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Severe hypertension and elevated plasma renin activity following transplantation of “hepatorenal donor” kidneys into anephric recipients
Severe Hypertension and Elevated Plasma Renin Activity Following Transplantation of “Hepatorenal Donor” Kidneys into Anephric Recipients
FRANKLIN LEONARD JEREMIAH
D. MCDONALD, A. BRENNAN, G. TURCOTTE,
M.D.* M.D.t M.D.
Ann Arbor, Michigan
From the Departments of Internal Medicine, Physiology and Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48104. This study was supported by a grantin-aid from The American Heart Association, a grant from The Michigan Kidney Foundation and U.S. Public Health Service Grant No. 5MOlR142-12. Send requests for reprints to Dr. Franklin D. McDonald, Renal Section, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48104. Manuscript received October 18, 1971. *Present address: Nephrology Division, Wayne State University School of Medicine, Hutzel Hospital, 432 East Hancock Avenue, Detroit, Michigan 48201. TFormer Fellow of The Michigan Kidney Foundation. Present address: The Mayo Clinic and Foundation. Rochester, Minnesota.
Acute, severe hypertension was observed immediately after the transplantation of the kidneys of a “hepatorenal donor” into two anephric patients. Extremely high levels of plasma renin activity were found in both recipients. The transplantation of “high renin kidneys” into high substrate circulations likely explains this observation. It is viewed as the human counterpart of the increased sensitivity of anephric animals to injected renin. Despite minimal and inconsistent pathologic abnormalities of the kidney [l-4], patients with severe liver disease often have progressive, oliguric renal failure [5-121. It has been suggested that this “hepatorenal syndrome” is the result of a functional and reversible abnormality of renal hemodynamics [10,13]. The reversibility has been confirmed by the successful functioning of kidneys from “hepatorenal” donors after homotransplantation [14]. None of the recipients became severly hypertensive after the transplant, but only one had been nephrectomized beforehand [15]. We observed two patients who were anephric five and eight weeks, respectively, before receiving the kidneys of a “hepatorenal” donor. Acute, severe hypertension developed in each after the vascular clamps were removed. The plasma renin activity levels in both were markedly elevated at this time. We will show how the dynamics of the renin-angiotension system in the and in the nephrectomized human “hepatorenal syndrome” help to explain these observations. MATERIAL AND METHODS Renin activity was determined in peripheral venous plasma samples by rat bioassay. Concentration and purification of the samples were carried out as described by Brubacher and Vander [16]. The normal values for volunteers, fasted in the morning and after at least 30 minutes of quiet sitting, are 4.3 f 0.33 (standard error of the mean [SEMI) ng/ml after three to four days on a 120 meq sodium diet and 9.4 f 1.1 ng/ml after seven days on a 9 meq sodium diet. Other chemical determinations were performed using the AutoanalyzeP (Technicon).
Donor For six years prior to his death, the donor (V.M.S., AAVAH No. 38407-18-14) a 53 year old white male alcoholic, had been treated with diuretics because of edema associated with hepatic cirrhosis. He
January 1973
The American
Journal of Medicine
Volume 54
39
HYPERTENSION
FOLLOWING
TRANSPLANTATION
Methyldapa25CImgI.v.
1
;! 60
L
20 t
Dlazaxlde150mgI v rMethyldopo 500mg I.v
iVessels Unclamped
tv
? 2
OF “HEPATORENAL
6 8 IO HOURS AFTER INDUCTIONOF ANESTHESIA
12
Figure 1. Case 1. Changes in blood pressure and shortly after transplant procedure.
during
entered
Hospi-
the Ann
Arbor
tal on September cites
and
found
to
omas,
edema have
massive
Veterans’
13, 1970, resistant scleral ascites
Administration
because to diuretic
icterus, and
of increasing therapy.
