Indomethacin in Streptozocin-Induced Nephrogenic Diabetes Insipidus

Indomethacin in Streptozocin-Induced Nephrogenic Diabetes Insipidus Vera Delaney, PhD, MD, Yolanda de Pertuz, MD, Daniel Nixon, MD, and Edmund Bourke, MD • A 14-year-old female patient with metastatic carcinoid developed streptozocin-induced glomerular, proximal, and distal tubular dysfunction. The latter was in the form of nephrogenic diabetes insipidus, with urine volumes in excess of 11 Ll24 h. The prostaglandin synthetase inhibitor, indomethacin, rapidly corrected the polyuria both initially and on rechallenge, independent of change in glomerular filtration rate. © 1987 by the National Kidney Foundation, Inc. INDEX WORDS: Streptozocin; indomethacin; nephrotoxicity; prostaglandin.

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TREPTOZOCIN is a potent chemotherapeutic agent used principally for the treatment of islet cell and carcinoid tumors, with nephrotoxicity as a major side effect. This occurs in 28 % to 100% of patients, 1.2 with an uncertain relationship between dose and renal damage. 3 Histologic changes have been described in the glomerulus, tubules (proximal and distal), and interstitium. 4 The most common clinical manifestations of toxicity are proteinuria (1 to 10 g/24 h), and/or Fanconi syndrome with aminoaciduria, glycosuria, urinary phosphate, urate and potassium wasting, and type II (proximal) renal tubular acidosis (RTA).l Progressive chronic renal failure is a well-established sequel. In addition, there is one previous case report of streptozocin-induced nephrogenic diabetes insipidus. 5 We describe a patient with clinical evidence of glomerular, proximal, and distal tubular damage following streptozocin in whom antidiuretic hormone (ADH)-resistant polyuria (11.5 Ll24 h) was the presenting clinical feature. In view of the recently reported antidiuretic effects of the prostaglandin synthetase inhibitor, indomethacin in congenital and lithium-induced nephrogenic diabetes insipidus,6,7 we evaluated this agent in the present patient. Indomethacin was followed by an immediate and sustained normalization of urine output independent of changes in glomerular filtration rate (GFR), both initially and on rechallenge. The possible pathogenic mechanisms of this effect are discussed. CASE REPORT Sp, a 14-year-old black female with histologically proven carcinoid, metastatic to the liver, primary unknown, was begun on a course of intravenous (IV) chemotherapy with streptozocin (Zanosar; The Upjohn Company, Kalamazoo, MI) (1 g/d for five days), 5-fluorouracil (5-FU) (1,5 g/d for five days), and dacarbazine (DTIC; Miles Laboratories, Inc, Elkhart, IN)

