International Urology and Nephrology 22 (5), pp. 419-427 (1990)
Nonobstructive Urinary Tract Dilatation in Nephrogenic Diabetes Insipidus T. NAKADA, T. MIYAUCHI, H. SUMIYA, J. SHIMAZAKI Department of Urology, Chiba University, School of Medicine, Chiba, Japan (Received September 11, 1989) The follow-up study has been performed in 4 male patients with nephrogenic diabetes insipidus lasting for 4 to 15 years. Hydronephrosis or hydroureter appeared to be caused by polyuria with or without urinary tract obstruction. The efficacy of drainage operation is emphasized when polyuria surpasses the transporting ability of urine in the urinary tract.
Introduction Nephrogenic diabetes insipidus, first reported by Forssman [1 ], is a disorder characterized by callousness of the collecting duct to both endogenous and exogenous antidiuretic hormone (ADH). Clinical manifestation of this disease commonly presents with polyuria, polydipsia, fever, vomiting, dehydration and failure to thrive. The pathogenesis is speculative. However, in patients with this disease administration of ADH failed to induce the anticipated increase in cyclic adenine 3',5'-monophosphate (cAMP) in the urine. In addition, exogenous cAMP did not uniformly decrease urinary volume and free water clearance [2]. Subsequently defects in processes both proximal and distal to cAMP generation with resultant decreased water reabsorption have been presumed [2]. During the past decade attention has been focussed mainly on the biochemical or endocrine basis of the renal inability to absorb water in the distal tubule, and serious therapeutic problems underlying this disorder such as hydronephrosis, massively dilated ureter and distended bladder have not been extensively studied. Especially scanty is the literature dealing with long follow-up of obstructive or nonobstrucrive uropathy in patients with nephrogenic diabetes insipidus. This study mainly concerns nonobstructive dilatation of the upper or lower urinary tract in several patients with this disease.
Case reports Case 1. Y. K., an 18-year-old man, was first seen in June 1975, complaining of severe polyuria and occasional nocturnal enuresis since birth. His mother also had been polyuric all her life. He apparently had been investigated at the age of 2
VSP, Utrecht Akad~miai Kiad6, Budapest
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13 for nocturnal enuresis but only urinalysis and K U B had been done and no treatment was initiated. He has physically unremarkable stature but was hypertensive with a blood pressure of 176/108 m m Hg. Evaluation when he was 18 years old revealed serum creatinine of 1.8 mg/dl, blood urea nitrogen of 34 mg/dl and creatinine clearance of 53 ml/min. Values for the following laboratory studies
Fig. 1A. Case 1. Retrograde pyelogram: bilateral hydronephrosis Fig. IB. Case 1. Cystogram: distended bladder with trabeculation. Note left vesicoureteral reflux (arrow) International Urology and Nephrology 22, 1990
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remained within normal limits: serum sodium, serum potassium, serum chloride, serum calcium, serum phosphorus, lactic dehydrogenase, fasting blood sugar and serum glutamic oxaloacetic transaminase. Frequent qualitative analyses revealed no proteinuria. Daily urinary output ranged from 4500 ml to 7000 ml. Urine osmolality was less than 100 mOsm/kg and urine density was between 1004 and 1008. Water privation with an intravenous infusion of pitressin resulted in maximum urinary concentration of vasopressin. Diagnosis was nephrogenic diabetes insipidus. Cystoscopy showed the bladder heavily distended and moderately trabeculated. Intravenous pyelography failed to demonstrate the upper urinary tract probably because of the defect in urine concentrating ability. Retrograde pyelography demonstrated gross bilateral hydronephrosis (Fig. 1A) and cystography revealed an enlarged bladder with left vesicoureteral reflux (Fig. 1B). The post-void film or repeated intravesical catheterization showed large amount of residual urine, up to 200-400 ml. Transurethral incision for stenotic bladder neck was performed. When re-examined 6 months later, hydronephrosis of similar extent was confirmed radiologically. The patient continued to have polyuria but stopped coming to our clinic for a long time because of his work. When seen at our clinic again he had been off therapy for over 10 years and the response of the disease to vasopressin was resubstantiated. He was re-examined 12 years postoperatively. The daily urine volume had increased over the mark of 6000 ml and the creatinine clearance was 22 ml/min. The antidiuretic effect could not be obtained by salt-restrictive diet and subsequent thiazide therapy. The renal haemostatic function gradually deteriorated and he had to be started on haemodialysis 3 times weekly. Case 2. S. F., a 9-year-old boy, presented with an 8-year history of polyuria and polydipsia. His uncle was similarly affected. On admission, slight delay of statural growth was observed. Other physical findings were normal. Laboratory tests revealed: serum sodium 154 mEq/1, serum potassium 5.4 mEq/1, serum chloride 112 mEq/1, blood urea nitrogen 20 mg/dl, serum creatinine 0.8 mg/dl, and creatinine clearance 43 ml/min. Repeated urinalyses were normal except for low urine density, ranging from 1002 to 1004. Urine volume was approximately 4500 ml. The diagnosis of nephrogenic diabetes insipidus was made on the basis of high urine output, hypoosmolality of urine (usually less than 75 mOsm/kg) and hypernatraemia which were not influenced by vasopressin. Intravenous pyelogram failed to demonstrate clear visualization of the upper urinary tract, probably due to polyuria and reduced renal excretory function. Cystography demonstrated distended bladder and vesicoureteral reflux on both sides (Fig. 2A). Cystoscopy showed trabeculated bladder with the appearance of horseshoe type of right ureteral orifice. In August 1978, an operation for antivesicoureteral reflux according to the method of Politano and Leadbetter was performed. Eight years after surgery, intravenous pyelography demonstrated clear visualization of the upper urinary tract with slight hydronephrosis and hydroureter (Fig. 2B). Forty mg/day of thiazide therapy induced a reduction by 30-40 ~ of the urine flow. Nocturia, which had previously been of 5-6 times nightly also decreased to twice. 2*
