0022-534 7/78/ l 196-0715$02. 00/ 0 Vol. 119, J·une Printed in U.S . k
THE JouRNAL OF UROLOGY
Copyright© 1978 by The Williams & Wilkins Co.
Re1Jiew Article DIABETES INSIPIDUS AND HYDRONEPHROSIS STEPHEN R. SHAPIRO,* SARAH WOERNER, RAYMOND D. ADELMAN
AND
JOHN M. PALMER
From the Departments of Pediatrics and Urology, University of California, Dau is, California
Diabetes insipidus, an inability to maximally concentrate the is associated with polyuria and polydipsia. 1, 2 Normally, vasopressin produced by the supraoptic and paraventricular nuclei of the hypothalamus acts on the distal tubule and collecting ducts to increase water permeability, thereby promoting increased water reabsorption and urinary concentration to as great as 1,200 mOsm./kg. in the presence of maximal secretion of the hormone (fig. 1). 3 • 4 Diabetes insipidus can occur because of any one of the following mechanisms: 1) intake of excessive amounts of fluid, which results in inhibition of vasopressin, 2) failure of the posterior pituitary to to hyperosmolar stimuli with release of vasopressin 3) failure of the kidneys to respond even when maximal levels of vasopressin are present. Each of these categories has its clinical correlates (table 1). Diabetes insipidus may be suspected when a patient presents with the acute onset of polyuria, polydipsia and a dilute urine. 3 In primary polydipsia, since the hypothalamic-pituitary-renal axis is intact, urine usually concentrates in response to water deprivation, although in some patients urinary concentration may be suboptimal. With hypothalamic diabetes insipidus there is maximal urinary concentration only if vasopressin is given. Partial hypothalamic diabetes insipidus may be difficult to differentiate from psychogenic diabetes insipidus because moderate concentration of the urine can occur owing to decreased but not absent vasopressin. In nephrogenic diabetes insipidus urinary concentration is inadequate even when vasopressin is administered. Primary hypothalamics-- 14 and primary nephrogenic diabetes insipidus 1s--24 have been reported associated with bilateral Frequently, serial tests ofrenal function have not been performed. Hydronephrotic atrophy and a decline in renal function have been documented in some cases. 5 • rn. 20 - 22 However, it is not clear that a severe progressive decline in renal function occurs. There is not a single case of diabetes insipidus known to have required dialysis or renal transplantation. 25 Our 7 cases of diabetes insipidus with hydronephrosis followed for an average of 12¼ years are reviewed.
day. When hospitalized the child was soaking 12 to 24 daily. Physical examination was unremarkable except that and weight were in the third percentile for age. The urea nitrogen was 10 mg. per cent and serum creatinine was 0.5 mg. per cent. An excretory urogram (IVP) demonstrated bilateral hydronephrosis. The voiding cystourethrograrn was normal. Urine cultures were negative. Urine specific was 1.001 but the remainder of the urinalysis was With water restriction for 9 hours the child concentrated the urine to 870 mOsm./1. Diagnosis was primary diabetes insipidus and fluid was restricted to 4 to 5 day. Voluntary fluid intake became normal and the disappeared. A repeat IVP 4 months later upper tracts. Case 2. Primary hypothalamic diabetes insipidus. M. H., a 51/z-month-old boy, had had polyuria and polydipsia since infancy. There was no family history ofpolyuria. There was history of congenital left hemiplegia. Examination when the child was admitted to the hospital revealed mild weakness on the left side. Skull x-rays were negative. An IVP showed an enlarged bladder but normal upper tracts. Urine gravities ranged from 1.001 to 1.004. After 7 hours deprivation urine specific gravity increased to 1.004, urine osmolality to 230 mOsm./1. and serum osmolality to 325 mOsm./1. Urine concentration increased to 596 mOsm./1. after vasopressin was administered. Diagnosis was primary thalamic diabetes insipidus and the child was treated lysine-8-vasopressin. Case 3. Primary nephrogenic diabetes insipidus. S. Ho, an 11-year-old boy, presented in infancy with fever of unknown origin, dehydration and failure to thrive. Evaluation when he was 2 years old revealed a serum creatinine of 0.5 cent and a creatinine clearance of 100 ml. per minute. demonstrated bilateral hydronephrosis. Water with a 4 per cent weight loss resulted in a 11u,A,u1HS;,,..,,v,ucu and 5 patients had primary nephrogenic diabetes salt restriction and thiazides was continued. This 11-year-old boy is on a low salt diet (300 to 500 CASE REPORTS daily) with hydrodiuril used only when sodium intake ex,ce,icts Case 1. Primary polydipsic diabetes insipidus. J. B., a 20- 500 mg. per day. He is well clinically. The creatinine clearance month-old boy, was hospitalized for evaluation ofpolyuria and is 54 ml. per minute (corrected). The serum creatinine is 0.9 polydipsia. When the child was 8 months old food allergies mg. per cent. A repeat IVP shows some increased hvrln,n,,_ were diagnosed and he was placed on a liquid diet. Fluid phrosis. Urine output remains 4 to 6 l. daily. intake was increased gradually to 10 to 15, 8-ounce bottles per DISCUSSION
* Requests for reprints: 4301 X St., Suite 249, Sacramento Cali-
Polydipsic diabetes insipidus. Primary polydipsic diabetes insipidus (compulsive water drinking or psychogenic diabetes insipidus) has been recognized in adults 2 &-28 more re
fornia 95817. ' at annual meeting of Society for Pediatric Urology, Chicago, April 24, 1977. 715
SHAPIRO AND ASSOCIATES
716
cently, in infants and children. 2 0-32 Children generally present with polyuria and polydipsia, which improve with water restriction. A disturbed parent-child relationship has been noted in some cases. 3l>-31 Water intoxication owing to maternal misjudgment and excessive water intake has been reported. 32
SUPRAOPTIC NUCLEUS
SUPRAOPTICONEUROHYPOPHYSEAL TRACT
,,.....-...........,-POST. LOBE VEIN INF HYPOPHYSEAL ARTERY
Fm. 1. Neurohypophyseal system. Vasopressin, produced by supraoptic and paraventricular nuclei of hypothalamus, is transported along neurohypophyseal tracts to posterior pituitary where it can be released into blood stream in response to hyperosmolar plasma or severe volume depletion. Adapted from Gardner." TABLE
1. Classification of diabetes insipidus
Class 1 2
3
Description Primary polydipsic diabetes insipidus (compulsive water drinking or psychogenic diabetes insipidus) Hypothalamic diabetes insipidus Primary (familial or idiopathic) Secondary (tumor or trauma) DIDMOAD syndrome Partial hypothalamic diabetes insipidus Nephrogenic diabetes insipidus Primary (familial or sporadic) Secondary (acquired)
f
TABLE 2.
f
Diagnosis and course of 7 patients with diabetes insipidus
Diabetes Insipidus Diagnosis
Age at Presentation (mos.)
