR, Song YS, Lee SC, Kim HJ. Congenital nephrogenic diabetes insipidus presented with bilateral hydronephrosis: genetic analysis of V2R gene mutations. Yonsei Med J. 2006; 47: 126-130.
  8. Sung CC, Lin SH. Images in clinical medicine. Nonobstructive hydronephrosis with secondary olycythemia. N Engl J Med. 2011; 365: 1.
  9. Jin XD, Chen ZD, Cai SL, Chen SW. Nephrogenic diabetes insipidus with dilatation of bilateral renal pelvis ureter and bladder. Scand J Urol Nephrol. 2009; 43:73-75.
  10. Magaldi AJ. New insights into the paradoxical effect of thiazides in diabetes insipidus therapy. Nephrol Dial Transplant. 2000; 15: 1903-1905.
  11. Uyeki TM. Successful treatment with hydrochlorothiazide and amiloride in an infant with congenital nephrogenic diabetes insipidus. Pediatr Nephrol. 1993; 7: 554-556.
  12. Kirchlechner V, Koller YD, Seidl R,  Waldhauser F. Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride. Arch Dis Child. 1999; 80: 548-552.
  13. Libber MDS, Harrison MDH, Spector MDD. Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors. J Pediatr. 1986; 108: 305-311.
  14. Ryu HH, Chung JH, Shin BC, Kim HL. Congenital nephrogenic diabetes insipidus with end-stage renal disease. Korean J Intern Med. 2015; 30: 259-261.