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Fig. 2A. Case 2. Cystogram: slightly distended bladder with vesicoureteral reflux on both sides (arrows) Fig. 2B. Case 2. Intravenous pyelogram: 8 years after surgery clear visualization of slightly dilated upper urinary tract on both sides
His s y m p t o m s resolved postoperatively. He t o l e r a t e d well thiazide t h e r a p y for m a n y years a n d follow-up l a b o r a t o r y evaluations showed a l m o s t n o r m a l v a l u e s 10 years after surgery. International Urology and Nephrology 22, 1990
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C a s e 3. T. T., a 42-year-old man, had had polyt'~ria and polydipsia since young age. He had especially favoured cold drinking water since early childhood. He had previously been admitted to a clinic for the evaluation of hypertension where bilateral hydronephrosis had been found. There was no family history of
Fig. 3A. Case 3. Dripping intravenous pyelogram: bilateral hydronephrosis Fig. 3B. Case 3. Cystogram: enormously distended bladder with heavy trabeeulation International Urology and Nephrology 22, 1990
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polyuria. Physical examination on admission showed hypertension with a blood pressure of 188/112 mm Hg. Admission chemistries were: serum sodium 142 mEq/l, serum potassium 4.6 mEq/1, serum chloride 103 mEq/1, serum calcium 9.4 mg/dl, serum phosphorus 2.8 mg/dl, blood urea nitrogen 18 mg/dl, serum creatinine 1.4 mg/dl, serum uric acid 8.8 mg/dl and creatinine clearance 56 ml/min. Urinalysis was dipstick negative for glucose or protein, and urine specific gravities commonly ranged up to 1002. Urine volumes ranged up to 7 1 daily. He was given 5 U of aqueous pitressin subcutaneously every 4 hours up to a total dose of 20 U. Neither urine volume nor urine osmolality was notably changed following pitressin administration. Dripping intravenous pyelography disclosed bilateral hydronephrosis and hydroureter (Fig. 3A). A diagnosis of nephrogenic diabetes insipidus had been made and urodynamic studies were initiated. Post void residual urine was 150-200 ml. Although the force and calibre of the urinary stream were roughly normal, urodynamic studies disclosed some abnormalities. For example, uroftowmetry demonstrated that the flow rate was 15 ml/s and peak flow rate was 44 ml/s. Urethral pressure profile revealed a maximum pressure of 72 cm H~O and a functional length of 3.5 cm. Cystometry demonstrated that first desire for voiding was above 1000 ml and the perception of fullness was unrecognized because of increased capacity of distended bladder. Electromyographic potentials were in the range of 250 mV with normal frequency and a full interference pattern, and provided no presumed evidence of sphincter dyssynergia. In spite of prolonged administration of 75 rag/day of hydrochlorothiazide with supplemental salt restriction or occasional indomethacin therapy, antidiuretic effect had not been fully obtained. Urine output remained 7-9 1 daily and renal function deteriorated. In addition 100-300 ml of residual urine continued to be observed. It was speculated that the prodigiously elevated urine volume subverted the physiological ability of the upper urinary tract and the bladder, resulting in ultimate distension of these organs (Fig. 3B). Suprapubic cystostomy was done without discontinuing thiazide therapy. Postoperatively chronic renal failure was gradually ameliorated. Case 4. Y.T., a 4-year-old boy was admitted to our Department with profound polyuria and polydipsia. He was born as the first product of unrelated healthy parents and the family history was non-contributory. He reported extreme thirst since early infancy. At the age of 3 years, he started vomiting and having headaches. A diagnosis of nephrogenic diabetes insipidus was made in another hospital, but no therapy was given initially. On physical examination he was 99.6 cm tall and weighed 16.5 kg. Laboratory examination revealed serum sodium 137 mEq/1, serum potassium 4.8 mEq/1, serum chloride 102 mEq/1, serum creatinine 0.4 mg/dl, serum uric acid 5.5 mg/dl, blood urea nitrogen 4 mg/dl, serum calcium 9.6 mg/dl, serum phosphate 3.5 mg/dl, serum osmolality 280 mOsm/kg. The diagnosis of nephrogenic diabetes insipidus was reestablished by demonstrating inability to concentrate urine despite an appropriate osmolalitic stimulus by administration of 50 U of pitressin under 200 ml of drinking water load. Urine specific gravity ranged from 1000 to 1001. Cystoscopy revealed normal shaped ureteral orifices with regular peristalses. Neither trabeculation nor overt evidence International Urology and Nephrology 22, 1990
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Fig. 4. Case 4. Cystogram:remarkablydistendedbladder almost occupyingthe lowerabdomen