Age at Followup (yrs.)
JB-M MH-M
Primary polydipsic Primary hypothalamic
22 66
2½ 11
SH-M
Primary nephrogenic
12
11
CF-M
Primary nephrogenic
12
RD-M
Primary nephrogenic
SB-M
JJ-M
Pt.-Sex
It may be difficult to distinguish between primary polydipsia and a partial hypothalamic diabetes insipidus. A patient may drink compulsively because of damage to a satiety center or stimulation of the thirst center. In animals alteration in thirst follows destruction and stimulation of various centers in the central nervous system. 29 Therefore, primary polydipsia in humans may be organic and/or psychogenic. In our case 1 there was no evidence of an organic hypothalamic lesion, since voluntary water intake returned to normal after fluid restriction. Hypothalamic diabetes insipidus. Familial hypothalamic diabetes insipidus is caused by a greater than 90 per cent deficiency of vasopressin. An autosomal dominant and Xlinked inheritance has been described. 3 The disease usually is mild in childhood and becomes more severe with age. The hypocaloric dwarfism occasionally seen with nephrogenic diabetes insipidus generally does not occur. 8 Life expectancy is believed to be normal without specific treatment, although hydronephrosis and renal atrophy have been described. s--14 Recently, an association has been reported among hypothalamic diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD syndrome). All of the patients described by Page and associates had hydronephrosis that improved with the treatment of the diabetes insipidus. 33 Diabetes insipidus and diabetes mellitus may coexist in the same individual on a coincidental basis. 34, 35 At all ages the most frequent cause of acquired or secondary hypothalamic diabetes insipidus is tumor. Craniopharyngioma is the most common but, in contrast to the other central nervous system tumors, diabetes insipidus usually occurs postoperatively. Diabetes insipidus has been reported in association with the Laurence-Moon-Biedl syndrome, 36 encephalitis, meningitis, vaccination or trauma. 37 Diagnosis of hypothalamic diabetes insipidus usually is made when urine becomes concentrated with administered vasopressin but not with water deprivation. 38 During water deprivation close supervision is required to prevent surreptitious water intake or extreme dehydration in the severely affected patient. Treatment of hypothalamic diabetes insipidus consists of intramuscular vasopressin tannate in oil3 or intranasal vasopressin. A new analog, 1-deamino-8-D-arganine vasopressin, has a prolonged effect when given intranasally and appears promising. 39 The proposed mode of cellular action of vasopressin is shown in figure 3. 40 Patients with so-called idiopathic hypothalamic diabetes insipidus need periodic re-evaluation for a long interval before tumor can be ruled out. IVP Clinical Course
Therapy Initial Fluid restriction Lysine-8-vasopressin Thiazides, salt restriction
Mild hydronephrosis Normal upper tracts, enlarged bladder Severe bilat. hydronephrosis (age 2 yrs.)
10
Thiazides, salt restriction
Moderate bilat. hydronephrosis (age 5 yrs.)
12
25
Moderate bilat. hydronephrosis (age 10 yrs.)
Primary nephrogenic
24
21
Thiazides, salt restriction, aldactone None
Primary nephrogenic
36
21
Thiazides
Normal upper tracts, enlarged bladder
Followup Normal
Well clinically Well clinically
Well clinically, urine output 4-6 1./day, creatinine clearance 54 ml./min., serum creatinine 0. 9 mg.% Unchanged (age Well clinically, urine output >3 1./day, serum creatinine 0.9 6yrs.) mg.% Unchanged (age Still polyuric and polydipsic 15 yrs.) Unchanged (age 11 yrs.)
Moderate bilat. hydronephrosis (age 11 yrs.)
Still polyuric and polydipsic
Well clinically, voids every hour, maternal grandfather with nephrogenic diabetes insipidus age 86
'
DIABETES INSIPIDUS AND HYDRONEPHROSIS
717
FIG. 2. Primary nephrogenic diabetes insipidus. A, IVP reveals bilateral hydroureteronephrosis. B, cystogram demonstrates enlarged bladder capacity.
Stimulated by ADH
Inhibited by Prostaglandin E1
~ / Adenylate ATP
Cyclase
Adenosine 3; 5 1-Phosphate Cyc Ii c AMP
J
Cyclic AMP
- - - - - - 5 ' AMP Phosphodiesterase
Protein kinase Phosphorylation Microtubular protein
Increased Water Permeability FIG. 3. Cellular mode of action of antidiuretic hormone. Adapted from Dousa40
Ncphrogenic diabetes insipidus. Primary nephrogenic diabetes insipidus is believed to have a sex-linked recessive mode of inheritance. 2 It affects male subjects primarily and rarely occurs in female subjects. •0 The Hopewell hypothesis suggests that most patients in North America are descendants of Ulster Scot, who settled in Nova Scotia in the 18th Century. 41 One of our patients (case 3), in fact, can trace his lineage back to Ulster Scot. Rare instances of authentic nephrogenic diabetes insipidus have been encountered with no evidence of affected relatives, suggesting new mutations. 3 • 24 • 42 Polyuria in the infant with nephrogenic diabetes insipidus may result in polyhydramnios. 43 Symptoms may be severe in infancy, although the polyuria and polydipsia can be overlooked during the diaper stage. Fevers of undetermined origin, 44 failure to thrive 8• 17 and persistent constipation may occur. Frequent bouts ofhypertonic dehydration with convulsions account for the high mortality rate in some family histories41 and may explain the occasionally observed mental retardation. 45 In secondary or acquired nephrogenic diabetes insipidus the patients are unable to concentrate the urine maximally despite administration of pharmacological doses of vasopressin. The causes are listed in table 3_ 4 &-52 The location of the cellular
defect in nephrogenic diabetes insipidus m humans is not known. Hydronephrosis and diabetes insipid us. Hydronephrosis has been produced in mice described by Silverstein and associates53 with primary polydipsic diabetes insipidus, in the mice described by Valtin and associates with nephrogenic diabetes insipidus54 and in the Brattleboro rat with hypothalamic diabetes insipidus. 55 There are no data in experimental animals regarding how long polyuria must be present for hydronephrosis to develop or whether it may be reversed. Hydronephrosis has been reported in humans with diabetes insipidus. The cause of the hydronephrosis is speculative, although polyuria alone seems to be the primary factor. When urinary volume per unit of time exceeds the capabilities of the ureter dilatation occurs. Theoretically, the dilatation could result in ureteral decompensation and renal deterioration owing to hydronephrotic atrophy. Many operative procedures have been performed to improve urinary drainage (table 4). 5 • 7• 14 • 16 • 17 • 22 • 23 • 56 The value of these operations in improving renal function in the absence of urinary obstruction remains unproved, since there is no evidence of anyone dying of diabetes insipidus owing to a serial decline in renal function. Until further information is available operative intervention should
718
SHAPIRO AND ASSOCIATES
TABLE 3.