(600 mg), to be administered at monthly intervals. Oral nicotinamide (200 mg twice a day) and Theo-Dur (theophylline; Key Pharmaceuticals, Inc, Miami, FL) (300 mg twice a day) were started before chemotherapy and continued at. the same dosages throughout. Before starting the second course of chemotherapy, the patient denied urinary symptoms, including polyuria, and physical examination was unremarkable, with a body weight of 55 kg. She had a normal urinalysis, complete blood count (CBC), liver function tests, chest x-ray, and ECG, Plasma electrolytes (mmoIlL) were Na+ 140, K+ 4.1, CI- 1\1, and HCO, 24, Total proteins were 6.9 and albumin 4.1 g/dL. Other plasma chemistries (mg/dL) included BUN 14, serum creatinine level 0.8, blood glucose 120, calcium 904, phosphorus 4.7, and uric acid 5.9. Creatinine clearance was III mLimin, with a urine volume of 980 mLl24 h. Plasma serotonin was 1,572 ng/mL (normal 50 to 200) and 24-hour urinary 5-hydroxyindole-acetic acid (5-HIAA), 137 ng (normal 0 to 10). Plasma theophylline was 12.6 mg/L (therapeutic range 10 to 20 mg/L). Twelve days following the second course of chemotherapy, after receiving a total of 10 g of streptozocin, 15 g 5-FU, and 1,200 mg DTIC, the patient presented with polyuria, polydipsia, and clinical dehydration. Body weight was 50 kg. Urinalysis showed a sp gr of 1,008, urinary osmolality of 223 mosm/kg, pH 6,0, I + protein, 2 + glucose, and a negative sediment. Plasma electrolytes (mmoIlL) were Na+ 148, K+ 2.2, CI- 122, HCO, 10, and arterial pH was 7,23. Plasma proteins remained normal. Other blood chemistries (mg/dL) were glucose 92, calcium 804, phosphorus lA, magnesium lA, uric acid 1.2, BUN 20, and creatinine 1.2. Plasma serotonin was 1,480 ng/mL and plasma theophylline, 13 mg/L. The 24-hour urine volume was 11.5 L (Fig I), with an osmolality of 131 mosm/kg. Based on a calculated plasma osmolality (2 Na + + glucose/l8 + BUN/ 2.8) of 306 mosm/kg, the estimated free water clearance was From the Department of Medicine, Emory University School of Medicine, Atlanta. Supported by a grant from Dialysis Clinics Incorporated, Nashville, TN. Address reprint requests to Ji>ra Delaney, MD, Assistant Professor of Medicine, Division of Nephrology and Inorganic Metabolism, Department of Medicine, Emory University School of Medicine, 69 Butler St, Atlanta, GA 30303, © 1987 by the National Kidney Foundation, Inc.

0272-6386/87/0901-0012$03,00/0

American Journal of Kidney Diseases, Vol IX, No 1 (January), 1987: pp 79-83

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Fig 1. Twenty-four-hour urine volume, plasma K, plasma theophylline, and urine 5-HIAA following streptozocin (8) and indomethacin (I). Numbers in parentheses represent the dosage of indomethacin in milligrams. ole I indicates withholding of indomethacin.

4.5 mLlmin. The following 24-hour urinary values were obtained: protein 5.014 g , Na + 29 mmol, K+ 150 mmol (plasma K 3.1 mmollL), phosphorus 1,739 mg (plasma phosphorus 2.2 mg/dL), and 5-HIAA 132 ng. Creatinine clearance was 60 mLl min. Treatment with IV saline (0.45N) and oral and IV potassium and phosphate supplements over the next 72 hours increased plasma K+ and phosphorus to 3.2 mmoliL (range 2.7 to 3.8 mmollL) and 2.7 mg/dL (range 2.2 to 3.9 mg/dL), respectively. Polyuria persisted, but body weight increased to 52 kg. Creatinine clearance remained constant at 61.5 mLlmin. Blood glucose was persistently normal (70 to 100 mg/dL). Plasma HCO remained at 10 mmol/L (range 9 to II mmollL), with an early morning urinary pH of6.5 (range 6 to 7.5) . After a 12-hour period of fluid deprivation and a decrease in body weight to 47.2 kg , aqueous vasopressin (5 units IV) did not significantly decrease urine output (6.3 mLlmin) or increase urine osmolality (125 mosm/kg), and total 24-hour urinary volume was 9.7 L. Indomethacin, 50 mg orally, three times a day, was followed by an immediate reduction in 24-hour urinary volume from 9.4 to 0.6 L, and an increase in urine osmolality from 129 to 1,160 mosm/kg, with no change in creatinine clearance (59 mLlmin). Body weight increased from 48.7 kg before indomethacin to 55 kg three days later. Plasma K remained at 3.1 mmol/L, but 24hour urinary K+ decreased from 150 to 70 mmol. Urine Na+ increased from 29 to 59 mmol/24 h. Urinary protein declined from 5.0 to 1.5 g, and urinary phosphorus decreased from I. 73 to 1.40 g124 h. The patient was discharged on indomethacin 50