of bladder neck obstruction was observed. Bladder capacity was expanded up to 800 ml without residual urine. Vesicoureteral reflux was not demonstrated fluoroscopically. Cystography showed a remarkably distended bladder (Fig. 4). Intravenous pyelography failed to demonstrate the upper urinary tract because of excessive amount of urine output. Treatment consisted of 20 mg/day of hydrochlorothiazide in two divided doses and a low-salt diet. This resulted in an improvement of polyuria and excessive fluid intake. Over the years this caused him to gain weight, but renal function 4 years after the first medication slightly deteriorated and the degree of bilateral hydronephrosis remains unchanged.
Discussion
Primary nephrogenic diabetes insipidus is accepted to have a sex-linked recessive pattern of inheritance [1 ]. It involves male patients predominantly and occurs infrequently in female subjects. Indeed, all patients reported here are males. Polyuria is a common symptom in adults and older children with this disease but in infants it is usually absent [3, 4]. Presumably infants, unable to inform their thirst, are more prone to anhydration and a decrease in GFR, with resulting decline of urine output [5]. Thus the management of children with nephrogenic diabetes insipidus consists fundamentally of supplying adequate oral water to maintain hydration [5]. It is generally believed that some drug therapy International Urology and Nephroloyy 22, 1990
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reducing diuresis prevents effectively declining renal function [6, 7]. Apart from the defect in concentrating ability, renal function is regarded usually as normal [8]. An analogous syndrome may occur secondary to obstructive uropathy or diversified other forms of renal disease [8]. But the concentrating defect in such cases is commonly less conspicuous and repair of the latent disorder will often result in improvement [8]. However, high urine output of nephrogenic diabetes insipidus induced conspicuous dilatation of the urinary tract without coexisting obstruction [9]. Indeed, hydronephrotic atrophy and a reduced renal function have been documented in some cases [10, 11 ]. The true aetiology of hydronephrosis is uncertain, although polyuria alone appears to be the primary cause [6]. When urinary volume per unit of time surpasses the capability of the urine transport, renal or ureteral dilatation may occur. The dilatation could result in ureteral and renal changes attributed to hydronephrotic atrophy [6]. Prolonged follow-up of our patients with nephrogenic diabetes insipidus yielded complicated results. By the age of 13 years Case 1 had developed urinary tract dilatation because of prolonged excessive urinary output. Although TUR temporarily reduced residual urine, his condition had progressed to chronic renal failure when he visited us again several years after surgery. Haemcdialysis had to be started at 35 years of age. In Case 2, dilated bilateral refluxing ureters were surgically repaired at the age of 9. Successive thiazide therapy reduced polyuria probably due to the natriuretic effect of the drug reducing plasma sodium level and, as a consequence, the extracellular volume. Indeed, levels of serum sodium, blood urea nitrogen, serum creatinine and creatinine clearance were much improved during thiazide therapy which probably lowered the glomerular filtration rate and shifted renal blood flow to the inner cortical and juxtamedullary water-retaining nephrons [12]. In Case 3 or 4, nephrogenic diabetes insipidus produced gross dilatation of both ureters and the bladder as a result of polyuria. Thiazide administration alone failed to control polyuria but the respective efficacy of thiazide and subsequent cystostomy improved renal function in Case 3. The abnormal fluid and electrolyte status in Case 4 could be successfully treated with a regimen of low-salt diet, hydrochlorothiazide, potassium supplement, oxprenolol, hydralazine, amiloride or indomethacin [5, 13, 14, 15]. We chose thiazide or hydrochlorothiazide, because it appeared to be potentially less toxic than other drugs. Although treatment with thiazide or hydrochlorothiazide was associated with a decrease in urine volume, free water clearance or creatinine clearance had occasionally not been much improved. Polyuria seems to have its onset relatively early in life in some instances. Thus, drainage operation sometimes needs to be performed in a relatively young generation even in the absence of urinary tract obstruction. It has been shown that pelvic pressure is elevated during increasing diuresis [16]. It is natural to speculate that such urodynamic alteration leads to hydronephrosis. Mortensen et al. perfused pig pyeloureters and measured pelvic pressure continuously [17]. They found that peristaltic frequency was significantly higher in the high-pressure group than in the low-pressure group [17]. Their study indicates that the pelvic compliance may work so as to normalize the intraInternational Urolo#y and Nephrolooy 22, 1990
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pelvic or intraureteral pressure a n d finally enhances the t r a n s p o r t i n g ability of urine. I f polyuria exceeds the t r a n s p o r t i n g capability of the upper u r i n a r y tract for a long period, hydronephrosis or hydroureter may occur. Recently extensive glomerular i m m a t u r i t y asseciated with nephrogenic diabetes insipidus was reported [18]. We have not performed renal biopsy in this study. Histopathological analysis of the kidney in a n early stage of the disease may help to predict the prognosis.