Causes of acquired or secondary nephrogenic diabetes insipidus
Drug induced: Lithium Tetracyclines Methoxyflurane Sulfonylureas Diatrizoate toxicity at arteriography Propoxyphene Analgesic nephropathy Sickle cell anemia Hypokalemia Hypercalcemia Chronic uremic nephropathy Obstructive uropathy: Posterior urethral valves Benign prostatic hypertrophy Retroperitoneal fibrosis Chronic pyelonephritis Amyloidosis Sarcoidosis
TABLE 4.
Operative procedures to improve urinary drainage in cases of diabetes insipidus
Reference Friedland and associates' Wheeler and Adelson 7 Weller and associates" Miller and Winston 16 Ten Bense! and Peters 17 Steel and associates22 Ramsey and associates23 Jones and associates"
Operations Transurethral resection of prostate Y-V plasty of bladder neck Transurethral resection of bladder neck Transurethral resection of prostate, pyeloileocystostomy, bilat. ureteral reimplants Suprapubic cystostomy Y-V plasty of bladder neck, partial cystectomy, transurethral resection of bladder neck Y-V plasty of bladder neck Suprapubic cystostomy
be reserved for cases in which there has been clear evidence of obstruction. 15 Treatment of polydipsic diabetes insipidus consists of water restriction. Hypothalamic diabetes insipidus should be treated with one of the various forms of vasopressins. Nephrogenic diabetes insipidus requires a high caloric diet, salt restriction and diuretics. The paradoxical effect of diuretics in reducing the urine volume depends on salt depletion. 57 Thiazides seem to be the most effective. 58 Therapy is particularly important in the severely affected infant to ensure proper growth and development. 3 Even with appropriate therapy urine volumes rarely are reduced to normal levels (table 3) and hydronephrosis, if present, may persist (case 3). If polydipsia persists non-fluoridated water is recommended to avoid fluorosis. 59 All children with persistent polyuria should be followed with serial IVPs and serial tests of renal function. The exact incidence of complications in diabetes insipidus, such as hydronephrosis and decline in renal function, remains unknown and will become available only with life-time followup. Drs. C. Duane Larsen and Julian Irias allowed us to include their patients in this series. Dr. Matthew H. Connors reviewed the manuscript. REFERENCES
1. Coggins, C.H. and Leaf, A.: Diabetes insipidus. Amer. J. Med., 42: 807, 1967. 2. Forssman, H.: The recognition of nephrogenic diabetes insipidus. A very small page from the history of medicine. Acta Med. Scand., 197: 1, 1975. 3. Gardner, L. I.: Endocrine and Genetic Diseases of Childhood and Adolescence, 2nd ed. Philadelphia: W. B. Saunders Co., p. 127ff, 197 5. 4. Valtin, H.: Diabetes insipidus. Read at special Endocrine/Renal Seminar, University of California, Davis, School of Medicine, Davis, California, April 6, 1977. 5. Friedland, G. W., Axman, M. M., Russi, M. F. and Fair, W.R.: Renal back pressure atrophy with compromised renal function
due to diabetes insipidus. Case report. Radiology, 98: 359, 1971. 6. Cannon, J. F.: Diabetes insipidus: clinical and experimental studies with consideration of genetic relationships. Arch. Intern. Med., 96: 215, 1955. 7. Wheeler, J. S. and Adelson, W. J.: Pituitary diabetes insipidus associated with progressive urinary tract dilatation. J. Urol., 92: 64, 1964. 8. Vest, M., Talbot, N. B. and Crawford, J. D.: Hypocaloric dwarfism and hydronephrosis in diabetes insipidus. Amer. J. Dis. Child., 105: 175, 1963. 9. Pender, C. B. and Fraser, F. C.: Dominant inheritance of diabetes insipidus. Pediatrics, 11: 246, 1953. 10. Manson, A. D., Yalowitz, P.A., Randall, R. V. and Greene, L. F.: Dilatation of the urinary tract associated with pituitary and nephrogenic diabetes insipidus. J. Urol., 103: 327, 1970. 11. Pelkey, W. J., Powell, P.R. and Fagan, W. T., Jr.: Observations on urological aspects of diabetes insipidus. J. Urol., 91: 430, 1964. 12. Chung, R. C. H. and Mantell, L. K.: Urographic changes in diabetes insipidus; report of a case. J.A.M.A., 150: 1307, 1952. 13. Raff, S. B. and Gershberg, H.: Night sweats. A dominant symptom in diabetes insipidus. J.A.M.A., 234: 1252, 1975. 14. Weller, C. G., Elliott, W. and Gusman, A. R.: Hereditary diabetes insipidus: unusual urinary tract changes. J. Urol., 64: 716, 1950. 15. Wiggelinkhuizen, J., Retief, P. J.M., Wolff, B., Fisher, R. M. and Cremin, B. J.: Nephrogenic diabetes insipidus and obstructive uropathy. Amer. J. Dis. Child., 126: 398, 1973. 16. Miller, S. S. and Winston, M. D.: Nephrogenic diabetes insipidus. Radiology, 87: 893, 1966. 17. Ten Bense!, R. W. and Peters, E. R.: Progressive hydronephrosis, hydroureter, and dilatation of the bladder in siblings with congenital nephrogenic diabetes insipidus. J. Pediat., 77: 439, 1970. 18. MacDonald, W. B.: Congenital pitressin resistant diabetes insipidus of renal origin. Pediatrics, 15: 298, 1955. 19. Ellborg, A. and Forssman, H.: Nephrogenic diabetes insipidus in children. Acta Paediat., 44: 209, 1955. 20. Carter, R. D. and Goodman, A. D.: Nephrogenic diabetes insipidus accompanied by massive dilatation of the kidneys, ureters and bladder. J. Urol., 89: 366, 1963. 21. Silverstein, E. and Tobian, L.: Pitressin-resistant diabetes insipidus with massive hydronephrosis. Amer. J. Med., 30: 891, 1961. 22. Steel, J. F., Feeney, M. J., Howe, G. E. and Blum, J. A.: Nephrogenic diabetes insipidus and urologic management. Read at annual meeting of the Western Section, American Urological Association, San Francisco, California, March 1317, 1977. 23. Ramsey, E.W., Morrin, P.A. F. and Bruce, A. W.: Nephrogenic diabetes insipidus associated with massive hydronephrosis and bladder neck obstruction. J. Urol., 111: 225, 1974. 24. Feigin, R. D., Rimoin, D. L. and Kaufman, R. L.: Nephrogenic diabetes insipidus in a Negro kindrid. Amer. J. Dis. Child., 120: 64, 1970. 25. Weigel, K. M.: Personal communication. 26. Barlow, E. D. and De Wardener, H. E.: Compulsive water drinking. Quart. J. Med., 28: 235, 1959. 27. Reaves, L., III, Cauthen, J. and Garcia-Bengochea, F.: Psychogenic diabetes insipidus. A case report with description of certain differential diagnostic procedures. J. Neurosurg., 23: 344, 1965. 28. Leiken, S. J. and Caplan, H.: Psychogenic polydipsia. Amer. J. Psychiat., 123: 1573, 1967. 29. Stevko, R. M., Balsley, M. and Segar, W. E.: Primary polydipsia-compulsive water drinking. Report of two cases. J. Pediat., 73: 845, 1968. 30. Linshaw, M.A., Hipp, T. and Gruskin, A.: Infantile psychogenic water drinking. J. Pediat., 85: 520, 1974. 31. Kohn, B., Norman, M. E., Feldman, H., Thier, S. 0. and Singer, I.: Hysterical polydipsia (compulsive water drinking) in children. Amer. J. Dis. Child., 130: 210, 1976. 32. Crumpacker, R. W. and Kriel, R. L.: Voluntary water intoxication in normal infants. Neurology, 23: 1251, 1973. 33. Page, M. M., Asmal, A. C. and Edwards, C. R. W.: Recessive inheritance of diabetes: the syndrome of diabetes insipidus,
DIABETES INSIPIDUS AND HYDRONEPHROSIS
34. 35. 36. 37. 38. 39.