cutaneous peripheral
as-
He was
spider edema,
angiand
a
venous pattern. The blood urea nitrogen level was 71 mg/lOO ml, serum creatinine 2.6 mg/lOO ml, serum bilirubin 3.7 mg/lOO ml and the serum glutamic oxaloacetic transaminase (SGOT) 102 U/ml. Despite vigorous treatment with diuretics and fluid and sodium restriction, his urinary output decreased and his mental status deteriorated. He vomited blood and became comatose. Two days before his death the urinary output was less than 200 ml/day. The blood urea nitrogen was 139 mg/lOO ml, serum creatinine 7.4 mg/lOO ml and serum bilirubin 12 mg/ 100 ml. The urine specific gravity was 1.040. He died on October 9, and his kidneys were donated to the patients to be described. Postmortem examination confirmed the diagnosis of cirrhosis and, in addition, a previously unsuspected focus of hepatocellular carcinoma wasdound. prominent
abdominal
Recipients Case 1. This patient (H.H., UMMC No. 1183126) was a 27 year old white woman with a history of hypertension during each of her four pregnancies within the previous nine years. In 1969, at the time of a therapeutic abortion, her renal function was said to be normal despite a blood pressure of 200/150 mm Hg. In April 1970, she was admitted elsewhere with fatigue, nausea, vomiting and dyspnea. The blood pressure was 220/160 mm Hg and fell to 200/120 mm Hg with hydralazine therapy. The blood urea nitrogen level rose from 83 to 115 mg/lOO ml during her hospitalization. She was transferred to The University of Michigan Medical Center on May 9, 1970. Her blood pressure was 220/125 mm Hg. Physical ‘examination showed cardiomegaly, a protodiastolic gallop, papilledema,
40
January
1973
The American Journal of Medicine
DONOR”
KIDNEYS-MCDONALD
ET AL.
scattered wheezes throughout the lungs, a slightly enlarged liver and a trace of pedal edema. Serum creatinine was 20.7 mg/lOO ml. She was treated with peritoneal dialysis, methyldopa, hydrochlorothiazide and hydralazine. She was discharged, improved, on May 27 with a standing blood pressure of 140/105 mm Hg. Symptomatic uremia and hypertension persisted despite intensive therapy, and she had a weight loss of 20 pounds over the next two months. Plasma renin activity on August 28 was 19.8 ng/ml. On September 2 a bilateral nephrectomy was performed without complications. Her blood pressure was then easily controlled and the plasma renin activity fell to 0.35 ng/ml. On October 9 she received a kidney from the donor described. During induction of anesthesia her blood pressure rose to 190/130 mm Hg but shortly after the procedure was begun it fell to 140/100 mm Hg without specific therapy. Immediately after the vascular anastomosis was completed, there was an acute and persistent elevation in the blood pressure (Figure 1). Ventricular tachycardia developed and was successfully reverted to sinus rhythm with the intravenous administration of lidocaine. Within three hours of the vascularization of the transplant plasma renin activity was 86.3 ng/ml. The blood pressure was lowered by intravenous administration of diazoxide and methyldopa. Hemodialysis was continued intermittently and was terminated 19 days after the transplant at which time renal function was satisfactory. Initially daily administration of methyldopa, 500 mg orally, was necessary to control the blood pressure, but as renal function improved this was discontinued and the blood pressure remained in the normal range. A percutaneous renal biopsy specimen obtained on November 10 showed glomerular sclerosis and periglomerular fibrosis. At this time plasma renin activity was 3.7 ng/ml. The patient was discharged on November 15 on an immunosuppressive program, but she was rehospitalized in December 1970, for treatment of thrombophlebitis. In March 1971, an emergency laparotomy and repair of a perforated gastric ulcer were performed. In the postoperative period bilateral staphylococcal pneumonia developed which was treated with vancomycin. A spontaneous pneumothorax necessitated placement of a chest tube. Upper gastrointestirial bleeding recurred and the patient died on April 6, 1971. At autopsy the kidneys microscopically showed evidence of moderate cellular rejection in addition to the findings already described. The renal vessels were patent and the anastomosis uncompromised. 2. This patient was a 51 year old black man (D.R., UMMC No. 1182792) with a 10 year history of untreated hypertension. He had been hospitalized elsewhere in February 1970 for symptoms of peripheral edema and dyspnea. At that time his blood pressure was 210/150 mm Hg. Cardiomegaly, peripheral edema, ascites and bilateral pulmonary rales were found. He was treated with digitalis, diuretics and antihypertensives. His condition improved and he was discharged with a serum creatinine value of 8.3 mg/ Case
Volume 54
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TRANSPLANTATION