References 1. Forssman, H. : On hereditary diabetes insipidus, with special regard to a sex-linked form. Acta Med. Scand., Suppl. 159, 1 (1945). 2. Proesmans, W., Eggermont, E., Vanderschueren-Lodeweyckx, M., Tiddens, H., Ecckels, R.: The effect of exogenous 3',5'-adenosine monophosphate on urinary output in children with vasopressin-resistant diabetes insipidus. Pediatr. Res., 9, 509 (1975). 3. Dousa, T. P. : Cellular action of antidiuretic hormone in nephrogenic diabetes insipidus. Mayo Clin. Proc., 49, 188 (1974). 4. Gellai, M., Edwards, B. R., Valtin, H. : Urinary concentrating ability during dehydration in the absence of vasopressin. Am. J. Physiol., 237, F100 (1979). 5. Sprenger, K. J., Winship, W. S., Wittenberg, D. F.: Nephrogenie diabetes insipidus presenting with infantile hypotonia. A report of 2 cases. S A M J, 70, 228 (1986). 6. Shapiro, S., Woerner, S., Adelman, R. D., Palmer, J. M. : Diabetes insipidus and hydronephrosis. J. Urol., 119, 715 (1975). 7. Vierhapper, H., J6rg, J., Favre, L., Vallotton, M. B., Waldh~iusl, W.: Comparative therapeutic benefit of indomethacin, hydroehlorothiazide, acetyl-salicylic acid in a patient with nephrogenic diabetes insipidus. Acta Endocrinol., 106, 311 (1984). 8. Ramsey, E. W., Morrin, P. A. F., Bruce, A. W. : Nephrogenic diabetes insipidus associated with massive hydronephrosis and bladder neck obstruction. J. Urol., 111, 225 (1974) 9. Boyd, S., Raz, S., Ehrlich, R. M.: Diabetes insipidus and nonobstructive dilatation of urinary tract. Urology, 15, 266 (1986). 10. Miller, S. S., Winston, M. D.: Nephrogenic diabetes insipidus. Radiol., 87, 893 (1966). 11. Manson, A. D., Yalowitz, P. A., Randall, R. V., Greene, L. F. : Dilatation of the urinary tract associated with pituitary and nephrogenic diabetes insipidus. J. Urol., 103, 327 (1970). 12. Walter, S. J., Laycock, J. F., Shirley, D. G.: Micropuncture study of proximal tubular function after acute hydrochlorothiazide administration to Brattleboro rats with diabetes insipidus. Clin. Sci., 57, 427 (1979). 13. Andersen, Q., Jacobsen, B. B.: The renin-aldosterone system in nephrogenic diabetes insipidus and the influence of hydrochlorothiazide and indomethacin. Acta Pediatr. Scan&, 72, 717 (1983). 14. Lewis, D. J. M., Thomas, J. P.: Treatment of nephrogenic diabetes insipidus. N. Engl. J. Med., 315, 1292 (1986). 15. Rosen, G. H., Klein-Schwartz, W., Medani, C. R. : Indomethacin for nephrogenic diabetes insipidus in a four-week-old infant. Clin. Pharmacy, 15, 254 (1986). 16. Constantinous, C. E., Djurhuus, J. C. : Pyeloureteral dynamics in the intact and chronically obstructed multicalyceal kidney. Am. J. Physiol., 241, R398 (1981). 17. Mortensen, J., Frokaer, J., Tort, H. P., Djurhuus, J. C.: The influence of pyeloureteral peristalsis on pelvic pressure during increase in flow rate. Urol. Res., 16, 295 (1988). 18. Engerhardt, G., Zimmermann, A., D'Apuzzo, V., Oetliker, O.: Extensive glomerular immaturity associated with renal tubular acidosis, nephrogenic diabetes insipidus and nephroealcinosis. Eur. Urol., 13, 186 (1987). International Urologyand Nephrology22, 1990
Nonobstructive Urinary Tract Dilatation in Nephrogenic Diabetes Insipidus T. NAKADA, T. MIYAUCHI, H. SUMIYA, J. SHIMAZAKI Department of Urology, Chiba University, School of Medicine, Chiba, Japan (Received September 11, 1989) The follow-up study has been performed in 4 male patients with nephrogenic diabetes insipidus lasting for 4 to 15 years. Hydronephrosis or hydroureter appeared to be caused by polyuria with or without urinary tract obstruction. The efficacy of drainage operation is emphasized when polyuria surpasses the transporting ability of urine in the urinary tract.