mg three times a day, K-Lyte (bicarbonate-citrate; Mead Johnson Laboratories, Evansville, IN) 25 mmol four times a day, KPhos Neutral (K-Na diphosphate mixture; Beach Pharmaceuticals, Tampa, FL) 8 mmol four times a day, Theo-Dur 300 mg twice a day, and nicotinamide 200 mg twice a day. Streptozocin was eliminated from her chemotherapeutic regimen, but monthly 5-FU and DTIC were continued. On readmission 14 days later, body weight was 55.3 kg. Urinalysis showed a sp gr of 1,015 pH 7.0, 2 + protein, and 2 + glucose. Plasma electrolytes (mmoIlL) were Na+ 138, K+ 4.5 , HCO, 17, and CI- 117. Other chemistries (mg/dL) were BUN 8, creatinine 1.2, calcium 8.4, phosphorus 3.2, Mg 1.6, glucose 83, and uric acid 1.4. Plasma theophylline was 11 mg/L. lWenty-four-hour urine volume was 1,200 mL with an osmolality of 650 mosm/kg, K+ 73 mmol, protein 864 mg, phosphorus 680 mg, and 5-HIAA 157 ng. Creatinine clearance was 60 mLlmin. While maintaining the other medications, constant indomethacin was discontinued. Urine volume increased sharply to 6.5 Ll24 h, urinary oSll;lolality decreased to 196 mosm/kg, body weight decreased to 53 .8 (Fig I), with no change in plasma K (4.5 mmol/L), urinary K+ (73 mmol), or creatinine clearance (60 mLlmin). Reinstitution of indomethacin (50 mg three times daily) restored urine volume to between 1,000 and 2,500 mL/24 h, urinary osmolality to between 1,060 and 510, and body weight to 55 kg. Eighteen days later, the dosage of indomethacin was reduced to 25 mg three times a day. This was not followed by a significant diuresis or change in biochemical parameters (Fig 1). This dose was maintained for 4 months, during which time body weight was stable at approximately 53 kg, as were 24-hour urine volumes (1,200 to 1,500 mL) and plasma chemistries (K + 3.6to 4.7, HCO, 16 to 19, phosphorus 2.6 to 3.8, and uric acid 2.0 to 3.2). Twentyfour-hour urinary protein was 860 to 1,200 mg , and potassium and phosphorus excretions were normal. Plasma creatinine showed a progressive increase to 1.7 mg/dL, with a decrease in clearance to 33 mLlmin at the end of 4 months. Indomethacin, potassium, and phophorus supplements were discontinued. Urine output showed a slight increase from 900 to 2,200 mL, but subsequently normalized (900 to 1,200 mL). Plasma K+ remained at 4.0 mmollL, HCO, 18 mmollL, uric acid 4.2 mg/ dL , and phosphorus 4.5 mg/dL. Protein and phosphorus excretions remained at 950 and at 612 mg/24 h, respectively. Glycosuria (2 + on dipstick) continued, and early morning urinary pH remained at pH 6.0. Plasma creatinine continued to rise to 2.4 mg/dL, with a further drop in clearance to 23 mLlmin over the next 3 months.

COMMENTS

The onset of clinical renal dysfunction occurred after a total streptozocin dose of 10 g, 45 days after the first, and 12 days after the second course, compatible with nephrotoxicity due to this agent as described in the literature. 8 Most of the clinical and laboratory manifestations are likewise characteristic, including a decrease in GFR, marked proteinuria, normoglycemic glycosuria, hypophosphatemia, and hypokalemia, with inappropriate urinary phosphate and potassium wasting, hy-

