- Email: [email protected]
Adenocarcinoma of the Kidney and Hypertension: Report of 2 Cases with Special Emphasis on Renin
Vol. 118, December Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
ADENOCARCINOMA OF THE KIDNEY AND HYPERTENSION: REPORT OF 2 CASES WITH SPECIAL EMPHASIS ON RENIN MARCEL LEBEL,* JEAN TALBOT, JOHN GROSE
AND
JEANNINE MORIN
From Le Centre de Nephrologie, Services of Biochimie Medicale and Pathologie, L'Hotel-Dieu de Quebec and l'Universite Laval, Quebec, Canada
ABSTRACT
Renin studies were done on 2 patients with adenocarcinoma of the kidney and hypertension. In 1 case plasma renin activity was high in the peripheral and renaf veins, with a renal vein :ratio of 1.7 favoring the side of the tumor. Neph:rectomy cured the hypertension and renin values became normal. Tissue :renin was elevated in the tumor and surrounding parenchyma. Acidification studies of tissue extracts failed to demonstrate the existence of big renin. In case 2 all renin values were normal and the blood pressure remained elevated after the operation. Although :renin-secreting tumors remain an uncommon cause of malignant hypertension the condition should be recognized because it is potentially curable. The relationship between renal neoplasia and hypertension has interested clinicians for many years 1• 2 Since the last decade it has been recognized that the hypertension associated with renin-secreting tumors is potentially curable. Among them juxtaglomerular ceUH 2 and Wilms 13 • 14 are the most frequently encountered renin-secreting renal tumors. Hollifield and associates described a case of clear
MATERIALS AND METHODS
Case 1. A 42-year-old housewife consulted her family doctor because of violent headaches. Blood pressure was 300/155 and the patient was referred to the emergency room of our tal. She had had 4 pregnancies, 1 of which was a spontaneous abortion. Her doctor had noted the elevated blood pressure the end of the last pregnancy and the patient received diuret
Fm. 1. Case 1. A, early arterial phase of left selective arteriography. B, late arterial phase with early venous retmrn neovascularization.
cell carcinoma of the kidney with manifestations of hypertension and overproduction of renin the tumor. 15 Herein we report on 2 cases of adenocarcinoma of the and hypertension, with special emphasis on peripheral plasma, renal vein and tumor tissue renin determinations.
ics until delivery, which was 18 months before the investigation. The patient had not been followed for blood pressure elevations after delivery. At the current hospitalization physical examination showed a woman who appeared older than her age. Blood was 245/150, with a pulse rate of 120 per minute. examination disclosed bilateral hemorrhage and exudate, and distinct papilledema on the left side (grade IV, ner). There was no clinical evidence of congestive heart ure. Examination of the abdomen revealed a mass with lum·bar contact on the left side. Laboratory investigation showed blood urea nitrogen (BUN)
Accepted for publication December 3, 1976. Presented in part at annual meeting of Canadian Academy of Urology, Quebec City, Quebec, January 21, 1976. Supported by the Quebec Medical Research Council and in part the Pollack Foundation and the Kidney Foundation, Quebec
* Requests for reprints: Le Centre de Nephrologie, L'Hotel-Dieu de Quebec, 11 Cote du Palais, Quebec GIR 2J6, Quebec, Canada. 923
924
LEBEL AND ASSOCIATES
of 19 mg. per 100 ml. and creatinine value of 1.1 mg. per 100 ml., with a slightly decreased clearance at 103 ml. per minute per 1. 73 m. 2 body surface area. Urinalysis revealed 4 to 8 red blood cells per high power field, with a few granular and hyaline casts. No bacteria were found in the culture. A chest radiogram and electrocardiogram showed no cardiac hypertrophy on the left side. A 24-hour urinary excretion of epinephrine, norepinephrine and vanillyl mandelic acid was normal, as were morning and afternoon plasma cortisol and thyroid hormones. Plasma calcium was 9.4 mg. per 100 ml. and plasma potassium was at the lower limit of normal (3.3 mEq. per 1.). Hemoglobin was 12.9 gm. per 100 ml. and white blood count was 4,600 per mm. 3 • Erythrocyte sedimentation rate was 50 mm. in the first hour. There were 2 platelet counts showing thrombocytosis (570,000 and 830,000). Excretory urography (IVP) revealed a large space-occupying lesion in the lower pole of the left kidney compressing the renal pelvis and ureter, with hydronephrosis well demonstrated on the 24-hour film. The right kidney and the bladder were normal. Renal angiography showed a large vascular tumor in the left kidney (fig. 1). There was no stenosis or compression of the renal artery and its main divisions. At operation an 18 by 12 by 8 cm. tumor was found replacing a large part of the kidney and compressing the pelvis and the ureter. The renal vein was not invaded and lymph nodes were not involved. Blood pressure decreased to 126/85 during the week after the operation and remained at that level 2 months later (table 1). Platelet counts returned to normal values. Case 2. A 43-year-old man was referred to our hospital for an extensive investigation of hypertension. The patient had had abnormal blood pressure since he was about 22 years old. In April 1975 blood pressure was 185/120 and his family physician started him on hypotensive drugs after a diagnostic TABLE 1. Preoperative and postoperative blood pressure, serum potassium and upright plasma renin activity (ng. per ml. per hour) in case 1
Blood pressure (mm. Hg) Serum potassium (mEq./1.) Upright plasma renin activity (ng./ml./ hour)
Preop.
9Days Postop.
2Mos. Postop.