Introduction Nephrogenic diabetes insipidus, first reported by Forssman [1 ], is a disorder characterized by callousness of the collecting duct to both endogenous and exogenous antidiuretic hormone (ADH). Clinical manifestation of this disease commonly presents with polyuria, polydipsia, fever, vomiting, dehydration and failure to thrive. The pathogenesis is speculative. However, in patients with this disease administration of ADH failed to induce the anticipated increase in cyclic adenine 3',5'-monophosphate (cAMP) in the urine. In addition, exogenous cAMP did not uniformly decrease urinary volume and free water clearance [2]. Subsequently defects in processes both proximal and distal to cAMP generation with resultant decreased water reabsorption have been presumed [2]. During the past decade attention has been focussed mainly on the biochemical or endocrine basis of the renal inability to absorb water in the distal tubule, and serious therapeutic problems underlying this disorder such as hydronephrosis, massively dilated ureter and distended bladder have not been extensively studied. Especially scanty is the literature dealing with long follow-up of obstructive or nonobstrucrive uropathy in patients with nephrogenic diabetes insipidus. This study mainly concerns nonobstructive dilatation of the upper or lower urinary tract in several patients with this disease.
Case reports Case 1. Y. K., an 18-year-old man, was first seen in June 1975, complaining of severe polyuria and occasional nocturnal enuresis since birth. His mother also had been polyuric all her life. He apparently had been investigated at the age of 2
VSP, Utrecht Akad~miai Kiad6, Budapest
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13 for nocturnal enuresis but only urinalysis and K U B had been done and no treatment was initiated. He has physically unremarkable stature but was hypertensive with a blood pressure of 176/108 m m Hg. Evaluation when he was 18 years old revealed serum creatinine of 1.8 mg/dl, blood urea nitrogen of 34 mg/dl and creatinine clearance of 53 ml/min. Values for the following laboratory studies
Fig. 1A. Case 1. Retrograde pyelogram: bilateral hydronephrosis Fig. IB. Case 1. Cystogram: distended bladder with trabeculation. Note left vesicoureteral reflux (arrow) International Urology and Nephrology 22, 1990
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remained within normal limits: serum sodium, serum potassium, serum chloride, serum calcium, serum phosphorus, lactic dehydrogenase, fasting blood sugar and serum glutamic oxaloacetic transaminase. Frequent qualitative analyses revealed no proteinuria. Daily urinary output ranged from 4500 ml to 7000 ml. Urine osmolality was less than 100 mOsm/kg and urine density was between 1004 and 1008. Water privation with an intravenous infusion of pitressin resulted in maximum urinary concentration of vasopressin. Diagnosis was nephrogenic diabetes insipidus. Cystoscopy showed the bladder heavily distended and moderately trabeculated. Intravenous pyelography failed to demonstrate the upper urinary tract probably because of the defect in urine concentrating ability. Retrograde pyelography demonstrated gross bilateral hydronephrosis (Fig. 1A) and cystography revealed an enlarged bladder with left vesicoureteral reflux (Fig. 1B). The post-void film or repeated intravesical catheterization showed large amount of residual urine, up to 200-400 ml. Transurethral incision for stenotic bladder neck was performed. When re-examined 6 months later, hydronephrosis of similar extent was confirmed radiologically. The patient continued to have polyuria but stopped coming to our clinic for a long time because of his work. When seen at our clinic again he had been off therapy for over 10 years and the response of the disease to vasopressin was resubstantiated. He was re-examined 12 years postoperatively. The daily urine volume had increased over the mark of 6000 ml and the creatinine clearance was 22 ml/min. The antidiuretic effect could not be obtained by salt-restrictive diet and subsequent thiazide therapy. The renal haemostatic function gradually deteriorated and he had to be started on haemodialysis 3 times weekly. Case 2. S. F., a 9-year-old boy, presented with an 8-year history of polyuria and polydipsia. His uncle was similarly affected. On admission, slight delay of statural growth was observed. Other physical findings were normal. Laboratory tests revealed: serum sodium 154 mEq/1, serum potassium 5.4 mEq/1, serum chloride 112 mEq/1, blood urea nitrogen 20 mg/dl, serum creatinine 0.8 mg/dl, and creatinine clearance 43 ml/min. Repeated urinalyses were normal except for low urine density, ranging from 1002 to 1004. Urine volume was approximately 4500 ml. The diagnosis of nephrogenic diabetes insipidus was made on the basis of high urine output, hypoosmolality of urine (usually less than 75 mOsm/kg) and hypernatraemia which were not influenced by vasopressin. Intravenous pyelogram failed to demonstrate clear visualization of the upper urinary tract, probably due to polyuria and reduced renal excretory function. Cystography demonstrated distended bladder and vesicoureteral reflux on both sides (Fig. 2A). Cystoscopy showed trabeculated bladder with the appearance of horseshoe type of right ureteral orifice. In August 1978, an operation for antivesicoureteral reflux according to the method of Politano and Leadbetter was performed. Eight years after surgery, intravenous pyelography demonstrated clear visualization of the upper urinary tract with slight hydronephrosis and hydroureter (Fig. 2B). Forty mg/day of thiazide therapy induced a reduction by 30-40 ~ of the urine flow. Nocturia, which had previously been of 5-6 times nightly also decreased to twice. 2*