40. 41. 42. 43. 44.
45. 46.
diabetes mellitus, optic atrophy and deafness. Quart. J. Med., 45: 505, 1976. Gossain, V. V., Sugawara, M. and Hagen, G. A.: Co-existent diabetes mellitus and diabetes insipidus, a familial disease. J. Clin. Endocr., 41: 1020, 1975. Naijar, S. S. and Mahmud, A.: Diabetes insipidus and diabetes mellitus in a six-year-old girl. J. Pediat., 73: 251, 1968. Koepp, P.: Laurence-Moon-Biedl syndrome associated with diabetes insipidus neurohormonalis. Europ. J. Pediat., 121: 59, 1975. Machiedo, B., Bolanowski, P. J. P., Bauer, J. and Neville, W. E.: Diabetes insipidus secondary to penetrating thoracic trauma. Ann. Surg., 181: 31, 1975. Frasier, S. D., Kutnik, L.A., Schmidt, R. T. and Smith, F. G., Jr.: A water deprivation test for the diagnosis of diabetes insipidus in chil.dren. Amer. J. Dis. Child., 114: 157, 1967. Vavra I., Machova, A., Holocek, V., Cort, J. H., Zaoral, M. and Sorm, F.: Effect of a synthetic analogue of vasopressin in animals and in patients with diabetes insipidus. Lancet, 1: 948, 1968. Dousa, T. P.: Cellular action of antidiuretic hormone in nephrogenic diabetes insipidus. Mayo Clin. Proc., 49: 188, 1974. Bode, H. H. and Crawford, J. D.: Nephrogenic diabetes insipidus in North America-the Hopewell hypothesis. New Engl. J. Med., 280: 750, 1969. Kaplan, S. A., Yuceoglu, A. M. and Strauss, J.: Vasopressinresistant diabetes insipidus. Amer. J. Dis. Child., 97: 308, 1959. Perlman, M., Potashnik, G. and Wise, S.: Hydramnion and fetal renal anomalies. Amer. J. Obst. Gynec., 125: 966, 1976. Schrager, G. 0., Josephson, B. H., Fine, B. F. and Berger, G.: Nephrogenic diabetes insipidus presenting as fever of unknown origin in the neonatal period. Clin. Pediat., 15: 1070, 1976. Ruess, A. L. and Rosenthal, I. M.: Intelligence in nephrogenic diabetes insipidus. Amer. J. Dis. Child., 105: 358, 1963. Singer, I. and Forrest, J. N., Jr.: Drug-induced states of nephrogenic diabetes insipidus. Kidney Int., 10: 82, 1976.
719
47. Kovnat, P. J., Lin, K. Y. and Popky, G.: Azotemia and nephrogenic diabetes insipidus after arteriography. Radiology, 108: 541, 1973. 48. Baum, N. H., Burger, R. and Carlton, C. E., Jr.: Nephrogenic diabetes insipidus associated with posterior urethral valves. Urology, 4: 581, 1974. 49. Mooney, J. K., Herdon, W. E. and Lattimer, J. K.: A new dimension in the diagnosis of posterior urethral valves in children. J. Urol., 113: 272, 1975. 50. Baum, N. H., Anhalt, M., Carlton, C. E., Jr. and Scott, R., Jr.: Post-obstructive diuresis. J. Urol., 114: 53, 1975. 51. Lemmon, W. T., Jr. and Kiser, W. S.: Idiopathic retroperitoneal fibrosis: diagnostic enigma: report of a case simulating diabetes insipidus and a review of the literature. J. Urol., 96: 658, 1966. 52. Knowlan, D., Corrado, M., Schreiner, G. E. and Baker, R.: Periureteral fibrosis, with a diabetes insipidus-like syndrome occurring with progressive partial obstruction of a ureter unilaterally. Amer. J. Med., 28: 22, 1960. 53. Silverstein, E., Solokoff, L., Mickelsen, 0. and Jay, G. E., Jr.: Primary polydipsia and hydronephrosis in an inbred strain of mice. Amer. J. Path., 38: 143, 1961. 54. Valtin, H., Sokol, H. W. and Sunde, D.: Genetic approaches to the study of the regulation and actions of vasopressin. Rec. Prog. Horm. Res., 31: 447, 1975. 55. Valtin, H.: Hereditary hypothalamic diabetes insipidus in rats (Brattleboro strain). A useful experimental model. Amer. J. Med., 42: 814, 1967. 56. Jones, N. F., Barraclough, M. A., Barnes, N. and Cottom, D. G.: Nephrogenic diabetes ins~idus. Effects of 3, 5, cyclicadenosine monophosphate. Arch. Dis. Child., 47: 794, 1972. 57. Brown, D. M., Reynolds, J. W., Michael, A. F. and Ulstrom, R. A.: The use and mode of action of ethacrynic acid in nephrogenic diabetes insipidus. Pediatrics, 37: 447, 1966. 58. Sinha, S. N.: Thiazide treatment of diabetes insipidus. Practitioner, 203: 674, 1969. 59. Greenberg, L., Nelson, C. E. and Kramer, N.: Nephrogenic diabetes insipidus with fluorosis. Pediatrics, 54: 320, 1974.