190/120
126/85
130/80
3.4
4.3
4.3
52.0
2.9
2.3
study, including an IVP that appeared normal at that time. The blood pressure was not controlled with diuretics and alpha-methyldopa. The patient had no other disease and he was completely asymptomatic. Physical examination showed a healthy man with no evidence of congestive heart failure. Blood pressure was 190/120. Funduscopy revealed grade II (Keith-Wagner) changes. The rest of the examination was normal. Urinalysis did not disclose any microscopic hematuria and no bacteria were found in the culture. Creatinine concentration was 1.1 mg. per 100 ml., BUN 13 mg. per 100 ml. and creatinine clearance rate 122 ml. per minute per 1. 73 m. 2 body surface area. A chest radiogram and electrocardiogram were normal, as were thyroid hormones, urinary epinephrine, norepinephrine and vanillyl mandelic acid excretion. Plasma cortisol, serum potassium, hemoglobin, white blood count, thrombocyte count and erythrocyte sedimentation rate also were normal. A rapid sequence IVP showed slight distortion of calices in the lower pole of the right kidney. Right selective renal arteriography disclosed a well limited 6 cm. lesion in the lower pole of the kidney (fig. 2, A). The administration of epinephrine in the renal artery demonstrated tumor vessels (fig. 2, B). The patient underwent right radical nephrectomy. The high blood pressure improved with rest at the hospital but increased as soon as the patient was at home and it is still elevated. RENIN ASSAYS
Plasma renin activity was determined by a radioimmunoassay of angiotensin I generated during a 1-hour incubation at pH 6.0 using the New England Nuclear kit. We found an excellent correlation between this method 16 and the bioassay approach of Boucher and associates 17 (r equals 0.959, n equals 102, p less than 0.001). Normal values obtained by the present method (n equals 12) are 1.7 plus or minus 0.74 recumbent, 2.52 plus or minus 1.1 after 4 hours of upright posture and 6.6 TABLE
2. Peripheral plasma renin activity (ng. per ml. per hour) in
cases 1 and 2 with normal values Recumbent Upright Intravenous furosemide
Case 1
Case 2
34.6 52.0 53.7
0.38 1.44 8.04
Control Subjects* 1.07 2.5 6.16
0.74 1.1 2.7
* Mean plus or minus standard deviation.
FIG. 2. Case 2. A, right selective arteriography. B, demonstration of tumor vessels after epinephrine injection in renal artery
925
ADENOCARCINOMA OF KIDNEY AND HYPERTENSION
Fm. 3. Case 1. Acidophilic cell carcinoma with marked nuclear pleomorphism and multinucleated cells. Reduced from x 100 TABLE
3. Renal vein renin studies (ng. per ml. per hour)
Left renal vein Right renal vein Inferior vena cava
Case 1
Case 2
49.6* 29.5 31.5
8.64 2.04* 8.7
of Day and associates. 18 The renin content was then measured as described previously for tissue renin. RESULTS
* Side of tumor.
Renin content (ng. per gm. per hour) in different areas of tumor and kidney tissues before and after acidification
TABLE 4.
Case 1
Tumor tissue Adjacent kidney tissue
Case2
Before
After
4,600 0 27,400 56,320 117,000
4,800 0 5,400 60,400 51,600
Before
After
0
0
0 2,000
3,000
0
plus or minus 2. 7 ng. per ml. per hour with upright posture and half an hour after 20 mg. intravenous furosemide (table 2).16
Tissue from tumors and adjacent kidney areas was frozen immediately after excision. For extraction purposes the frozen tissue was weighed, cut into small pieces and homogenized with a Broeck-type hand operated homogenizer in 40 ml. 0.9 per cent sodium chloride solution per gm. frozen weight. After 15 minutes on ice the homogenate was centrifuged at 4C and 3,000 revolutions per minute for 10 minutes. The supernatant was divided into aliquots and kept frozen until the time of incubation. Serial dilutions were made with 0.9 per cent sodium chloride and 0.1 ml. of each dilution was incubated for 3 hours at 37C with 1.0 ml. nephrectomized sheep plasma as substrate. This angiotensin I generation step was done with the same buffer and inhibitors as in the plasma renin activity procedure. Subsequent quantification of angiotensin I by radioimmunoassay was achieved by the same procedure used for plasma renin activity and the results were expressed as renin concentration calibrated against standard human renin (batch 68/356, National Institute for Biological and Control, Holly Hill, London). One unit of the standard renin induced the formation of 98,000 ng. per hour AI using nephrectomized and estrogen-treated sheep plasma as substrate. For big renin studies the tissue extracts were acidified to pH 3.3 with lN hydrochloric acid and dialyzed for 24 hours at 4C using glycine buffer at pH 3.3, according to the approach
Case 1 . Histology under light microscopy showed a tumor comprised of largely acidophilic cytoplasmic cells (fig. 3). An inconspicuous stroma was made up of a fine framework of reticulum fibers containing lymphocytes and capillaries frequently coated with lipophages. There were small foci of necrosis. The tumoral cells were either isolated or arranged in alveolar patterns. The cell volume was extremely variable. Dense cytoplasmic inclusions, not stained by periodic acid, Schiff or Bowie coloration, were observed in some cell populations. There was marked nuclear pleomorphism and frequent monstrosities were present. The chromatin was coarse and contained large nucleoli. The preoperative plasma renin activity level was excessively high, 34.6 in the recumbent posture, 52.0 in the upright posture and 53. 7 mg. per ml. per hour 30 minutes after the intravenous injection offurosemide (table 2). Upright plasma renin activity was determined 9 days and again 2 months postoperatively and showed normal values of 2.9 and 2.3 ng. per ml. per hour, respectively (table 1). Normalization of blood pressure and electrolytes was observed simultaneously (table 1). Left renal vein plasma renin activity (side of the tumor) was 49.6 ng. per ml. per hour. The right renal vein was similar to the inferior vena cava (29.6 versus 31.5) with a ratio (left to right) of 1. 7 favoring the side of the tumor (table 3).