100 ml and a blood urea nitrogen level of 96 mg/lOO ml. In April a peritoneal dialysis was performed. Two months later he was admitted to The University of Michigan Medical Center with symptoms of uwmia. His blood pressure was 240/120 mm Hg lying and 220/110 mm Hg standing. Physical examination disclosed hypertensive retinopathy, cardiac enlargement and peripheral sensory neuropathy. The hematocrit was 20 per cent, blood urea nitrogen 135 mg/lOO ml, serum creatinine 18 mg/lOO ml and the urine culture was negative. A 24-hour creatinine clearance was 3 ml/minute. On June 23, a regular program of hemodialysis was begun. Hypertension was no problem once regular hemodialysis was started. On July 19 a bilateral nephrectomy was performed and the patient received a cadaver kidney. On August 14 the transplanted kidney had to be removed because of deteriorating function and hemodialysis was restarted. On October 9 he received one of the kidneys of the donor described. Shortly after the vascular clamps were removed and the circulation to the transplant was begun there was an acute elevation of the blood pressure (Figure 2). Within three hours of the transplant, the plasma renin activity was 91 ng/ml. The hypertension responded well to the intramuscular administration of hydralazine. Although the blood pressure level remained moderately elevated for three days, no further treatment was required. Regular hemodialysis was continued and the urinary output increased. On October 25 the immunosuppressive program was stopped when a pneumonia developed which did not respond to antibiotic therapy. At this time the plasma renin activity was 3.9 ng/ml of plasma. Aerobatter aerogenes and Pseudomonas aeruginosa were cultured from the sputum. Renal function deteriorated thereafter and on November 16, the patient died. Postmortem examination revealed bilateral pneumonitis with cavitation and abscess formation. Cytomegalovirus was cultured from both lungs. The kidney showed marked interstitial edema with early fibrosis and a marked interstitial infiltrate composed of lymphocytes, plasma cells and polymorphonuclear leukocytes. No compromise of the vascular anastomosis or renal arteries was seen. COMMENTS the histologic lesions of the kidneys of patients with renal failure accompanying severe liver disease may be characteristic [l-3], they are neither specific nor universal. It is difficult then to ascribe to them critical pathogenetic significance. It is, however, widely accepted that renal blood flow and glomerular filtration rate are reduced in the “hepatorenal syndrome” [5-l 31 and systemic blood pressure tends to be low terminally [12]. Variable results are reported for plasma volume [7-9,121, blood volume [17] and cardiac output [5,7,11]. Certainly these data cannot be marshalled in a universal explanation of the altered Although
OF “HEPATORENAL
DONOR”
KIDNEYS-MCDONALD
Hydmlozlne20mg Iim
I” 240 r
LVessek
d
g w
40
ET AL.
Unclamped
t
kzo;,.,,...,.,.,,..,. 2 HOURS AFTER
3
INDUCTION
4 OF ANESTHESIA
Figure 2. Case 2. Changes in blood pressure and shortly after transplant procedure.
6
0
IO
during
renal hemodynamics. The concept of reduced effective plasma volume has been introduced to explain these [4], but this, too, does not enjoy universal acceptance [18]. Schroeder et al. [lo] studied the clearance and extraction of paraaminohippurate (PAH) in patients with this syndrome. They suggested that there is a decrease in blood flow to the renal cortex and perhaps an increase in medullary flow. Epstein et al. [13] confirmed the reduction in cortical blood flow rate and distribution by application of the 133Xenon washout technic. Indeed, there was a clear inverse correlation between the percentage of flow to the cortical zone and the severity of renal functional impairment. Further, two lines of evidence suggest that the renal hemodynamic abnormalities identified are both functional and reversible: (1) Angiographic abnormalities observed in these patients were not present when the studies were repeated postmortem, and (2) there was marked hemodynamic instability in this group suggested by continually changing disappearance rates during the 133Xenon curves. Finally, it was suggested that the hemodynamic abnormalities identified in their study were the result of active vasoconstriction, but failure to reverse them with intrarenal arterial infusion of phentolamine diminished the likelihood of a participation in this of the sympathetic nervous system or circulating catecholamines. The reversible nature of the renal hemodynamic and functional abnormalities is confirmed by the successful function of transplants taken from “hepatorenal” donors in the hands of Koppel et al. [14] as well as our experience with patient H.H. (Case 1). In our patient D.R. (Case 2) renal function also seemed to be improving when his immunosuppressive agents were radically modified in an attempt to treat his pneumonia. Hartroft and Hartroft [I91 showed that in patients with cirrhosis and ascites the juxtaglomerular index is higher
January 1973
The American Journal of Medicine
Volume 54
41
HYPERTENSION FOLLOWING TRANSPLANTATION OF “HEPATORENAL DONOR” KIDNEYS-MCDONALD