INDOMETHACIN IN NEPHROGENIC DIABETES INSIPIDUS

pouricemia, and RTA. These features are in keeping with the histologically observed glomerular and proximal tubular changes. 4 The progressive decline in renal function over the 9 months following cessation of streptozocin is also typical, 9 although not invariable,8 and attributable to the development of interstitial fibrosj,\. \0 Although clinically significant defects in distal nephron function are not characteristic, structural changes in the collecting ducts have been observed. Distal RTA has been reported. 11 A distal component seems likely in the RTA in the present case. Although detailed studies of urinary acidification were not performed, a serum bicarbonate of 10 mmollL on three successive days , with a systemic arterial pH of 7.23 and an early morning urinary pH of 6 .5, implies a distal tubular defect. ADHresistant polyuria following streptozocin, though rare, has also been previously described. S In the present patient, the onset of polyuria was cotemporaneous with the development of proteinuria and the Fanconi syndrome. Polyuria of up to 11.5 LI 24 h, with hypernatremia, a urinary osmolality of 131 mosm/kg, a positive free water clearance, and a 4- to 6- kg documented weight loss are compatible with nephrogenic diabetes insipidus. The absence of an increase in urinary osmolality or a decrease in urine volume when IV vasopressin was administered after 12 hours of fluid deprivation is diagnostic of nephrogenic diabetes insipidus. Alternative causes of the renal syndrome seen in the present patient, besides streptozocin nephrotoxicity, require consideration. Severe hypokalemia was initially present, suggesting a role for hypokalemic polydipsia and polyuria. Potassium depletion with a total deficit in excess of 200 mEq can result in urinary concentration defects, but a 24-hour urinary osmolality less than plasma is not observed in spite of deficits of up to 500 mEq. 12 Polyuria is not a feature of experimental human potassium deficiency l 3 nor is it seen consistently in patients with Bartter's syndrome in whom potassium depletion is both prolonged and severe. 14 Furthermore, polyuria recurred on cessation of indomethacin administration in spite of restoration and maintenance of nor mokalemi a (plasma K+ 4.5 mmollL) in the present patient, suggesting an alternate pathogenetic factor. The aminophylline derivative, Theo-Dur, can cause ADH resistance and could theoretically have contributed to the observed polyuria. Urine volumes in excess of 6 L

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have not been reported following oral Theo-Dur, either at the therapeutic levels maintained in the present patient or at toxic plasma levels. IS Moreover, since the patient had been on continuous Theo-Dur therapy, it seems most unlikely to be the cause of the sudden onset of polyuria. Indomethacin, a relatively common cause of acute renal dysfunction,16 has not been associated with chronic renal insufficiency. In the present case, the GFR had decreased 40% before the institution of indomethacin. The GFR did not decrease further following its initial administration nor improve following its cessation, making it an unlikely etiologic factor in the observed gradual decline in renal function. 5-FU and DTIC chemotherapeutic agents , also administered during the same timecourse as streptozocin, have not been associated with renal damageY Indomethacin, a prostaglandin synthetase inhibitor, had a dramatic effect on urine output initially and on rechallenge (Fig 1). Moreover, urinary osmolality, which was resistant to vasopressin, increased markedly following indomethacin. The findings suggest that a sudden overproduction of prostaglandins was causative. Possible stimuli to renal prostaglandin overproduction in the present case include hypokalemia, 18 hyperbradykininemia,19 and cellular injury.20 Hypokalemia is unlikely to be the main etiologic factor in the observed polyuria, as mentioned. Bradykinin and other vasoactive hormones are increased in patients with carcinoid syndrome and are responsible for some of the characteristic symptoms. 21 5HIAA and metabolites were elevated, but remained stable (Fig 1) throughout the period of observation, suggesting , but not proving, that a sudden increase in hormone production by the tumor was not the major cause of the polyuria. Prostaglandins are important mediators of inflammation .20 Streptozocin induces damage to renal tubular cells and thus favors local prostaglandin overproduction. This may be short-lived due to healing or cell death and could thus account for sudden and transient polyuria, as seen in the present patient. However, the progressive azotemia seen over the 9-month period of observation is another possible explanation for the amelioration of the polyuria. The mechanism of action of indomethacin in streptozocin-induced diabetes insipidus may be multifactorial. Indomethacin can cause oliguria in