Tissue renin content was measured in 3 different areas of the tumor and 2 of the adjacent kidney tissues. The presence of renin was detected in 2 of 3 areas studied in the tumor, and the results were 4,600 and 27,400 ng. per gm. per hour (table 4) and tissue renin levels determined in 2 different parts of the surrounding kidney tissue were 56,320 and 117,000 ng. per gm. per hour (table 4). Activation of tissue extract by acid pH did not unmask evidence of tumor prorenin or big renin. There was no increase in renin value either in tumor or adjacent kidney tissue after acidification (table 4). Case 2. Histology revealed typical features of clear cell adenocarcinoma. The tumor was comprised of large polygonal cells with optically empty cytoplasm and a fine meshwork delineating vacuoles. Tumoral cells were arranged in tubular,
926
LEBEL AND ASSOCIATES
FIG. 4. Case 2. Electron microscopy of clear cell carcinoma of kidney. LD-lipid droplets. G-glycogen particulates. BM-basement membrane. Inset illustrates microvilli. Reduced from x 12,000.
cord or nest patterns. Nuclei were small and regularly shaped. Nuclear chromatin was fine and usually without any nucleolus. Electron microscopic studies showed tumoral cytoplasm filled with glycogen particulates, lipid vacuoles and a few dense bodies (lysosomes) (fig. 4). Golgi complexes were poorly developed. There were irregular club-shaped microvilli extensions into some luminal spaces (fig. 4, inset). At the base of the cells frequent infoldings of cytoplasmic membrane were observed. Cellular junctions were present and included rare · well formed desmosomes. Preoperative plasma renin activity results were normal either in basal condition (0.38 ng. per ml. per hour) or after orthostatic stimulation (1.44 ng. per ml. per hour) and the intravenous injection of furosemide (8.04 ng. per ml. per hour) (table 2). No abnormal plasma renin activity level was demonstrated in renal veins and the vena cava (table 3). We failed to find any tissue renin in 2 areas of the tumor. A single determination on the normal adjacent tissue was 2,000 ng. per gm. per hour (table 4). These values remained similar after the activation of tissue extract by acid pH (table 4). DISCUSSION
We describe 2 cases o_f adenocarcinoma of the kidney with hypertension, in which renin was studied in plasma, renal vein effluent and tumor tissue. The renin values differ markedly in the 2 patients, suggesting basic etiologic differences for the hypertension. The preoperative hypertension in the first case was associated with excessively elevated plasma renin activity. After removal of the tumor the hypertension and hyperreninemia were normalized, implicating the tumor as the cause of both abnormalities. The mild hypokalemia, probably secondary to the hyperaldosteronism induced by the increased renin release, also was corrected after an operation. In case 2, however, the preoperative plasma renin activity was normal and the hypertension persisted despite removal of the tumor. The hypertension associated with this case was coincidental rather than secondary to the carcinoma. Case 1, with acidophilic adenocarcinoma of the kidney and malignant hypertension, had a recumbent plasma renin activity 18.0 times the upper limit of normal, which increased further with upright posture from 34.6 to 52 ng. per ml. per hour. A similar postural influence on renin has been reported
in juxtaglomerular cell tumor7 and also in a case of clear cell carcinoma of the kidney. 15 This phenomenon indicates that the renin release is not necessarily autonomous in renal tumors. Also, the renal vein renin in case 1 was high. The finding of a positive plasma renin activity gradient (1. 7) from the inferior vena cava to the renal vein ipsilateral to the tumor and no gradient from the contralateral side suggests renin production by the kidney containing the tumor. Therefore, with renal tumors, as in renal artery stenosis, the plasma renin activity ratio of the involved versus contralateral normal kidney and inferior vena cava should be calculated because the half-life of renin is long enough to allow the recirculation of renin secreted by the affected kidney and could, thus, contribute to falsely elevated plasma renin activity in the normal contralateral side. Furthermore, cure of hypertension after nephrectomy is additional evidence that this kidney was responsible for the hypertension. Under these circumstances renin can come from the tumor or adjacent compressed tissue or both. We found the presence of renin in the tumor and also a significant concentration in the surrounding kidney tissue showing the contribution of tumor and compressed tissues to the elevated vein effluent measurements. These tumors, as demonstrated histologically in case 1, contain necrotic zones, which can explain why 1 of 3 areas does not contain renin (table 4). Renal tissue renin content also can vary from area to area; the immediate compressed tissue surrounding the tumor also may contain more renin than the opposite normal pole of the kidney. These observations stress the importance of looking into more than 1 area in tissue studies. Moreover, the tumor can secrete an abnormal product, such as renin of a higher molecular weight, which could be activated in the circulation. Some investigators have demonstrated in animals (rabbits and pigs) an inactive form of renin of a higher molecular weight, the so-called big renin. 19' 20 Day and Luetscher reported a case of Wilms tumor in which a large amount of big renin in plasma and tumor tissue was found. 21 This inactive form of renin has a molecular weight of 63,000 compared to normal renin, which is around 43,000. 22 This molecule can be activated by acid pH 21 , 22 to yield a product that is physiologically and immunologically similar to normal renin. 22 Thus, it may be a prohormone analogous to proinsulin secreted by insulinoma23 and by patients with