THE JouRNAL OF UROLOGY
Copyright© 1978 by The Williams & Wilkins Co.
Re1Jiew Article DIABETES INSIPIDUS AND HYDRONEPHROSIS STEPHEN R. SHAPIRO,* SARAH WOERNER, RAYMOND D. ADELMAN
AND
JOHN M. PALMER
From the Departments of Pediatrics and Urology, University of California, Dau is, California
Diabetes insipidus, an inability to maximally concentrate the is associated with polyuria and polydipsia. 1, 2 Normally, vasopressin produced by the supraoptic and paraventricular nuclei of the hypothalamus acts on the distal tubule and collecting ducts to increase water permeability, thereby promoting increased water reabsorption and urinary concentration to as great as 1,200 mOsm./kg. in the presence of maximal secretion of the hormone (fig. 1). 3 • 4 Diabetes insipidus can occur because of any one of the following mechanisms: 1) intake of excessive amounts of fluid, which results in inhibition of vasopressin, 2) failure of the posterior pituitary to to hyperosmolar stimuli with release of vasopressin 3) failure of the kidneys to respond even when maximal levels of vasopressin are present. Each of these categories has its clinical correlates (table 1). Diabetes insipidus may be suspected when a patient presents with the acute onset of polyuria, polydipsia and a dilute urine. 3 In primary polydipsia, since the hypothalamic-pituitary-renal axis is intact, urine usually concentrates in response to water deprivation, although in some patients urinary concentration may be suboptimal. With hypothalamic diabetes insipidus there is maximal urinary concentration only if vasopressin is given. Partial hypothalamic diabetes insipidus may be difficult to differentiate from psychogenic diabetes insipidus because moderate concentration of the urine can occur owing to decreased but not absent vasopressin. In nephrogenic diabetes insipidus urinary concentration is inadequate even when vasopressin is administered. Primary hypothalamics-- 14 and primary nephrogenic diabetes insipidus 1s--24 have been reported associated with bilateral Frequently, serial tests ofrenal function have not been performed. Hydronephrotic atrophy and a decline in renal function have been documented in some cases. 5 • rn. 20 - 22 However, it is not clear that a severe progressive decline in renal function occurs. There is not a single case of diabetes insipidus known to have required dialysis or renal transplantation. 25 Our 7 cases of diabetes insipidus with hydronephrosis followed for an average of 12¼ years are reviewed.
day. When hospitalized the child was soaking 12 to 24 daily. Physical examination was unremarkable except that and weight were in the third percentile for age. The urea nitrogen was 10 mg. per cent and serum creatinine was 0.5 mg. per cent. An excretory urogram (IVP) demonstrated bilateral hydronephrosis. The voiding cystourethrograrn was normal. Urine cultures were negative. Urine specific was 1.001 but the remainder of the urinalysis was With water restriction for 9 hours the child concentrated the urine to 870 mOsm./1. Diagnosis was primary diabetes insipidus and fluid was restricted to 4 to 5 day. Voluntary fluid intake became normal and the disappeared. A repeat IVP 4 months later upper tracts. Case 2. Primary hypothalamic diabetes insipidus. M. H., a 51/z-month-old boy, had had polyuria and polydipsia since infancy. There was no family history ofpolyuria. There was history of congenital left hemiplegia. Examination when the child was admitted to the hospital revealed mild weakness on the left side. Skull x-rays were negative. An IVP showed an enlarged bladder but normal upper tracts. Urine gravities ranged from 1.001 to 1.004. After 7 hours deprivation urine specific gravity increased to 1.004, urine osmolality to 230 mOsm./1. and serum osmolality to 325 mOsm./1. Urine concentration increased to 596 mOsm./1. after vasopressin was administered. Diagnosis was primary thalamic diabetes insipidus and the child was treated lysine-8-vasopressin. Case 3. Primary nephrogenic diabetes insipidus. S. Ho, an 11-year-old boy, presented in infancy with fever of unknown origin, dehydration and failure to thrive. Evaluation when he was 2 years old revealed a serum creatinine of 0.5 cent and a creatinine clearance of 100 ml. per minute. demonstrated bilateral hydronephrosis. Water with a 4 per cent weight loss resulted in a 11u,A,u1HS;,,..,,v,ucu and 5 patients had primary nephrogenic diabetes salt restriction and thiazides was continued. This 11-year-old boy is on a low salt diet (300 to 500 CASE REPORTS daily) with hydrodiuril used only when sodium intake ex,ce,icts Case 1. Primary polydipsic diabetes insipidus. J. B., a 20- 500 mg. per day. He is well clinically. The creatinine clearance month-old boy, was hospitalized for evaluation ofpolyuria and is 54 ml. per minute (corrected). The serum creatinine is 0.9 polydipsia. When the child was 8 months old food allergies mg. per cent. A repeat IVP shows some increased hvrln,n,,_ were diagnosed and he was placed on a liquid diet. Fluid phrosis. Urine output remains 4 to 6 l. daily. intake was increased gradually to 10 to 15, 8-ounce bottles per DISCUSSION
* Requests for reprints: 4301 X St., Suite 249, Sacramento Cali-
Polydipsic diabetes insipidus. Primary polydipsic diabetes insipidus (compulsive water drinking or psychogenic diabetes insipidus) has been recognized in adults 2 &-28 more re
fornia 95817. ' at annual meeting of Society for Pediatric Urology, Chicago, April 24, 1977. 715
SHAPIRO AND ASSOCIATES
716
cently, in infants and children. 2 0-32 Children generally present with polyuria and polydipsia, which improve with water restriction. A disturbed parent-child relationship has been noted in some cases. 3l>-31 Water intoxication owing to maternal misjudgment and excessive water intake has been reported. 32
SUPRAOPTIC NUCLEUS
SUPRAOPTICONEUROHYPOPHYSEAL TRACT
,,.....-...........,-POST. LOBE VEIN INF HYPOPHYSEAL ARTERY
Fm. 1. Neurohypophyseal system. Vasopressin, produced by supraoptic and paraventricular nuclei of hypothalamus, is transported along neurohypophyseal tracts to posterior pituitary where it can be released into blood stream in response to hyperosmolar plasma or severe volume depletion. Adapted from Gardner." TABLE
1. Classification of diabetes insipidus
Class 1 2
3
Description Primary polydipsic diabetes insipidus (compulsive water drinking or psychogenic diabetes insipidus) Hypothalamic diabetes insipidus Primary (familial or idiopathic) Secondary (tumor or trauma) DIDMOAD syndrome Partial hypothalamic diabetes insipidus Nephrogenic diabetes insipidus Primary (familial or sporadic) Secondary (acquired)
f
TABLE 2.
f
Diagnosis and course of 7 patients with diabetes insipidus
Diabetes Insipidus Diagnosis
Age at Presentation (mos.)
