Treatment of Nephrogenic Diabetes Insipidus: [Letter]

Abstract

To the Editor: Thiazides, which have been the mainstay in the treatment of nephrogenic diabetes insipidus since 1959, decrease urine volume and increase urine osmolality by producing a mild sodium depletion.1 However, distal tubular exchange of sodium for potassium almost invariably results in hypokalemia, which is seldom corrected by potassium supplements or potassium-sparing diuretics.2 Kleeman and colleagues3 showed that hexamethonium produced a fall in glomerular filtration and a reduction in urine volume in patients with nephrogenic diabetes insipidus. Since the age of 21, the patient had received hydrochlorothiazide in combination with either amiloride, triamterene, or spironolactone. Another possible risk associated with hypokalemia is cardiac arrhythmia.4, 5 Potassium supplements, in the doses commonly given, may have little effect on serum potassium in patients taking diuretics with no correlation between serum potassium and the intake of potassium supplements in patients undergoing long-term therapy with diuretics.6 Up to 60 mM potassium chloride or more daily may be required to correct thiazide-induced hypokalemia.7 A combination of thiazide and hypotensive agents controlled the polyuria and nocturia in this man with nephrogenic diabetes insipidus.

To the Editor: Thiazides, which have been the mainstay in the treatment of nephrogenic diabetes insipidus since 1959, decrease urine volume and increase urine osmolality by producing a mild sodium depletion.1 However, distal tubular exchange of sodium for potassium almost invariably results in hypokalemia, which is seldom corrected by potassium supplements or potassium-sparing diuretics.2 Kleeman and colleagues3 showed that hexamethonium produced a fall in glomerular filtration and a reduction in urine volume in patients with nephrogenic diabetes insipidus. We report here on a patient in whom this observation was exploited to prevent hypokalemia caused by thiazide treatment.

The 25-year-old patient first presented at the age of 15 months with profound polydipsia and polyuria. A diagnosis of nephrogenic diabetes insipidus was established, but no treatment was given initially. His brother reported extreme thirst, as did his mother (to a lesser degree), but both have refused investigation. Since the age of 21, the patient had received hydrochlorothiazide in combination with either amiloride, triamterene, or spironolactone. Although the urine output was reduced, the treatment always induced hypokalemia, sometimes with serum potassium levels as low as 2.8 mmol per liter. Spironolactone also caused gynecomastia.

In September 1985 the patient was admitted to the hospital, where nephrogenic diabetes insipidus was again confirmed by an evaluation showing that the high urine output and hypoosmolality were not influenced by vasopressin. A urinalysis and a microscopical examination of the urine were normal. Thiazide alone reduced the urine output, but the serum potassium fell to less than 3.0 mmol per liter within days. A month later the patient was readmitted and given a constant diet for 16 days that included 98 mM sodium, 73 mM potassium, and free access to water. After three days, treatment with oxprenolol and hydralazine was started, and the dosages were increased to produce a bradycardia and a slight reduction in blood pressure. Four days later, hydrochlorothiazide (100 mg) and amiloride (10 mg) were added; they produced a profound fall in urine output, from about 14 to 8 liters per day (Fig. 1). There was an initial fall in the serum potassium level, but over the next 52 days, it rose to 4.1 mmol per liter, and the reduced urine output was sustained. Nocturia, which had previously occurred four or five times nightly, disappeared.

At that point the patient was readmitted and a constant diet restarted. Hypotensive agents were stopped, but the diuretics were continued. Hypokalemia (3.0 mmol of serum potassium per liter) recurred, but there was no substantial change in urine output. Serum creatinine levels remained normal throughout the period of treatment.

Hypokalemia may cause impairment of glucose tolerance and of urine-concentrating ability, which could exaggerate polyuria and polydipsia in patients with nephrogenic diabetes insipidus. Another possible risk associated with hypokalemia is cardiac arrhythmia.4^, 5 Potassium supplements, in the doses commonly given, may have little effect on serum potassium in patients taking diuretics with no correlation between serum potassium and the intake of potassium supplements in patients undergoing long-term therapy with diuretics.6 Up to 60 mM potassium chloride or more daily may be required to correct thiazide-induced hypokalemia.7 A combination of thiazide and hypotensive agents controlled the polyuria and nocturia in this man with nephrogenic diabetes insipidus. There were no side effects. Hypokalemia was prevented by the hypotensive drugs but appeared promptly when these agents were discontinued. Whether oxprenolol, hydralazine, or both, were responsible for the potassium-sparing effect was not addressed in this single case report.

References

1. 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 -97.

2. Alon U, Chan JCM. Hydrochlorothiazide-amiloride in the treatment of congenital nephrogenic diabetes insipidus. Am J Nephrol 1985;5:9 -13.

3. Kleeman CR, Maxwell MH, Rockney R. Production of hypertonic urine in humans in the probable absence of antidiuretic hormone (ADH). Proc Soc Exp Biol Med 1957;96:189 -91.

4. Gettes L, Surawicz B. Effects of low and high concentrations of potassium on the simultaneously recorded Purkinje and ventricular action potentials of the perfused pig moderator band. Circ Res 1968;23:717 -29.

5. Fisch C. Relation of electrolyte disturbances to cardiac arrhythmias. Circulation 1973;47:408 -19.

6. Ramsay LE, Boyle P, Ramsay MH. Factors influencing serum potassium in treated hypertension. Q J Med 1977;46:401 -10.

7. Schwartz AB, Swartz CD. Dosage of potassium chloride elixir to correct thiazide-induced hypokalemia. JAMA 1974;230:702 -4.

Illustration

Figure 1:

Effect of Treatment on Urine Volume, Urine Osmolality, and Serum Potassium in a Patient with Nephrogenic Diabetes Insipidus.

[Image Omitted: See PDF]

David J.M. Lewis M.B., B.CH.

J. Picton Thomas F.R.C.P.

University Hospital of Wales, Health Park, Cardiff, United Kingdom