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Fig. 2A. Case 2. Cystogram: slightly distended bladder with vesicoureteral reflux on both sides (arrows) Fig. 2B. Case 2. Intravenous pyelogram: 8 years after surgery clear visualization of slightly dilated upper urinary tract on both sides
His s y m p t o m s resolved postoperatively. He t o l e r a t e d well thiazide t h e r a p y for m a n y years a n d follow-up l a b o r a t o r y evaluations showed a l m o s t n o r m a l v a l u e s 10 years after surgery. International Urology and Nephrology 22, 1990
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C a s e 3. T. T., a 42-year-old man, had had polyt'~ria and polydipsia since young age. He had especially favoured cold drinking water since early childhood. He had previously been admitted to a clinic for the evaluation of hypertension where bilateral hydronephrosis had been found. There was no family history of
Fig. 3A. Case 3. Dripping intravenous pyelogram: bilateral hydronephrosis Fig. 3B. Case 3. Cystogram: enormously distended bladder with heavy trabeeulation International Urology and Nephrology 22, 1990
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polyuria. Physical examination on admission showed hypertension with a blood pressure of 188/112 mm Hg. Admission chemistries were: serum sodium 142 mEq/l, serum potassium 4.6 mEq/1, serum chloride 103 mEq/1, serum calcium 9.4 mg/dl, serum phosphorus 2.8 mg/dl, blood urea nitrogen 18 mg/dl, serum creatinine 1.4 mg/dl, serum uric acid 8.8 mg/dl and creatinine clearance 56 ml/min. Urinalysis was dipstick negative for glucose or protein, and urine specific gravities commonly ranged up to 1002. Urine volumes ranged up to 7 1 daily. He was given 5 U of aqueous pitressin subcutaneously every 4 hours up to a total dose of 20 U. Neither urine volume nor urine osmolality was notably changed following pitressin administration. Dripping intravenous pyelography disclosed bilateral hydronephrosis and hydroureter (Fig. 3A). A diagnosis of nephrogenic diabetes insipidus had been made and urodynamic studies were initiated. Post void residual urine was 150-200 ml. Although the force and calibre of the urinary stream were roughly normal, urodynamic studies disclosed some abnormalities. For example, uroftowmetry demonstrated that the flow rate was 15 ml/s and peak flow rate was 44 ml/s. Urethral pressure profile revealed a maximum pressure of 72 cm H~O and a functional length of 3.5 cm. Cystometry demonstrated that first desire for voiding was above 1000 ml and the perception of fullness was unrecognized because of increased capacity of distended bladder. Electromyographic potentials were in the range of 250 mV with normal frequency and a full interference pattern, and provided no presumed evidence of sphincter dyssynergia. In spite of prolonged administration of 75 rag/day of hydrochlorothiazide with supplemental salt restriction or occasional indomethacin therapy, antidiuretic effect had not been fully obtained. Urine output remained 7-9 1 daily and renal function deteriorated. In addition 100-300 ml of residual urine continued to be observed. It was speculated that the prodigiously elevated urine volume subverted the physiological ability of the upper urinary tract and the bladder, resulting in ultimate distension of these organs (Fig. 3B). Suprapubic cystostomy was done without discontinuing thiazide therapy. Postoperatively chronic renal failure was gradually ameliorated. Case 4. Y.T., a 4-year-old boy was admitted to our Department with profound polyuria and polydipsia. He was born as the first product of unrelated healthy parents and the family history was non-contributory. He reported extreme thirst since early infancy. At the age of 3 years, he started vomiting and having headaches. A diagnosis of nephrogenic diabetes insipidus was made in another hospital, but no therapy was given initially. On physical examination he was 99.6 cm tall and weighed 16.5 kg. Laboratory examination revealed serum sodium 137 mEq/1, serum potassium 4.8 mEq/1, serum chloride 102 mEq/1, serum creatinine 0.4 mg/dl, serum uric acid 5.5 mg/dl, blood urea nitrogen 4 mg/dl, serum calcium 9.6 mg/dl, serum phosphate 3.5 mg/dl, serum osmolality 280 mOsm/kg. The diagnosis of nephrogenic diabetes insipidus was reestablished by demonstrating inability to concentrate urine despite an appropriate osmolalitic stimulus by administration of 50 U of pitressin under 200 ml of drinking water load. Urine specific gravity ranged from 1000 to 1001. Cystoscopy revealed normal shaped ureteral orifices with regular peristalses. Neither trabeculation nor overt evidence International Urology and Nephrology 22, 1990
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Fig. 4. Case 4. Cystogram:remarkablydistendedbladder almost occupyingthe lowerabdomen