Age at Followup (yrs.)
JB-M MH-M
Primary polydipsic Primary hypothalamic
22 66
2½ 11
SH-M
Primary nephrogenic
12
11
CF-M
Primary nephrogenic
12
RD-M
Primary nephrogenic
SB-M
JJ-M
Pt.-Sex
It may be difficult to distinguish between primary polydipsia and a partial hypothalamic diabetes insipidus. A patient may drink compulsively because of damage to a satiety center or stimulation of the thirst center. In animals alteration in thirst follows destruction and stimulation of various centers in the central nervous system. 29 Therefore, primary polydipsia in humans may be organic and/or psychogenic. In our case 1 there was no evidence of an organic hypothalamic lesion, since voluntary water intake returned to normal after fluid restriction. Hypothalamic diabetes insipidus. Familial hypothalamic diabetes insipidus is caused by a greater than 90 per cent deficiency of vasopressin. An autosomal dominant and Xlinked inheritance has been described. 3 The disease usually is mild in childhood and becomes more severe with age. The hypocaloric dwarfism occasionally seen with nephrogenic diabetes insipidus generally does not occur. 8 Life expectancy is believed to be normal without specific treatment, although hydronephrosis and renal atrophy have been described. s--14 Recently, an association has been reported among hypothalamic diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD syndrome). All of the patients described by Page and associates had hydronephrosis that improved with the treatment of the diabetes insipidus. 33 Diabetes insipidus and diabetes mellitus may coexist in the same individual on a coincidental basis. 34, 35 At all ages the most frequent cause of acquired or secondary hypothalamic diabetes insipidus is tumor. Craniopharyngioma is the most common but, in contrast to the other central nervous system tumors, diabetes insipidus usually occurs postoperatively. Diabetes insipidus has been reported in association with the Laurence-Moon-Biedl syndrome, 36 encephalitis, meningitis, vaccination or trauma. 37 Diagnosis of hypothalamic diabetes insipidus usually is made when urine becomes concentrated with administered vasopressin but not with water deprivation. 38 During water deprivation close supervision is required to prevent surreptitious water intake or extreme dehydration in the severely affected patient. Treatment of hypothalamic diabetes insipidus consists of intramuscular vasopressin tannate in oil3 or intranasal vasopressin. A new analog, 1-deamino-8-D-arganine vasopressin, has a prolonged effect when given intranasally and appears promising. 39 The proposed mode of cellular action of vasopressin is shown in figure 3. 40 Patients with so-called idiopathic hypothalamic diabetes insipidus need periodic re-evaluation for a long interval before tumor can be ruled out. IVP Clinical Course
Therapy Initial Fluid restriction Lysine-8-vasopressin Thiazides, salt restriction
Mild hydronephrosis Normal upper tracts, enlarged bladder Severe bilat. hydronephrosis (age 2 yrs.)
10
Thiazides, salt restriction
Moderate bilat. hydronephrosis (age 5 yrs.)
12
25
Moderate bilat. hydronephrosis (age 10 yrs.)
Primary nephrogenic
24
21
Thiazides, salt restriction, aldactone None
Primary nephrogenic
36
21
Thiazides
Normal upper tracts, enlarged bladder
Followup Normal
Well clinically Well clinically
Well clinically, urine output 4-6 1./day, creatinine clearance 54 ml./min., serum creatinine 0. 9 mg.% Unchanged (age Well clinically, urine output >3 1./day, serum creatinine 0.9 6yrs.) mg.% Unchanged (age Still polyuric and polydipsic 15 yrs.) Unchanged (age 11 yrs.)
Moderate bilat. hydronephrosis (age 11 yrs.)
Still polyuric and polydipsic
Well clinically, voids every hour, maternal grandfather with nephrogenic diabetes insipidus age 86
'
DIABETES INSIPIDUS AND HYDRONEPHROSIS
717
FIG. 2. Primary nephrogenic diabetes insipidus. A, IVP reveals bilateral hydroureteronephrosis. B, cystogram demonstrates enlarged bladder capacity.
Stimulated by ADH
Inhibited by Prostaglandin E1
~ / Adenylate ATP
Cyclase
Adenosine 3; 5 1-Phosphate Cyc Ii c AMP
J
Cyclic AMP
- - - - - - 5 ' AMP Phosphodiesterase
Protein kinase Phosphorylation Microtubular protein
Increased Water Permeability FIG. 3. Cellular mode of action of antidiuretic hormone. Adapted from Dousa40
Ncphrogenic diabetes insipidus. Primary nephrogenic diabetes insipidus is believed to have a sex-linked recessive mode of inheritance. 2 It affects male subjects primarily and rarely occurs in female subjects. •0 The Hopewell hypothesis suggests that most patients in North America are descendants of Ulster Scot, who settled in Nova Scotia in the 18th Century. 41 One of our patients (case 3), in fact, can trace his lineage back to Ulster Scot. Rare instances of authentic nephrogenic diabetes insipidus have been encountered with no evidence of affected relatives, suggesting new mutations. 3 • 24 • 42 Polyuria in the infant with nephrogenic diabetes insipidus may result in polyhydramnios. 43 Symptoms may be severe in infancy, although the polyuria and polydipsia can be overlooked during the diaper stage. Fevers of undetermined origin, 44 failure to thrive 8• 17 and persistent constipation may occur. Frequent bouts ofhypertonic dehydration with convulsions account for the high mortality rate in some family histories41 and may explain the occasionally observed mental retardation. 45 In secondary or acquired nephrogenic diabetes insipidus the patients are unable to concentrate the urine maximally despite administration of pharmacological doses of vasopressin. The causes are listed in table 3_ 4 &-52 The location of the cellular
defect in nephrogenic diabetes insipidus m humans is not known. Hydronephrosis and diabetes insipid us. Hydronephrosis has been produced in mice described by Silverstein and associates53 with primary polydipsic diabetes insipidus, in the mice described by Valtin and associates with nephrogenic diabetes insipidus54 and in the Brattleboro rat with hypothalamic diabetes insipidus. 55 There are no data in experimental animals regarding how long polyuria must be present for hydronephrosis to develop or whether it may be reversed. Hydronephrosis has been reported in humans with diabetes insipidus. The cause of the hydronephrosis is speculative, although polyuria alone seems to be the primary factor. When urinary volume per unit of time exceeds the capabilities of the ureter dilatation occurs. Theoretically, the dilatation could result in ureteral decompensation and renal deterioration owing to hydronephrotic atrophy. Many operative procedures have been performed to improve urinary drainage (table 4). 5 • 7• 14 • 16 • 17 • 22 • 23 • 56 The value of these operations in improving renal function in the absence of urinary obstruction remains unproved, since there is no evidence of anyone dying of diabetes insipidus owing to a serial decline in renal function. Until further information is available operative intervention should
718
SHAPIRO AND ASSOCIATES
TABLE 3.