ADENOCARCINOlV!A OF KIDNEY AND HYPERTENSION
familiar hyperproinsulinemia 24 or to the large form of gastrin secreted in Zollinger Ellison syndrome. 2 " Using the approach of Day and Luetscher21 to detect big renin in both of our patients we did not find any difference in renin values before and after acidic activation (table 4). In a more extensive and recent study Day a.nd associates found big renin in 2 more cases of Wilms tumor but failed to detect big renin in their case of renal cell carcinoma .18 These findings indicate that renin is not necessarily present in all pathological conditions in which renin is implicated. We -····,-···--"·~- that hypernephroma need not classic features such as hematuria, which was cases. Hypertension can be the unique clue and we stress that treatment of hypertension should not be initiated without investigation. A renin-producing neoplasm be considered in all hypertensive patients vvith unex""''""''-- hyperreninemia. Although it is an uncommon cause the condition should be recognized because it curable. In all tumor tissue studies an attempt to recognize inactive precursors (renin zyrnoand big renin) that might have physiological Mrs. Danieile Lizotte and Miss Danielle Vaugeois provided technical assistance, Mrs. C. Labrecque and Mrs. N. Dumont ·with nursing, Drs. l\lL L. Langis and G. collaborated and Dr. D. R. Bangham ~~.,,.."'·~~. the human renin standards. REFERENCES
L Braasch, W. F., Walters, W. and Hammer, H.J.: Hypertension and the surgical kidney. J.A.M.A., 115: 1837, 1940. 2. Horton, B. T.: The relationship of hypertension to renal neoplasm. Proc. Staff Meet. Mayo Clin., 15: 472, 1940. 3. Robertson, P. W., Klidjian, A., Harding, L. K.) Walters 1 G., Lee, M. A. and Robb-Smith, A. H. T.: Hypertension due to a renin-secreting renal tumour. Amer. J. Med., 43: 963, 1967. 4. I., Kitamura, S., Hoshino, T., Seida, H. and Watanabe, T.: hitherto unreported vascular tumor of the kidney: a proposal of "juxtaglomerular cell tumor". Acta Path. J ap., 18: 197, 1!168. 5, R. L. and Sanchez, S. A.: Renin-secreting renal neoplasm hypertension with hypokalemia. Ann. Intern. Med., 75: 725, 1971. 6. Bonnin, J. M., Hodge, R. L. and Lumbers, E. R.: A. reninsecreting renal tumour associated with hypertension. Aust. N. Zeal. J. Med., 2: 178, 1972. 7. Conn, J. W., Cohen, E. L., Lucas, C. P., McDonald, W. J., H. G., Blough, W. M., Jr., Evelend, W. C., Bookstein, and Lapides, J.: Primary reninism. Hypertension, hyperreninemia, and secondary aldosteronism due to renin-producjuxtaglomerular cell tumors. Arch. Intern. Med., 130: 1972. 8. Schambelan, M., Howes, E. L., Jr,, Stockigt, J. R., Noakes, C. A. and Biglieri, E. G.: Role of renin and aldosterone in hypertension due to a renin-secreting tumor. Amer. J. Med.,
55: 86, 1973. 9. Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson, J. I. S., Tree, M., Bell, P.R. F., Davidson, J. K. and Ruthven, I. S.: Hypertension and secondary hyperaldosteronism assod· ated with a renin-secreting renal juxtaglomerular-cell turn.our. Lancet, 2: 1228, 1973. 10. Hirose, M., Arakawa, K., Kikuchi, M., Kawasaki, T., Kato, H. and Nagayama, T.: Primary reninism hamartomatous alteration. J.A.M.A., 230: 1288, 1974. 11. More, I. A., Jackson, A. M. and MacSween, R. N.: Reninsecreting tumor associated with hypertension. Cancer, 2093, 1974. 12. Qhjavik, 0. S., Aas, M., Fauchald, P., Brodwall, E. K. and Flatmark, A.: tumour with severe hypertension. Acta 329, 1975. 13. Mitchell, J. D., Baxter, T. J., Blair·West, J. R. and D. A.: Renin levels in nephroblastoma (Wilms' Report of a renin secreting tumour. Arch. Dis. Child., 376, 1969. 14. Ganguly, A., Gribble, J., Tune, B., Kempson, R. Luetscher, J. A.: Renin-secreting Wilms' tumor with severe hypertension. Report of a case and brief review of reninsecreting tumors. Ann. Intern. Med., 79: 835, J.973. 15. Hollifield, J. W., Page, D. L., Smith, C., Michelakis, NL, Staab, E. and Rhamy, R.: Renin-secreting clear cell carcinom.a of the kidney. Arch. Intern. Med., 135: 859, 1975. 16. Talbot, J., Loiselle, J. M., Page, M. and Belleau, L. J .. JV!esure de l'activite de la renine plasmatique: etude comparative essai biologique et d'un essai radioimmunologique. La ViG Medicale au Canada Fran1,ais., 4: 37, 1975. 17. Boucher, R., Veyrat, R., De Champlain, J, and Genest, J.: New procedures for measurement of human plasma angi.otensin and renin activity levels. Canad. Med. Ass. J., 90: 194, J.964. 18. Day, R. P., Luetscher, J. A. and Gonzales, C. M.: Occurrence of big renin in human plasma, amniotic fluid and kidney extracts. J. Clin. Endocr., 40: 1078, 1975. 19. Leckie, B. J. and McConnell, A.: A renin inhibitor from rabbit kidney: conversion of a large inactive renin to a smaller active enzyme. Circ. Res., 36: 513, 1975. 20. Boyd, G. W.: A protein-bound form of porcine renal renin. Res., 35: 426, 1974. 21. Day, R. P. and Luetscher, J. A.: Big :renin: a possible proJ..o:r. mone in kidney and plasma of a patient with Wilm's tumo:c. J. Clin. Endocr., 38: 923, 1974. 22. Day, R. P. and Luetscher, J. A.: Biochemical nr,nrn°rtw~ renin extracted from human plasma. J. 1085, 1975. 23. Melani, F., Ryan, W. G., Rubenstein, A. H. and Steiner, D. F.: Proinsulin secretion by a pancreatic beta-cell adenoma. Proinsulin and C-peptide secretion. New Engl. J. Med., 283: 713, 1970. 24. Gabbay, K. H., DeLuca, K., Fisher, J. N., Jr., Mako, M . E. Rubenstein, A. H.: Familiar hyperproinsulinemia. An somal dominant defect. New Engl. J. Med., 294: 911, 1976. 25. Yalow, R. S. and Berson, S. A.: Size and change distinctions between endogenous human plasma peripheral blood and heptoadecapeptide gastrins. ;i8; 609, 1970.