of bladder neck obstruction was observed. Bladder capacity was expanded up to 800 ml without residual urine. Vesicoureteral reflux was not demonstrated fluoroscopically. Cystography showed a remarkably distended bladder (Fig. 4). Intravenous pyelography failed to demonstrate the upper urinary tract because of excessive amount of urine output. Treatment consisted of 20 mg/day of hydrochlorothiazide in two divided doses and a low-salt diet. This resulted in an improvement of polyuria and excessive fluid intake. Over the years this caused him to gain weight, but renal function 4 years after the first medication slightly deteriorated and the degree of bilateral hydronephrosis remains unchanged.
Discussion
Primary nephrogenic diabetes insipidus is accepted to have a sex-linked recessive pattern of inheritance [1 ]. It involves male patients predominantly and occurs infrequently in female subjects. Indeed, all patients reported here are males. Polyuria is a common symptom in adults and older children with this disease but in infants it is usually absent [3, 4]. Presumably infants, unable to inform their thirst, are more prone to anhydration and a decrease in GFR, with resulting decline of urine output [5]. Thus the management of children with nephrogenic diabetes insipidus consists fundamentally of supplying adequate oral water to maintain hydration [5]. It is generally believed that some drug therapy International Urology and Nephroloyy 22, 1990
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reducing diuresis prevents effectively declining renal function [6, 7]. Apart from the defect in concentrating ability, renal function is regarded usually as normal [8]. An analogous syndrome may occur secondary to obstructive uropathy or diversified other forms of renal disease [8]. But the concentrating defect in such cases is commonly less conspicuous and repair of the latent disorder will often result in improvement [8]. However, high urine output of nephrogenic diabetes insipidus induced conspicuous dilatation of the urinary tract without coexisting obstruction [9]. Indeed, hydronephrotic atrophy and a reduced renal function have been documented in some cases [10, 11 ]. The true aetiology of hydronephrosis is uncertain, although polyuria alone appears to be the primary cause [6]. When urinary volume per unit of time surpasses the capability of the urine transport, renal or ureteral dilatation may occur. The dilatation could result in ureteral and renal changes attributed to hydronephrotic atrophy [6]. Prolonged follow-up of our patients with nephrogenic diabetes insipidus yielded complicated results. By the age of 13 years Case 1 had developed urinary tract dilatation because of prolonged excessive urinary output. Although TUR temporarily reduced residual urine, his condition had progressed to chronic renal failure when he visited us again several years after surgery. Haemcdialysis had to be started at 35 years of age. In Case 2, dilated bilateral refluxing ureters were surgically repaired at the age of 9. Successive thiazide therapy reduced polyuria probably due to the natriuretic effect of the drug reducing plasma sodium level and, as a consequence, the extracellular volume. Indeed, levels of serum sodium, blood urea nitrogen, serum creatinine and creatinine clearance were much improved during thiazide therapy which probably lowered the glomerular filtration rate and shifted renal blood flow to the inner cortical and juxtamedullary water-retaining nephrons [12]. In Case 3 or 4, nephrogenic diabetes insipidus produced gross dilatation of both ureters and the bladder as a result of polyuria. Thiazide administration alone failed to control polyuria but the respective efficacy of thiazide and subsequent cystostomy improved renal function in Case 3. The abnormal fluid and electrolyte status in Case 4 could be successfully treated with a regimen of low-salt diet, hydrochlorothiazide, potassium supplement, oxprenolol, hydralazine, amiloride or indomethacin [5, 13, 14, 15]. We chose thiazide or hydrochlorothiazide, because it appeared to be potentially less toxic than other drugs. Although treatment with thiazide or hydrochlorothiazide was associated with a decrease in urine volume, free water clearance or creatinine clearance had occasionally not been much improved. Polyuria seems to have its onset relatively early in life in some instances. Thus, drainage operation sometimes needs to be performed in a relatively young generation even in the absence of urinary tract obstruction. It has been shown that pelvic pressure is elevated during increasing diuresis [16]. It is natural to speculate that such urodynamic alteration leads to hydronephrosis. Mortensen et al. perfused pig pyeloureters and measured pelvic pressure continuously [17]. They found that peristaltic frequency was significantly higher in the high-pressure group than in the low-pressure group [17]. Their study indicates that the pelvic compliance may work so as to normalize the intraInternational Urolo#y and Nephrolooy 22, 1990
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pelvic or intraureteral pressure a n d finally enhances the t r a n s p o r t i n g ability of urine. I f polyuria exceeds the t r a n s p o r t i n g capability of the upper u r i n a r y tract for a long period, hydronephrosis or hydroureter may occur. Recently extensive glomerular i m m a t u r i t y asseciated with nephrogenic diabetes insipidus was reported [18]. We have not performed renal biopsy in this study. Histopathological analysis of the kidney in a n early stage of the disease may help to predict the prognosis.
