An 18-year-old male transferred to a local chronic kidney disease clinic. He has a history of polyuria since birth. He voids once about every 2 hours including overnight. He has chronic polydipsia and he has drunk up to 2 gallons of water per day for as long as he can remember.
His current medications include hydrochlorothiazide 100 mg daily and indomethacin. Family history reveals that his maternal grandfather and one brother are afflicted with the same condition.
On exam he is of normal height and stature. He is carrying a water bottle. His blood pressure is 108/62. He has negative orthostatics, clear lungs, and no peripheral edema. His Na is 142 and Cr is 0.8 mg/dL. Potassium, calcium, and glucose are within normal limits.
Urine studies reveal no albuminuria by dipstick and his specific gravity is 1.002. Urine osmolality is 45 mOsm/kg.
Representative images of both kidneys on a recent renal ultrasound are shown here:
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This patient is suffering from polyuria, borderline hypernatremia, and polydipsia since birth. Multiple male members of his family are similarly afflicted. This constellation of symptoms and findings is suggestive of hereditary diabetes insipidus (DI).
There is an X-linked mode of inheritance in nearly 90% of patients with hereditary forms of diabetes insipidus. The particular mutation leads to a defect in the vasopressin-2 (V2) receptor. The V2 receptor is located on the basolateral surface of the principal cells in the distal part of the nephron. V2 receptors are responsible for binding vasopressin and thereby starting a cascade of intracellular activity that leads to insertion of aquaporin channels into the luminal membrane of principal cells and subsequent reabsorption of water. Patients with V2 receptor mutations cannot effect this reabsorption of water and thus require large amounts of free water intake to match daily losses of dilute urine.
Treatment with diuretics may seem counter-intuitive in DI. However, hydrochlorothiazide is frequently prescribed, as this agent, in concert with a low-salt diet, can induce a setting of mild volume depletion thus leading to more avid proximal sodium reabsorption and decreased distal delivery and loss of water. NSAIDs can also be of benefit given their effect on renal prostaglandins.
Other causes of nephrogenic DI of varying degrees include lithium, hypercalcemia, chronic hypokalemia, advanced age, advanced chronic kidney disease, the Bardet-Biedl syndrome, and pregnancy. In certain cases of partial nephrogenic DI, giving DDAVP could be theoretically beneficial. However, in our patient with X-linked nephrogenic DI, the defect results in a phenotypic near-complete DI, and thus giving DDAVP is neither helpful nor indicated.
From a young age, patients with hereditable nephrogenic DI are encouraged to practice double voiding to facilitate complete emptying of the bladder. This practice may limit excessive urinary retention and thus hydronephrosis. Sustained hydronephrosis can lead to nephropathy and decline in GFR. Such patients are also at risk for developing eventual secondary focal segmental glomerulosclerosis.
The imaging in this patient demonstrates bilateral hydronephrosis. The patient was encouraged to resume double voiding, which he had stopped due to inconvenience in recent weeks. He was also referred to urology for further imaging and urodynamic studies.
This case was prepared by Kevin T. Harley, MD, Assistant Clinical Professor of Medicine, Division of Nephrology & Hypertension, at the University of California Irvine.
- Earley LE, Orloff J. The Mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin Invest 1962;41:1988-1997.
- Fujiwara TM, Bichet DG. Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 2005;16:2836-2846.