THE JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
ADENOCARCINOMA OF THE KIDNEY AND HYPERTENSION: REPORT OF 2 CASES WITH SPECIAL EMPHASIS ON RENIN MARCEL LEBEL,* JEAN TALBOT, JOHN GROSE
AND
JEANNINE MORIN
From Le Centre de Nephrologie, Services of Biochimie Medicale and Pathologie, L'Hotel-Dieu de Quebec and l'Universite Laval, Quebec, Canada
ABSTRACT
Renin studies were done on 2 patients with adenocarcinoma of the kidney and hypertension. In 1 case plasma renin activity was high in the peripheral and renaf veins, with a renal vein :ratio of 1.7 favoring the side of the tumor. Neph:rectomy cured the hypertension and renin values became normal. Tissue :renin was elevated in the tumor and surrounding parenchyma. Acidification studies of tissue extracts failed to demonstrate the existence of big renin. In case 2 all renin values were normal and the blood pressure remained elevated after the operation. Although :renin-secreting tumors remain an uncommon cause of malignant hypertension the condition should be recognized because it is potentially curable. The relationship between renal neoplasia and hypertension has interested clinicians for many years 1• 2 Since the last decade it has been recognized that the hypertension associated with renin-secreting tumors is potentially curable. Among them juxtaglomerular ceUH 2 and Wilms 13 • 14 are the most frequently encountered renin-secreting renal tumors. Hollifield and associates described a case of clear
MATERIALS AND METHODS
Case 1. A 42-year-old housewife consulted her family doctor because of violent headaches. Blood pressure was 300/155 and the patient was referred to the emergency room of our tal. She had had 4 pregnancies, 1 of which was a spontaneous abortion. Her doctor had noted the elevated blood pressure the end of the last pregnancy and the patient received diuret
Fm. 1. Case 1. A, early arterial phase of left selective arteriography. B, late arterial phase with early venous retmrn neovascularization.
cell carcinoma of the kidney with manifestations of hypertension and overproduction of renin the tumor. 15 Herein we report on 2 cases of adenocarcinoma of the and hypertension, with special emphasis on peripheral plasma, renal vein and tumor tissue renin determinations.
ics until delivery, which was 18 months before the investigation. The patient had not been followed for blood pressure elevations after delivery. At the current hospitalization physical examination showed a woman who appeared older than her age. Blood was 245/150, with a pulse rate of 120 per minute. examination disclosed bilateral hemorrhage and exudate, and distinct papilledema on the left side (grade IV, ner). There was no clinical evidence of congestive heart ure. Examination of the abdomen revealed a mass with lum·bar contact on the left side. Laboratory investigation showed blood urea nitrogen (BUN)
Accepted for publication December 3, 1976. Presented in part at annual meeting of Canadian Academy of Urology, Quebec City, Quebec, January 21, 1976. Supported by the Quebec Medical Research Council and in part the Pollack Foundation and the Kidney Foundation, Quebec
* Requests for reprints: Le Centre de Nephrologie, L'Hotel-Dieu de Quebec, 11 Cote du Palais, Quebec GIR 2J6, Quebec, Canada. 923
924
LEBEL AND ASSOCIATES
of 19 mg. per 100 ml. and creatinine value of 1.1 mg. per 100 ml., with a slightly decreased clearance at 103 ml. per minute per 1. 73 m. 2 body surface area. Urinalysis revealed 4 to 8 red blood cells per high power field, with a few granular and hyaline casts. No bacteria were found in the culture. A chest radiogram and electrocardiogram showed no cardiac hypertrophy on the left side. A 24-hour urinary excretion of epinephrine, norepinephrine and vanillyl mandelic acid was normal, as were morning and afternoon plasma cortisol and thyroid hormones. Plasma calcium was 9.4 mg. per 100 ml. and plasma potassium was at the lower limit of normal (3.3 mEq. per 1.). Hemoglobin was 12.9 gm. per 100 ml. and white blood count was 4,600 per mm. 3 • Erythrocyte sedimentation rate was 50 mm. in the first hour. There were 2 platelet counts showing thrombocytosis (570,000 and 830,000). Excretory urography (IVP) revealed a large space-occupying lesion in the lower pole of the left kidney compressing the renal pelvis and ureter, with hydronephrosis well demonstrated on the 24-hour film. The right kidney and the bladder were normal. Renal angiography showed a large vascular tumor in the left kidney (fig. 1). There was no stenosis or compression of the renal artery and its main divisions. At operation an 18 by 12 by 8 cm. tumor was found replacing a large part of the kidney and compressing the pelvis and the ureter. The renal vein was not invaded and lymph nodes were not involved. Blood pressure decreased to 126/85 during the week after the operation and remained at that level 2 months later (table 1). Platelet counts returned to normal values. Case 2. A 43-year-old man was referred to our hospital for an extensive investigation of hypertension. The patient had had abnormal blood pressure since he was about 22 years old. In April 1975 blood pressure was 185/120 and his family physician started him on hypotensive drugs after a diagnostic TABLE 1. Preoperative and postoperative blood pressure, serum potassium and upright plasma renin activity (ng. per ml. per hour) in case 1
Blood pressure (mm. Hg) Serum potassium (mEq./1.) Upright plasma renin activity (ng./ml./ hour)
Preop.
9Days Postop.
2Mos. Postop.
