Polydipsia, polyuria, and hypertension associated with renin-secreting Wilms tumor

Polydipsia, polyuria, and hypertension associated with renin-secreting Wilms tumor

June 1978 The Journal o f P E D 1 A T R 1 C S 921 Polydipsia, polyuria, and hypertension associated with renin-secreting Wilms tumor A 16-month-old ...

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June 1978 The Journal o f P E D 1 A T R 1 C S

921

Polydipsia, polyuria, and hypertension associated with renin-secreting Wilms tumor A 16-month-old black male infant had unusual thirst, polyuria, hyponatremia, and hypertension. His polyuria was unresponsive to vasopressin therapy, and his high blood pressure was not effectively controlled by antihypertensive drugs. Radiographic examinations revealed an occult Wilms tumor in the right kidney. After removal of the tumor, the signs and symptoms were relieved. The tumor had a renin activity about 280 times that of the adjacent renal cortex, and many intraeytoplasmic secretory granules were found on electron microscopy. The pathogenesis of these clinical manifestations appears to be mediated through the physiologie pathways of renin-angiotensin I I and renin-aldosterone.

Kumudchandra J. Sheth, M.B., M.R.C.P., D.C.H., F.R.C.P.(C),* Thomas T. Tang, M.D., Ph.D., Mark E. Blaedel, M.D., and Thomas A. Good, M.D., Milwaukee,

Wis.

A L r H O U O H the association o f h y p e r t e n s i o n a n d W i l m s t u m o r was first observed 40 years ago, 1 the i n t e r m e d i a t e m e c h a n i s m was u n k n o w n until r e n i n p r o d u c t i o n by the t u m o r was d e m o n s t r a t e d Y :~ T h e pathogenesis b e c a m e even more intriguing w h e n m a r k e d electrolyte imbalance'-" 4 a n d polyuria and polydipsia ~ were also n o t e d in some patients. W e h a v e reviewed 11 r e p o r t e d examples o f renin-secrefing r e n a l tumors a n d report one o f o u r own, seeking a physiologic basis for the association o f clinical manifestations with these tumors.

CASE REPORT Four weeks prior to admission, a 16-month-old black male infant was noted to be drinking about two quarts of fluid and to require diaper changes as often as 24 times daily. He became anorexic and had lost about three pounds after the onset of illness. Birth, growth, and development were otherwise normal. Physical examination revealed a well-nourished, pale infant without signs of dehydration; body weight was 9.98 kg and blood pressure was 150/80 mm Hg. The abdomen was protuberant, but neither enlarged organs nor a mass could be palpated. Other

From the Departments of Pediatr!cs and Pathology, Milwaukee Children's Hospital and Medical College of Wisconsin. *Reprint address: Department of Pediatrics, Milwaukee Children's Hospital, P.O. Box 1997, Milwaukee, WI 53201.

0022-3476/78/0692-0921500.40/0 9 1978 The C. V. Mosby Co.

physical findings were noncontributory. Laboratory data showed a hemoglobin concentration of 14.2 gm/dl and a white blood cell count of 13,000/ram 3 with normal differential. Sickle cell test was negative. Serum sodium value was 120 m E q / l , potassium 3.7 mEq/1, chloride 84 mEq/1, bicarbonate 23 mEq/1, blood pH 7.55, blood urea nitrogen 10 mg/dl, serum osmolarity 254 mOsmol/1, and urine specific gravity 1.001. Electrocardiogram showed sinus tachycardia and probable left ventricular hypertrophy. Radiographs of the chest and skull were unremarkable. The intravenous pyelogram, renal tomography, and aortogram demonstrated a 4 cm vascularized mass on the upper lateral aspect of the right kidney. Abbreviations used AI: angiotensin I AII: angiotensin II VMA: vanillylmandelic acid JG: juxtaglomerular On the second hospital day, the infant became severely dehydrated, irritable, and lethargic. Blood pressure was 200/120 mm Hg, and papilledema on the right was noted. He was treated with reserpine and hydralazine. Propranolol was not used at any time. The blood pressure fluctuated between 145 and 180 mm Hg systolic and between 65 and 135 mm Hg diastolic. Average urine output was 8,127 ml/24 hours with a urinary sodium concentration of 50 mEq/1, urinary potassium 22 mEq/1, and urinary osmolarity 136 mOsmol/l. The polyuria did not decrease with dehydration, saline load, o1"vasopressin injection. Before surgery,