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high renin/high angiotensin states where vasodilatory prostaglandins modulate the vasoconstrictor effects of angiotensin. 22 Since an essential accompaniment of this phenomenon is a precipitous fall in GFR, it can be excluded in the present patient. Prostaglandin synthetase inhibitors can also alter intrarenal hemodynamics more subtly, promoting preferential proximal tubular reabsorption of both solutes and water with reduced distal delivery, as seen in Bartter's syndrome and some proximal tubular disorders. 14.23 It is likely that this effect contributed to the delcine in urine output, since the fractional excretion of phosphate decreased from 91 % to 62 % within 24 hours of starting the drug. Indomethacin also has a site of action in the collecting duct. Here endogenous prostaglandin E promotes ADH resistance 24 by inhibiting cyclic adenosine monophosphate (cAMP) generation. Inhibition of this effect by indomethacin, or other prostaglandin synthetase inhibitors, increases the

effectiveness of ADH and can cause an antidiuresis. 25 Moreover, independent of its prostaglandin inhibitory action, indomethacin also decreases the activity of the cAMP degradative enzyme, phosphodiesterase, further potentiating the action of ADH.26 The indomethacin-induced antidiuretic effect reported in congenital 6 and lithium-induced? nephrogenic diabetes insipidUS has been attributed to this enhanced ADH sensitivity, and it seems likely that this effect also played a role in the present patient. In conclusion, indomethacin was safe, effective, and reproducible in normalizing streptozocin-induced nephrogenic diabetes insipidus, possibly through a combined proximal and distal tubular effect. ACKNOWLEDGMENT We wish to thank Norma Miller for excellent secretarial assistance.

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13. Black DAK, Milne MD: Experimental potassium depletion in man. Clin Sci 11:397-415, 1952 14. Delaney VB, Oliver JF, Simms M, et al: Bartter's syndrome: Physiological and pharmacological studies. Q J Med 50:213-232, 1981 15. Jacobs MH, Senior RM, Kessler Q: Clinical experience with theophylline. Relationships between dosage, serum concentration and toxicity. JAMA 235:1983-1986, 1976 16. Garella S, Matarese RA: Renal effects of prostaglandins and clinical adverse effects of nonsteroidal antiinflammatory agents. Medicine 63:165-182, 1984 17. Schilsky RL: Renal and metabolic toxicities of cancer chemotherapy. Semin Oncol 9:75-83, 1982 18. Galvez OQ, Bay WH, Roberts BW, et al: The hemodynamic effects of potassium deficiency in the dog. Circ Res 40:111-116,1977 (suppll) 19. Zusman RM, Keiser HR: Prostaglandin biosynthesis by rabbit renomedullary interstitial cells in tissue culture. Stimulation by angiotensin II, bradykinin and arginine vasopressin. J Clin Invest 60:215-223, 1977 20. Floman Y, Zor U: Mechanism of steroid action in inflammation: Inhibition of prostaglandin synthesis and release. Prostaglandins 12:403-415, 1976 21. Frolich JC, Margolius HS: Prostaglandins, the Kallikrein-Kinin system, Bartter's syndrome and the carcinoid syndrome, in Felig P, Baxter JD,Broadus AE, et al (eds): Endocrinology and Metabolism. New York, McGraw-Hill, 1981, pp 1247-1274 22. Delaney VB, Segel DP: Indomethacin induced renal insufficiency: Recurrence on rechallenge. South Med J 78: 13901392, 1985 23. Dillon MJ, Shah V, Mitchell MD: Bartter's syndrome: 10 cases in childhood. Q J Med 191:429-446, 1979 24. Beck Np, Kaneko T, Zor U, et al: Effects of vasopressin

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and prostaglandin E, on the adenylate cyclase-cycic 3 '5' adenosine monophosphate system of the renal medulla of the rat. J elin Invest 50:2461 - 2465 , 1971 25. Berl T, Raz A, Wald H , et al: Prostaglandin synthesis

83 inhibitor and the action of vasopressin studies in man and rat. Am J Physiol 232:F529-F537, 1977 26. Flower RJ: Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev 26:33-67 , 1974