190/120
126/85
130/80
3.4
4.3
4.3
52.0
2.9
2.3
study, including an IVP that appeared normal at that time. The blood pressure was not controlled with diuretics and alpha-methyldopa. The patient had no other disease and he was completely asymptomatic. Physical examination showed a healthy man with no evidence of congestive heart failure. Blood pressure was 190/120. Funduscopy revealed grade II (Keith-Wagner) changes. The rest of the examination was normal. Urinalysis did not disclose any microscopic hematuria and no bacteria were found in the culture. Creatinine concentration was 1.1 mg. per 100 ml., BUN 13 mg. per 100 ml. and creatinine clearance rate 122 ml. per minute per 1. 73 m. 2 body surface area. A chest radiogram and electrocardiogram were normal, as were thyroid hormones, urinary epinephrine, norepinephrine and vanillyl mandelic acid excretion. Plasma cortisol, serum potassium, hemoglobin, white blood count, thrombocyte count and erythrocyte sedimentation rate also were normal. A rapid sequence IVP showed slight distortion of calices in the lower pole of the right kidney. Right selective renal arteriography disclosed a well limited 6 cm. lesion in the lower pole of the kidney (fig. 2, A). The administration of epinephrine in the renal artery demonstrated tumor vessels (fig. 2, B). The patient underwent right radical nephrectomy. The high blood pressure improved with rest at the hospital but increased as soon as the patient was at home and it is still elevated. RENIN ASSAYS
Plasma renin activity was determined by a radioimmunoassay of angiotensin I generated during a 1-hour incubation at pH 6.0 using the New England Nuclear kit. We found an excellent correlation between this method 16 and the bioassay approach of Boucher and associates 17 (r equals 0.959, n equals 102, p less than 0.001). Normal values obtained by the present method (n equals 12) are 1.7 plus or minus 0.74 recumbent, 2.52 plus or minus 1.1 after 4 hours of upright posture and 6.6 TABLE
2. Peripheral plasma renin activity (ng. per ml. per hour) in
cases 1 and 2 with normal values Recumbent Upright Intravenous furosemide
Case 1
Case 2
34.6 52.0 53.7
0.38 1.44 8.04
Control Subjects* 1.07 2.5 6.16
0.74 1.1 2.7
* Mean plus or minus standard deviation.
FIG. 2. Case 2. A, right selective arteriography. B, demonstration of tumor vessels after epinephrine injection in renal artery
925
ADENOCARCINOMA OF KIDNEY AND HYPERTENSION
Fm. 3. Case 1. Acidophilic cell carcinoma with marked nuclear pleomorphism and multinucleated cells. Reduced from x 100 TABLE
3. Renal vein renin studies (ng. per ml. per hour)
Left renal vein Right renal vein Inferior vena cava
Case 1
Case 2
49.6* 29.5 31.5
8.64 2.04* 8.7
of Day and associates. 18 The renin content was then measured as described previously for tissue renin. RESULTS
* Side of tumor.
Renin content (ng. per gm. per hour) in different areas of tumor and kidney tissues before and after acidification
TABLE 4.
Case 1
Tumor tissue Adjacent kidney tissue
Case2
Before
After
4,600 0 27,400 56,320 117,000
4,800 0 5,400 60,400 51,600
Before
After
0
0
0 2,000
3,000
0
plus or minus 2. 7 ng. per ml. per hour with upright posture and half an hour after 20 mg. intravenous furosemide (table 2).16
Tissue from tumors and adjacent kidney areas was frozen immediately after excision. For extraction purposes the frozen tissue was weighed, cut into small pieces and homogenized with a Broeck-type hand operated homogenizer in 40 ml. 0.9 per cent sodium chloride solution per gm. frozen weight. After 15 minutes on ice the homogenate was centrifuged at 4C and 3,000 revolutions per minute for 10 minutes. The supernatant was divided into aliquots and kept frozen until the time of incubation. Serial dilutions were made with 0.9 per cent sodium chloride and 0.1 ml. of each dilution was incubated for 3 hours at 37C with 1.0 ml. nephrectomized sheep plasma as substrate. This angiotensin I generation step was done with the same buffer and inhibitors as in the plasma renin activity procedure. Subsequent quantification of angiotensin I by radioimmunoassay was achieved by the same procedure used for plasma renin activity and the results were expressed as renin concentration calibrated against standard human renin (batch 68/356, National Institute for Biological and Control, Holly Hill, London). One unit of the standard renin induced the formation of 98,000 ng. per hour AI using nephrectomized and estrogen-treated sheep plasma as substrate. For big renin studies the tissue extracts were acidified to pH 3.3 with lN hydrochloric acid and dialyzed for 24 hours at 4C using glycine buffer at pH 3.3, according to the approach
Case 1 . Histology under light microscopy showed a tumor comprised of largely acidophilic cytoplasmic cells (fig. 3). An inconspicuous stroma was made up of a fine framework of reticulum fibers containing lymphocytes and capillaries frequently coated with lipophages. There were small foci of necrosis. The tumoral cells were either isolated or arranged in alveolar patterns. The cell volume was extremely variable. Dense cytoplasmic inclusions, not stained by periodic acid, Schiff or Bowie coloration, were observed in some cell populations. There was marked nuclear pleomorphism and frequent monstrosities were present. The chromatin was coarse and contained large nucleoli. The preoperative plasma renin activity level was excessively high, 34.6 in the recumbent posture, 52.0 in the upright posture and 53. 7 mg. per ml. per hour 30 minutes after the intravenous injection offurosemide (table 2). Upright plasma renin activity was determined 9 days and again 2 months postoperatively and showed normal values of 2.9 and 2.3 ng. per ml. per hour, respectively (table 1). Normalization of blood pressure and electrolytes was observed simultaneously (table 1). Left renal vein plasma renin activity (side of the tumor) was 49.6 ng. per ml. per hour. The right renal vein was similar to the inferior vena cava (29.6 versus 31.5) with a ratio (left to right) of 1. 7 favoring the side of the tumor (table 3).