References 1. Forssman, H. : On hereditary diabetes insipidus, with special regard to a sex-linked form. Acta Med. Scand., Suppl. 159, 1 (1945). 2. Proesmans, W., Eggermont, E., Vanderschueren-Lodeweyckx, M., Tiddens, H., Ecckels, R.: The effect of exogenous 3',5'-adenosine monophosphate on urinary output in children with vasopressin-resistant diabetes insipidus. Pediatr. Res., 9, 509 (1975). 3. Dousa, T. P. : Cellular action of antidiuretic hormone in nephrogenic diabetes insipidus. Mayo Clin. Proc., 49, 188 (1974). 4. Gellai, M., Edwards, B. R., Valtin, H. : Urinary concentrating ability during dehydration in the absence of vasopressin. Am. J. Physiol., 237, F100 (1979). 5. Sprenger, K. J., Winship, W. S., Wittenberg, D. F.: Nephrogenie diabetes insipidus presenting with infantile hypotonia. A report of 2 cases. S A M J, 70, 228 (1986). 6. Shapiro, S., Woerner, S., Adelman, R. D., Palmer, J. M. : Diabetes insipidus and hydronephrosis. J. Urol., 119, 715 (1975). 7. Vierhapper, H., J6rg, J., Favre, L., Vallotton, M. B., Waldh~iusl, W.: Comparative therapeutic benefit of indomethacin, hydroehlorothiazide, acetyl-salicylic acid in a patient with nephrogenic diabetes insipidus. Acta Endocrinol., 106, 311 (1984). 8. Ramsey, E. W., Morrin, P. A. F., Bruce, A. W. : Nephrogenic diabetes insipidus associated with massive hydronephrosis and bladder neck obstruction. J. Urol., 111, 225 (1974) 9. Boyd, S., Raz, S., Ehrlich, R. M.: Diabetes insipidus and nonobstructive dilatation of urinary tract. Urology, 15, 266 (1986). 10. Miller, S. S., Winston, M. D.: Nephrogenic diabetes insipidus. Radiol., 87, 893 (1966). 11. Manson, A. D., Yalowitz, P. A., Randall, R. V., Greene, L. F. : Dilatation of the urinary tract associated with pituitary and nephrogenic diabetes insipidus. J. Urol., 103, 327 (1970). 12. Walter, S. J., Laycock, J. F., Shirley, D. G.: Micropuncture study of proximal tubular function after acute hydrochlorothiazide administration to Brattleboro rats with diabetes insipidus. Clin. Sci., 57, 427 (1979). 13. Andersen, Q., Jacobsen, B. B.: The renin-aldosterone system in nephrogenic diabetes insipidus and the influence of hydrochlorothiazide and indomethacin. Acta Pediatr. Scan&, 72, 717 (1983). 14. Lewis, D. J. M., Thomas, J. P.: Treatment of nephrogenic diabetes insipidus. N. Engl. J. Med., 315, 1292 (1986). 15. Rosen, G. H., Klein-Schwartz, W., Medani, C. R. : Indomethacin for nephrogenic diabetes insipidus in a four-week-old infant. Clin. Pharmacy, 15, 254 (1986). 16. Constantinous, C. E., Djurhuus, J. C. : Pyeloureteral dynamics in the intact and chronically obstructed multicalyceal kidney. Am. J. Physiol., 241, R398 (1981). 17. Mortensen, J., Frokaer, J., Tort, H. P., Djurhuus, J. C.: The influence of pyeloureteral peristalsis on pelvic pressure during increase in flow rate. Urol. Res., 16, 295 (1988). 18. Engerhardt, G., Zimmermann, A., D'Apuzzo, V., Oetliker, O.: Extensive glomerular immaturity associated with renal tubular acidosis, nephrogenic diabetes insipidus and nephroealcinosis. Eur. Urol., 13, 186 (1987). International Urologyand Nephrology22, 1990