Causes of acquired or secondary nephrogenic diabetes insipidus
Drug induced: Lithium Tetracyclines Methoxyflurane Sulfonylureas Diatrizoate toxicity at arteriography Propoxyphene Analgesic nephropathy Sickle cell anemia Hypokalemia Hypercalcemia Chronic uremic nephropathy Obstructive uropathy: Posterior urethral valves Benign prostatic hypertrophy Retroperitoneal fibrosis Chronic pyelonephritis Amyloidosis Sarcoidosis
TABLE 4.
Operative procedures to improve urinary drainage in cases of diabetes insipidus
Reference Friedland and associates' Wheeler and Adelson 7 Weller and associates" Miller and Winston 16 Ten Bense! and Peters 17 Steel and associates22 Ramsey and associates23 Jones and associates"
Operations Transurethral resection of prostate Y-V plasty of bladder neck Transurethral resection of bladder neck Transurethral resection of prostate, pyeloileocystostomy, bilat. ureteral reimplants Suprapubic cystostomy Y-V plasty of bladder neck, partial cystectomy, transurethral resection of bladder neck Y-V plasty of bladder neck Suprapubic cystostomy
be reserved for cases in which there has been clear evidence of obstruction. 15 Treatment of polydipsic diabetes insipidus consists of water restriction. Hypothalamic diabetes insipidus should be treated with one of the various forms of vasopressins. Nephrogenic diabetes insipidus requires a high caloric diet, salt restriction and diuretics. The paradoxical effect of diuretics in reducing the urine volume depends on salt depletion. 57 Thiazides seem to be the most effective. 58 Therapy is particularly important in the severely affected infant to ensure proper growth and development. 3 Even with appropriate therapy urine volumes rarely are reduced to normal levels (table 3) and hydronephrosis, if present, may persist (case 3). If polydipsia persists non-fluoridated water is recommended to avoid fluorosis. 59 All children with persistent polyuria should be followed with serial IVPs and serial tests of renal function. The exact incidence of complications in diabetes insipidus, such as hydronephrosis and decline in renal function, remains unknown and will become available only with life-time followup. Drs. C. Duane Larsen and Julian Irias allowed us to include their patients in this series. Dr. Matthew H. Connors reviewed the manuscript. REFERENCES
1. Coggins, C.H. and Leaf, A.: Diabetes insipidus. Amer. J. Med., 42: 807, 1967. 2. Forssman, H.: The recognition of nephrogenic diabetes insipidus. A very small page from the history of medicine. Acta Med. Scand., 197: 1, 1975. 3. Gardner, L. I.: Endocrine and Genetic Diseases of Childhood and Adolescence, 2nd ed. Philadelphia: W. B. Saunders Co., p. 127ff, 197 5. 4. Valtin, H.: Diabetes insipidus. Read at special Endocrine/Renal Seminar, University of California, Davis, School of Medicine, Davis, California, April 6, 1977. 5. Friedland, G. W., Axman, M. M., Russi, M. F. and Fair, W.R.: Renal back pressure atrophy with compromised renal function
due to diabetes insipidus. Case report. Radiology, 98: 359, 1971. 6. Cannon, J. F.: Diabetes insipidus: clinical and experimental studies with consideration of genetic relationships. Arch. Intern. Med., 96: 215, 1955. 7. Wheeler, J. S. and Adelson, W. J.: Pituitary diabetes insipidus associated with progressive urinary tract dilatation. J. Urol., 92: 64, 1964. 8. Vest, M., Talbot, N. B. and Crawford, J. D.: Hypocaloric dwarfism and hydronephrosis in diabetes insipidus. Amer. J. Dis. Child., 105: 175, 1963. 9. Pender, C. B. and Fraser, F. C.: Dominant inheritance of diabetes insipidus. Pediatrics, 11: 246, 1953. 10. Manson, A. D., Yalowitz, P.A., Randall, R. V. and Greene, L. F.: Dilatation of the urinary tract associated with pituitary and nephrogenic diabetes insipidus. J. Urol., 103: 327, 1970. 11. Pelkey, W. J., Powell, P.R. and Fagan, W. T., Jr.: Observations on urological aspects of diabetes insipidus. J. Urol., 91: 430, 1964. 12. Chung, R. C. H. and Mantell, L. K.: Urographic changes in diabetes insipidus; report of a case. J.A.M.A., 150: 1307, 1952. 13. Raff, S. B. and Gershberg, H.: Night sweats. A dominant symptom in diabetes insipidus. J.A.M.A., 234: 1252, 1975. 14. Weller, C. G., Elliott, W. and Gusman, A. R.: Hereditary diabetes insipidus: unusual urinary tract changes. J. Urol., 64: 716, 1950. 15. Wiggelinkhuizen, J., Retief, P. J.M., Wolff, B., Fisher, R. M. and Cremin, B. J.: Nephrogenic diabetes insipidus and obstructive uropathy. Amer. J. Dis. Child., 126: 398, 1973. 16. Miller, S. S. and Winston, M. D.: Nephrogenic diabetes insipidus. Radiology, 87: 893, 1966. 17. Ten Bense!, R. W. and Peters, E. R.: Progressive hydronephrosis, hydroureter, and dilatation of the bladder in siblings with congenital nephrogenic diabetes insipidus. J. Pediat., 77: 439, 1970. 18. MacDonald, W. B.: Congenital pitressin resistant diabetes insipidus of renal origin. Pediatrics, 15: 298, 1955. 19. Ellborg, A. and Forssman, H.: Nephrogenic diabetes insipidus in children. Acta Paediat., 44: 209, 1955. 20. Carter, R. D. and Goodman, A. D.: Nephrogenic diabetes insipidus accompanied by massive dilatation of the kidneys, ureters and bladder. J. Urol., 89: 366, 1963. 21. Silverstein, E. and Tobian, L.: Pitressin-resistant diabetes insipidus with massive hydronephrosis. Amer. J. Med., 30: 891, 1961. 22. Steel, J. F., Feeney, M. J., Howe, G. E. and Blum, J. A.: Nephrogenic diabetes insipidus and urologic management. Read at annual meeting of the Western Section, American Urological Association, San Francisco, California, March 1317, 1977. 23. Ramsey, E.W., Morrin, P.A. F. and Bruce, A. W.: Nephrogenic diabetes insipidus associated with massive hydronephrosis and bladder neck obstruction. J. Urol., 111: 225, 1974. 24. Feigin, R. D., Rimoin, D. L. and Kaufman, R. L.: Nephrogenic diabetes insipidus in a Negro kindrid. Amer. J. Dis. Child., 120: 64, 1970. 25. Weigel, K. M.: Personal communication. 26. Barlow, E. D. and De Wardener, H. E.: Compulsive water drinking. Quart. J. Med., 28: 235, 1959. 27. Reaves, L., III, Cauthen, J. and Garcia-Bengochea, F.: Psychogenic diabetes insipidus. A case report with description of certain differential diagnostic procedures. J. Neurosurg., 23: 344, 1965. 28. Leiken, S. J. and Caplan, H.: Psychogenic polydipsia. Amer. J. Psychiat., 123: 1573, 1967. 29. Stevko, R. M., Balsley, M. and Segar, W. E.: Primary polydipsia-compulsive water drinking. Report of two cases. J. Pediat., 73: 845, 1968. 30. Linshaw, M.A., Hipp, T. and Gruskin, A.: Infantile psychogenic water drinking. J. Pediat., 85: 520, 1974. 31. Kohn, B., Norman, M. E., Feldman, H., Thier, S. 0. and Singer, I.: Hysterical polydipsia (compulsive water drinking) in children. Amer. J. Dis. Child., 130: 210, 1976. 32. Crumpacker, R. W. and Kriel, R. L.: Voluntary water intoxication in normal infants. Neurology, 23: 1251, 1973. 33. Page, M. M., Asmal, A. C. and Edwards, C. R. W.: Recessive inheritance of diabetes: the syndrome of diabetes insipidus,
DIABETES INSIPIDUS AND HYDRONEPHROSIS
34. 35. 36. 37. 38. 39.