VoL 92, No. 6, pp. 921-924

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Sheth et al

The Journal o f Pediatrics June 1978

Fig. 1. Wilms tumor showing abortive forms of a glomerulus and ~:enal tubules amidst numerous undifferentiated small ovoid or fusiform cells. (Hematoxylin and eosin, X 400.)

serum sodium levels averaged 128 rnEq/l and serum potassium 3.7 mEq/1. Urinary VMA output was 39 mg/24 hours (normal 1.8 to 9.0). Urinary catecholamines were measured at 500 t~g/24 hours inormal 30 to 155), while the serum epinephrine concentration was 48 ng/dl (normal 18 to 27), serum norepinephrine level was 18 ng/dl (noa;mal 48 to 70), and plasma renin activity was 6,240 ng angiotensin I/dl/hour by the radioimmunoassay method (normal recumbent 52 to 158). On the ninth hospital day, the right kidney was excised. The tumor, about 4 cm in diameter and weighing 35 gm, was confined within the renal capsule and was located on the superior lateral aspect of the right kidney without involvement of the renal blood vessels at the hilum. The tumor compressed but did not invade the kidney. Histologically, it was characteristic of Wilms tumor with glomeruloid and tubular structures; JG cell hyperplasia and renin granules were not evident (Fig. 1). However, on electron microscopy, the tumor cells contained many secreting ganules (Fig. 2). There was extensive cytoplasmic vacuolization and hydropic degeneration of the proximal convoluted tubules. Shortly after surgery, his craving for water decreased; this was associated with marked reduction in urine output and an increase in the urinary specific gravity to 1.014. On the second postoperative day, the blood pressure was 132/84 mm Hg. Plasma renin activity decreased to 255 ng AI/dl/hour on the third postoper ative day. The mean serum sodium value increased to 138 mEq/1, and serum potassium remained 3.7 mEq/1. There were decreases in urinary VMA output to 3.1 rag/24 hours and urinary catecholamines to 40/~g/24 hours, while urinary aldosterone was normal at 12 /Lg/24 hours (normal 5 to 25). Unfortunately, serum epinephrine and norepinephrine were not estimated after surgery. The patient was discharged two weeks after the surgery anff remained normotensive and free of polyuria and polydipsia.

BIOCHEMICAL

ASSAYS

The tumor tissue and surrounding renal cortex were assayed for renin activity according to the method of Goodfriend? and for epinephrine and norepinephrine according to the modified method of Merrils. ~ The results are summarized in Table I. DISCUSSION The results of biochemical assays suggest that the Wilms tumor is the primary source of renin. The improvement of hypertension, polydipsia, polyuria, hyponatremia, and vanillylmandelic aciduria following removal of the renin-secreting tumor also suggests that renin may play a significant role in these diverse clinical manifestations. The hypertension probably is attributable to the vas0constrictive effect of elevated plasma angiotensin II 7 in the presence of hyperreninemia. The increased renin is most likely due to secretion by the tumor and possibly due to compression of the surrounding renal tissue rather than compression of the renal artery. Concurrently, the high level of circulating renin may induce aldosteronism with subsequent hypokalemia and electrolYte imbalance, which in turn contribute to polyuria and vasopressin resistance by affecting the renal tubules ~ and to polydipsia by influencing the thirst center. ~ The insatiable thirst may also be aroused by high plasma concentration of AII secondary to increased renin secretion by the tumor, since in this child desire subsided immediately after resection of the tumor and before the