Tissue renin content was measured in 3 different areas of the tumor and 2 of the adjacent kidney tissues. The presence of renin was detected in 2 of 3 areas studied in the tumor, and the results were 4,600 and 27,400 ng. per gm. per hour (table 4) and tissue renin levels determined in 2 different parts of the surrounding kidney tissue were 56,320 and 117,000 ng. per gm. per hour (table 4). Activation of tissue extract by acid pH did not unmask evidence of tumor prorenin or big renin. There was no increase in renin value either in tumor or adjacent kidney tissue after acidification (table 4). Case 2. Histology revealed typical features of clear cell adenocarcinoma. The tumor was comprised of large polygonal cells with optically empty cytoplasm and a fine meshwork delineating vacuoles. Tumoral cells were arranged in tubular,
926
LEBEL AND ASSOCIATES
FIG. 4. Case 2. Electron microscopy of clear cell carcinoma of kidney. LD-lipid droplets. G-glycogen particulates. BM-basement membrane. Inset illustrates microvilli. Reduced from x 12,000.
cord or nest patterns. Nuclei were small and regularly shaped. Nuclear chromatin was fine and usually without any nucleolus. Electron microscopic studies showed tumoral cytoplasm filled with glycogen particulates, lipid vacuoles and a few dense bodies (lysosomes) (fig. 4). Golgi complexes were poorly developed. There were irregular club-shaped microvilli extensions into some luminal spaces (fig. 4, inset). At the base of the cells frequent infoldings of cytoplasmic membrane were observed. Cellular junctions were present and included rare · well formed desmosomes. Preoperative plasma renin activity results were normal either in basal condition (0.38 ng. per ml. per hour) or after orthostatic stimulation (1.44 ng. per ml. per hour) and the intravenous injection of furosemide (8.04 ng. per ml. per hour) (table 2). No abnormal plasma renin activity level was demonstrated in renal veins and the vena cava (table 3). We failed to find any tissue renin in 2 areas of the tumor. A single determination on the normal adjacent tissue was 2,000 ng. per gm. per hour (table 4). These values remained similar after the activation of tissue extract by acid pH (table 4). DISCUSSION
We describe 2 cases o_f adenocarcinoma of the kidney with hypertension, in which renin was studied in plasma, renal vein effluent and tumor tissue. The renin values differ markedly in the 2 patients, suggesting basic etiologic differences for the hypertension. The preoperative hypertension in the first case was associated with excessively elevated plasma renin activity. After removal of the tumor the hypertension and hyperreninemia were normalized, implicating the tumor as the cause of both abnormalities. The mild hypokalemia, probably secondary to the hyperaldosteronism induced by the increased renin release, also was corrected after an operation. In case 2, however, the preoperative plasma renin activity was normal and the hypertension persisted despite removal of the tumor. The hypertension associated with this case was coincidental rather than secondary to the carcinoma. Case 1, with acidophilic adenocarcinoma of the kidney and malignant hypertension, had a recumbent plasma renin activity 18.0 times the upper limit of normal, which increased further with upright posture from 34.6 to 52 ng. per ml. per hour. A similar postural influence on renin has been reported
in juxtaglomerular cell tumor7 and also in a case of clear cell carcinoma of the kidney. 15 This phenomenon indicates that the renin release is not necessarily autonomous in renal tumors. Also, the renal vein renin in case 1 was high. The finding of a positive plasma renin activity gradient (1. 7) from the inferior vena cava to the renal vein ipsilateral to the tumor and no gradient from the contralateral side suggests renin production by the kidney containing the tumor. Therefore, with renal tumors, as in renal artery stenosis, the plasma renin activity ratio of the involved versus contralateral normal kidney and inferior vena cava should be calculated because the half-life of renin is long enough to allow the recirculation of renin secreted by the affected kidney and could, thus, contribute to falsely elevated plasma renin activity in the normal contralateral side. Furthermore, cure of hypertension after nephrectomy is additional evidence that this kidney was responsible for the hypertension. Under these circumstances renin can come from the tumor or adjacent compressed tissue or both. We found the presence of renin in the tumor and also a significant concentration in the surrounding kidney tissue showing the contribution of tumor and compressed tissues to the elevated vein effluent measurements. These tumors, as demonstrated histologically in case 1, contain necrotic zones, which can explain why 1 of 3 areas does not contain renin (table 4). Renal tissue renin content also can vary from area to area; the immediate compressed tissue surrounding the tumor also may contain more renin than the opposite normal pole of the kidney. These observations stress the importance of looking into more than 1 area in tissue studies. Moreover, the tumor can secrete an abnormal product, such as renin of a higher molecular weight, which could be activated in the circulation. Some investigators have demonstrated in animals (rabbits and pigs) an inactive form of renin of a higher molecular weight, the so-called big renin. 19' 20 Day and Luetscher reported a case of Wilms tumor in which a large amount of big renin in plasma and tumor tissue was found. 21 This inactive form of renin has a molecular weight of 63,000 compared to normal renin, which is around 43,000. 22 This molecule can be activated by acid pH 21 , 22 to yield a product that is physiologically and immunologically similar to normal renin. 22 Thus, it may be a prohormone analogous to proinsulin secreted by insulinoma23 and by patients with