40. 41. 42. 43. 44.
45. 46.
diabetes mellitus, optic atrophy and deafness. Quart. J. Med., 45: 505, 1976. Gossain, V. V., Sugawara, M. and Hagen, G. A.: Co-existent diabetes mellitus and diabetes insipidus, a familial disease. J. Clin. Endocr., 41: 1020, 1975. Naijar, S. S. and Mahmud, A.: Diabetes insipidus and diabetes mellitus in a six-year-old girl. J. Pediat., 73: 251, 1968. Koepp, P.: Laurence-Moon-Biedl syndrome associated with diabetes insipidus neurohormonalis. Europ. J. Pediat., 121: 59, 1975. Machiedo, B., Bolanowski, P. J. P., Bauer, J. and Neville, W. E.: Diabetes insipidus secondary to penetrating thoracic trauma. Ann. Surg., 181: 31, 1975. Frasier, S. D., Kutnik, L.A., Schmidt, R. T. and Smith, F. G., Jr.: A water deprivation test for the diagnosis of diabetes insipidus in chil.dren. Amer. J. Dis. Child., 114: 157, 1967. Vavra I., Machova, A., Holocek, V., Cort, J. H., Zaoral, M. and Sorm, F.: Effect of a synthetic analogue of vasopressin in animals and in patients with diabetes insipidus. Lancet, 1: 948, 1968. Dousa, T. P.: Cellular action of antidiuretic hormone in nephrogenic diabetes insipidus. Mayo Clin. Proc., 49: 188, 1974. Bode, H. H. and Crawford, J. D.: Nephrogenic diabetes insipidus in North America-the Hopewell hypothesis. New Engl. J. Med., 280: 750, 1969. Kaplan, S. A., Yuceoglu, A. M. and Strauss, J.: Vasopressinresistant diabetes insipidus. Amer. J. Dis. Child., 97: 308, 1959. Perlman, M., Potashnik, G. and Wise, S.: Hydramnion and fetal renal anomalies. Amer. J. Obst. Gynec., 125: 966, 1976. Schrager, G. 0., Josephson, B. H., Fine, B. F. and Berger, G.: Nephrogenic diabetes insipidus presenting as fever of unknown origin in the neonatal period. Clin. Pediat., 15: 1070, 1976. Ruess, A. L. and Rosenthal, I. M.: Intelligence in nephrogenic diabetes insipidus. Amer. J. Dis. Child., 105: 358, 1963. Singer, I. and Forrest, J. N., Jr.: Drug-induced states of nephrogenic diabetes insipidus. Kidney Int., 10: 82, 1976.
719
47. Kovnat, P. J., Lin, K. Y. and Popky, G.: Azotemia and nephrogenic diabetes insipidus after arteriography. Radiology, 108: 541, 1973. 48. Baum, N. H., Burger, R. and Carlton, C. E., Jr.: Nephrogenic diabetes insipidus associated with posterior urethral valves. Urology, 4: 581, 1974. 49. Mooney, J. K., Herdon, W. E. and Lattimer, J. K.: A new dimension in the diagnosis of posterior urethral valves in children. J. Urol., 113: 272, 1975. 50. Baum, N. H., Anhalt, M., Carlton, C. E., Jr. and Scott, R., Jr.: Post-obstructive diuresis. J. Urol., 114: 53, 1975. 51. Lemmon, W. T., Jr. and Kiser, W. S.: Idiopathic retroperitoneal fibrosis: diagnostic enigma: report of a case simulating diabetes insipidus and a review of the literature. J. Urol., 96: 658, 1966. 52. Knowlan, D., Corrado, M., Schreiner, G. E. and Baker, R.: Periureteral fibrosis, with a diabetes insipidus-like syndrome occurring with progressive partial obstruction of a ureter unilaterally. Amer. J. Med., 28: 22, 1960. 53. Silverstein, E., Solokoff, L., Mickelsen, 0. and Jay, G. E., Jr.: Primary polydipsia and hydronephrosis in an inbred strain of mice. Amer. J. Path., 38: 143, 1961. 54. Valtin, H., Sokol, H. W. and Sunde, D.: Genetic approaches to the study of the regulation and actions of vasopressin. Rec. Prog. Horm. Res., 31: 447, 1975. 55. Valtin, H.: Hereditary hypothalamic diabetes insipidus in rats (Brattleboro strain). A useful experimental model. Amer. J. Med., 42: 814, 1967. 56. Jones, N. F., Barraclough, M. A., Barnes, N. and Cottom, D. G.: Nephrogenic diabetes ins~idus. Effects of 3, 5, cyclicadenosine monophosphate. Arch. Dis. Child., 47: 794, 1972. 57. Brown, D. M., Reynolds, J. W., Michael, A. F. and Ulstrom, R. A.: The use and mode of action of ethacrynic acid in nephrogenic diabetes insipidus. Pediatrics, 37: 447, 1966. 58. Sinha, S. N.: Thiazide treatment of diabetes insipidus. Practitioner, 203: 674, 1969. 59. Greenberg, L., Nelson, C. E. and Kramer, N.: Nephrogenic diabetes insipidus with fluorosis. Pediatrics, 54: 320, 1974.