than that in normal subjects. Ayers [20] has shown that the plasma renin activity level of such patients is about fourfold higher and the renin substrate concentration about 50 per cent lower than in control subjects. These findings were confirmed by Schroeder et al. [17], who also found a correlation between plasma renin activity and the severity of renal functional impairment. It has been known that the nephrectomized animal has an increased sensitivity to injected renin [21-281, but not to angiotension nor norepinephrine [24,28]. Blaquier et al. [24] showed that the response was not only greater but also more prolonged and associated with a higher plasma angiotension Ii level. Also, when the plasma of a nephrectomized animal was given to a normal animal, the blood pressure response to a dose of renin was greater than when the plasma of a normal rat was given beforehand [24]. Confirmation of a humoral factor responsible for this came from the studies of Bing and Magill [28], which showed that the normal and nephrectomized rats of a cross-circulated pair had similarly increased sensitivity to injected renin and increased in vitro angiotension generation after addition of exogenous renin to the plasma. When plasma from nephrectomized animals was given to normal rats their response to exogenous re,nin was greater than when they were given plasma from normal rats. It is now well accepted that the plasma renin activity is lower and the plasma renin substrate concentration is 5 to 15 times higher within a few hours of nephrectomy in experimental animals and man [22,25,26,29-391. It is generally agreed that the augmented pressor response to renin injection in animals under these circumstances is accounted for, at least in part, by the high plasma substrate concentration [25,27,35,36]. However, considerable debate continues regarding whether or not this augmentation is modified either by a decrease in plasma angiotensinase after nephrectomy [22,24,29], or by a change in the velocity of the renin-substrate reaction [24-26,36,38]. With this background we ought to be able to offer an explanation for the acute, severe hypertension observed in our patients immediately after the transplanted kidneys became part of the general circulation. The donor surely had the “hepatorenal syndrome.” It is almost certain then that he had high plasma [17,20] and renal renin
ET AL
levels [19]. We are unable to decide to what extent the elevated plasma angiotensinase level described by Hirasawa [40] and suggested by Laragh et al. [41] contributed to his hypotension. The recipients, on the other hand, had been nephrectomized five and eight weeks before the transplant. In only patient H.H. (Case 1) was plasma renin activity measured between nephrectomy and transplant. It is likely that the level was quite low in both and that both had rather high renin substrate levels. We postulate that what followed the transplants was an exact human counterpart of the experiments described herein, in which exogenous renin given to nephrectomized animals, causes severe hypertension. Here, “high renin kidneys” were placed into “high substrate circulations.” The extremely high plasma renin activity values in each patient within a few hours after the transplant support this hypothesis. Within 24 hours the transplanted kidney can secrete renin [42,43]. Further, the levels seen with early rejection [31,32,43,44] or acute tubular necrosis [31] after transplantation are not of the magnitude seen in our two patients. Indeed, neither of these phenomena is necessarily associated with augmented plasma renin activity [32]. Finally, it is not possible to explain the acute hypertension in these patients on the basis of administration of pressor agents since they received none. Nor can it be explained by inappropriate blood or fluid replacement during the procedure. We are most conservative with fluid replacement during surgery in these patients until it becomes clear whether or not renal function has been established. Also, the central venous pressure and body weight failed to rise. The present observation of acute severe hypertension immediately after vascular anastomosis in two anephric patients who received the kidneys of a “hepatorenal” donor should not deter the use of this source of kidney donors. One should be prepared for this complication which did result in a potentially fatal arrhythmia in one of our patients and could result in acute heart failure. Early treatment should control the hypertension and prevent the latter two complications. ACKNOWLEDGMENT We gratefully acknowledge the editorial advice of Drs. John M. Weller, Richard Malvin and Paul Churchill and the secretarial assistance of Mrs. Elizabeth Cord.
REFERENCES 1.
42
Fisher ER, Perez-Stable
E: Cirrhotic (hepatic) lobular glomerulonephritis: correlation of ultrastructural and clinical features. Amer J Med 52: 869, 1968.
2.
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of Medicine
Volume
Bloodworth JMB, Sommers SC: “Cirrhotic glomerulorenal lesion associated with hepatic cirsclerosis,” rhosis. Lab Invest 8: 962, 1959.