ADENOCARCINOlV!A OF KIDNEY AND HYPERTENSION
familiar hyperproinsulinemia 24 or to the large form of gastrin secreted in Zollinger Ellison syndrome. 2 " Using the approach of Day and Luetscher21 to detect big renin in both of our patients we did not find any difference in renin values before and after acidic activation (table 4). In a more extensive and recent study Day a.nd associates found big renin in 2 more cases of Wilms tumor but failed to detect big renin in their case of renal cell carcinoma .18 These findings indicate that renin is not necessarily present in all pathological conditions in which renin is implicated. We -····,-···--"·~- that hypernephroma need not classic features such as hematuria, which was cases. Hypertension can be the unique clue and we stress that treatment of hypertension should not be initiated without investigation. A renin-producing neoplasm be considered in all hypertensive patients vvith unex""''""''-- hyperreninemia. Although it is an uncommon cause the condition should be recognized because it curable. In all tumor tissue studies an attempt to recognize inactive precursors (renin zyrnoand big renin) that might have physiological Mrs. Danieile Lizotte and Miss Danielle Vaugeois provided technical assistance, Mrs. C. Labrecque and Mrs. N. Dumont ·with nursing, Drs. l\lL L. Langis and G. collaborated and Dr. D. R. Bangham ~~.,,.."'·~~. the human renin standards. REFERENCES
L Braasch, W. F., Walters, W. and Hammer, H.J.: Hypertension and the surgical kidney. J.A.M.A., 115: 1837, 1940. 2. Horton, B. T.: The relationship of hypertension to renal neoplasm. Proc. Staff Meet. Mayo Clin., 15: 472, 1940. 3. Robertson, P. W., Klidjian, A., Harding, L. K.) Walters 1 G., Lee, M. A. and Robb-Smith, A. H. T.: Hypertension due to a renin-secreting renal tumour. Amer. J. Med., 43: 963, 1967. 4. I., Kitamura, S., Hoshino, T., Seida, H. and Watanabe, T.: hitherto unreported vascular tumor of the kidney: a proposal of "juxtaglomerular cell tumor". Acta Path. J ap., 18: 197, 1!168. 5, R. L. and Sanchez, S. A.: Renin-secreting renal neoplasm hypertension with hypokalemia. Ann. Intern. Med., 75: 725, 1971. 6. Bonnin, J. M., Hodge, R. L. and Lumbers, E. R.: A. reninsecreting renal tumour associated with hypertension. Aust. N. Zeal. J. Med., 2: 178, 1972. 7. Conn, J. W., Cohen, E. L., Lucas, C. P., McDonald, W. J., H. G., Blough, W. M., Jr., Evelend, W. C., Bookstein, and Lapides, J.: Primary reninism. Hypertension, hyperreninemia, and secondary aldosteronism due to renin-producjuxtaglomerular cell tumors. Arch. Intern. Med., 130: 1972. 8. Schambelan, M., Howes, E. L., Jr,, Stockigt, J. R., Noakes, C. A. and Biglieri, E. G.: Role of renin and aldosterone in hypertension due to a renin-secreting tumor. Amer. J. Med.,
55: 86, 1973. 9. Brown, J. J., Fraser, R., Lever, A. F., Morton, J. J., Robertson, J. I. S., Tree, M., Bell, P.R. F., Davidson, J. K. and Ruthven, I. S.: Hypertension and secondary hyperaldosteronism assod· ated with a renin-secreting renal juxtaglomerular-cell turn.our. Lancet, 2: 1228, 1973. 10. Hirose, M., Arakawa, K., Kikuchi, M., Kawasaki, T., Kato, H. and Nagayama, T.: Primary reninism hamartomatous alteration. J.A.M.A., 230: 1288, 1974. 11. More, I. A., Jackson, A. M. and MacSween, R. N.: Reninsecreting tumor associated with hypertension. Cancer, 2093, 1974. 12. Qhjavik, 0. S., Aas, M., Fauchald, P., Brodwall, E. K. and Flatmark, A.: tumour with severe hypertension. Acta 329, 1975. 13. Mitchell, J. D., Baxter, T. J., Blair·West, J. R. and D. A.: Renin levels in nephroblastoma (Wilms' Report of a renin secreting tumour. Arch. Dis. Child., 376, 1969. 14. Ganguly, A., Gribble, J., Tune, B., Kempson, R. Luetscher, J. A.: Renin-secreting Wilms' tumor with severe hypertension. Report of a case and brief review of reninsecreting tumors. Ann. Intern. Med., 79: 835, J.973. 15. Hollifield, J. W., Page, D. L., Smith, C., Michelakis, NL, Staab, E. and Rhamy, R.: Renin-secreting clear cell carcinom.a of the kidney. Arch. Intern. Med., 135: 859, 1975. 16. Talbot, J., Loiselle, J. M., Page, M. and Belleau, L. J .. JV!esure de l'activite de la renine plasmatique: etude comparative essai biologique et d'un essai radioimmunologique. La ViG Medicale au Canada Fran1,ais., 4: 37, 1975. 17. Boucher, R., Veyrat, R., De Champlain, J, and Genest, J.: New procedures for measurement of human plasma angi.otensin and renin activity levels. Canad. Med. Ass. J., 90: 194, J.964. 18. Day, R. P., Luetscher, J. A. and Gonzales, C. M.: Occurrence of big renin in human plasma, amniotic fluid and kidney extracts. J. Clin. Endocr., 40: 1078, 1975. 19. Leckie, B. J. and McConnell, A.: A renin inhibitor from rabbit kidney: conversion of a large inactive renin to a smaller active enzyme. Circ. Res., 36: 513, 1975. 20. Boyd, G. W.: A protein-bound form of porcine renal renin. Res., 35: 426, 1974. 21. Day, R. P. and Luetscher, J. A.: Big :renin: a possible proJ..o:r. mone in kidney and plasma of a patient with Wilm's tumo:c. J. Clin. Endocr., 38: 923, 1974. 22. Day, R. P. and Luetscher, J. A.: Biochemical nr,nrn°rtw~ renin extracted from human plasma. J. 1085, 1975. 23. Melani, F., Ryan, W. G., Rubenstein, A. H. and Steiner, D. F.: Proinsulin secretion by a pancreatic beta-cell adenoma. Proinsulin and C-peptide secretion. New Engl. J. Med., 283: 713, 1970. 24. Gabbay, K. H., DeLuca, K., Fisher, J. N., Jr., Mako, M . E. Rubenstein, A. H.: Familiar hyperproinsulinemia. An somal dominant defect. New Engl. J. Med., 294: 911, 1976. 25. Yalow, R. S. and Berson, S. A.: Size and change distinctions between endogenous human plasma peripheral blood and heptoadecapeptide gastrins. ;i8; 609, 1970.