Volume 92 Number 6

Renin-secreting Wilms tumor

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Fig. 2. Electron micrograph showing a Wilms tumor cell with many electron-dense secretory granules (arrows), 100 to 500 nm in diameter. Eitch granule is enyeloped by a barely visible thin membrane. (• 11,300.) electrolytes and water balances were established. Simpson and Routenberg '~ suggested that AII increases water intake by stimulating the dipsogenic area, a subfornical organ in the brain. Cooling and Day 1~ demonstrated that saralasin, in competitively blocking AII receptors, alleviates both thirst and hypertension. In fact, the association of polydipsia and hypertension has been frequently observed in renin-secreting tumors, '~-~ and AI1 seems to be the mediator of this phenomenon. The high urinary VMA, catecholamines, and serum epinephrine suggest an increase in catecholamine secretion. The source of catecholamine is not likely to be the tumor or kidney because concentrations in both tissues are relatively low. Spergel and associates ~ failed to demonstrate enzymes necessary for catecholamine synthesis in Wilms tumor, despite high urinary VMA. Although hyperreninemia is rarely associated with VMA hyperexcretion, it is possible that AII stimulates the adrenal medulla to secrete catecholamine as supported by the evidence o f Feldberg and Lewis. 1~ The presence of numerous electron-dense secretory granules in a tumor rich in renin suggests that these granules may be responsible for renin secretion. Similar observations by Mitchell et al 2 strengthen this idea. Since renin is primarily produced by JG cells and most of the JG cell tumors secrete renin, it may be assumed that some components of renin-secreting Wilms tumor are derived

Table I. Renin and catecholamine contents of Wilms tumor and kidney Wilms tumor*

Renin activity (ng AI/dl/hour) Epinephrine (ng) Norepinephrine (ng)

Renal cortex*

395 x 105

1.42 x 10~

29.0 6.0

1.5 18.0

*One gram of fresh tissue of tumor or renal cortex was used in each assay. from or closely related to JG cells; the difference between these tumors may be the degree of JG cell differentiation. A W i l m s tumor with JG cells may be discovered at a relatively early stage, because the physiological disturbances appear before the tumor attains a palpable size, as in this patient. Since renin and angiotensin II are believed to play a pivotal role in the development of hypertension, polydipsia, and polyuria by this type of Wilms tumor, preoperative tests with saralasin to antagonize AII or propranolol to suppress renin release could be useful in controlling the symptoms, thus confirming the diagnosis. Clinicians should be aware of the heralding symptoms of a hormone-producing tumor and be diligent in the search for the occult source. The authors are indebted to Dr. Theodore L. Goodfriend,

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University of Wisconsin Medical School, for renin assay, Dr. William J. Stekiel, Medical College of Wisconsin, for catecholamine assay, Dr. Kenneth A. Siegesmund for electron microscopy, and Edith Swan and Emmy L. Skasa for technical assistance.

The Journal of Pediatrics June 1978

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note on the effects of potassium deficiency and calcium excess, Lancet 1:268, 1959. Simpson JB, and Routenberg A: Subfornical organ: Site of drinking elicitation by angiotensin II, Science 181:1172, 1973. Colling MJ, and Day MD: Antagonism of central dipsogenic and peripheral vasoconstrictor response to angiotensin II with Sarl-AlaS-angiotensin II in the conscience cat, J Pharm Pharmacol 25.1005, 1973. Robertson PW, Klidjian A, Harding LR, Waiters G, Lee MR, and Robb-Smith AHT: Hypertension due to a reninsecreting renal tumor, Am J Med 53:963, 1967. Kihara I, Kitawmura S, Hoshimo T, Seida H, and Wantanabe T: Hitherto unreported vascular tumor of the kidney: A proposal ofjuxtag!omerular cell tumor, Acta Pathol Jap 18(2): 197, 1968. Eddy RL, and Sanches SA: Renin-secreting renal neoplasm and hypertension and hypokalemia, Ann Intern Med 75:725, 1971. Corm JW, Cohen EL, Lucas CP, McDonald WJ, Mayor GH, Blough WM, Eveland WC, Bookstein JJ, and Lapides T: Primary reninism, hypertension, hyperreninemia, and secondary aldosteronism due to renin-producing juxtaglomerular cell tumors, Arch Intern Med 130:682, 1972. Schambelan M, Howes EL Jr, Stockgt JR, Noakes CA, and Biglieri EG: Role of renin and aldosterone in hypertension due to a renin-secreting tumor, Am J Med 55:86, 1973. Brown J J, Fraser R, Lever AF, Morton JJ, Robertson JIS, Tree M, Bell PRF, Davidson JK, and Ruthven IS: Hypertension and secondary hyperaldosteronism associated with a renin-secreting renal juxtaglomerular cell tumor, Lancet 2:1288, 1973. Feldberg W, and Lewis GP: Further studies of the effects of peptides on the suprarenal medulla of cats, J Physiol (Lond) 178"239, 1965.