HYPERTENSION FOLLOWING TRANSPLANTATION OF “HEPATORENAL DONOR” KIDNEYS--MCDONALD
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Salomon MI, Sakaguchi H, Churg J, Dachs S, Grishman E, Mautner W, Paronetto F, Rosenthal WS: Renal lesions in hepatic disease. A study based on kidney biopsies. Arch Intern Med (Chicago) 115: 704. 1965. Papper S: The role of the kidney in Laennec’s cirrhosis of the liver. Medicine 37: 299, 1958. Lancestremere RG, Davidson PL, Earley LE. O’Brien FJ, Papper S: Renal failure in Laennec’s cirrhosis. Il. Simultaneous determination of cardiac output and renal hemodynamics. J Clin Invest 41: 1922, 1962. Baldus WP, Summerskill WHJ, Hunt JC, Maher FT: Renal circulation in cirrhosis: observations based on catheterization of the renal vein. J Clin Invest 43: 1090,1964. Tristani FE, Cohn JN: Systemic and renal hemodynamits in oliguric hepatic failure: effect of volume expansion. J Clin Invest 46: 1894, 1967. McCloy RM, Baldus WP, Tauxe WN, Summerskill WHJ: Plasma volume and renal circulatory function in cirrhosis. Ann Intern Med 66: 307, 1967. Reynolds TB, Lieberman FL, Redeker AG: Functional renal failure with cirrhosis: the effect of plasma expansive therapy. Medicine 46: 191, 1967. Schroeder ET, Shear L. Sancetta SM, Gabuzda GJ: Renal failure in patients with cirrhosis of the liver. III. Evaluation of intrarenal blood flow by paraaminohippurate extraction and response to angiotensin. Amer J Med 43: 887, 1967. Shear L, Hall PW, Gabuzda GJ: Renal failure in patients with cirrhosis of the liver. Il. Amer J Med 39: 199,1965. Papper S, Vaamonde CA: Renal failure in cirrhosis-role of plasma volume. Ann Intern Med 68: 958, 1968. Epstein M, Berk DP, Hollenberg NK, Adams DF. Chalmers TC. Abrams HL, Merrill JP: Renal failure in the patient with cirrhosis. Amer J Med 49: 174, 1970. Koppel MH, Coburn HW, Mims MM, Goldstein H, Boyle JD, Rubini ME: Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. New Eng J Med 280: 1367, 1969. Koppel MH: Personal communication. Brubacher ES, Vander AJ: Sodium deprivation and renin secretion in unanesthetized dogs. Amer J Physiol 214: 15, 1968. Schroeder ET, Eich RH, Smulyan H, Gould AB, Gabuzda GJ: Plasma renin levels in hepatic cirrhosis: relation to functional renal failure. Amer J Med 49: 186,197O. Lieberman FL, Ito S, Reynolds TB: Effective plasma volume in cirrhosis with ascites: evidence that a decreased value does not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), and a fall in GFR during drug-induced diuresis. J Clin Invest 48: 975, 1969. Hartroft WS, Hartroft PM: New approaches in the study of cardiovascular disease: aldosterone, renin. hypertensin and juxtoglomerular cells. Fed Proc 20: 845, 1961. Ayers CR: Plasma renin activity and renin substrate concentration in patients with liver disease. Circ Res 20: 594, 1967. Merrill A, Williams JR, Harrison JR: The site of action of the renal pressor substance. Amer J Med Sci 196: 18, 1938. Collins DA, Harakal CD: Changes in hypertensinase and hypertensinogen following nephrectomy. Circ Res 2: 196, 1954. Freedman A: Response to renin of unanesthetized normal and nephrectomized rats. Amer Heart J 20: 304, 1940.
January
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Blaquier P, Hoobler SW, Schroeder J, Gomez A, Kreulen T: Effect of bilateral nephrectomy and pressor response to renin. Amer J Physiol 203: 339, 1962. Blaquier P: Kinetic studies on renin-angiotensinogen reaction after nephrectomy. Amer J Physiol 208: 1083, 1965. Blaquier P, Basso N. de la Riva I: Kinetics of reninrenin substrate. Circ Res 20-21 (suppl II): 109, 1967. Bing J: Mechanism of the increased sensitivity to renin in nephrectomized animals. Acta Path Microbial Stand 60: 311,1964. Bing J, Magill F: Potentiation of sensitization to renin in normal rats by cross circulation with nephrectomized. Acta Path Microbial Stand 59: 485, 1963. Blair-West Jr, Coghlan JP, Denton DA, Scoggins BA, Wintour M, Wright RD: The renin angiotensin aldosterone system in sodium depletion. Med J Aust 2: 290, 1967. Haber E; Recent developments in pathophysiologic studies of the renin-angiotensin system. New Eng J Med 280: 148, 1969. West TH. Turcotte JG, Vander A: Plasma renin activity, sodium balance, and hypertension in a group of renal transplant recipients. J Lab Clin Med 73: 564, 1969. Blaufox MD, Birbari AE, Hickler RB, Merrill JP: Peripheral plasma renin activity in renal-homotransplant recipients. New Eng J Med 275: 1165, 1966. Vertes V, Cangiano JL, Berman LB, Gould A: Hypertension in end stage renal disease. New Eng J Med 280: 978, 1969. Hirasawa K. Yamamoto H, Matsui A, Shinozaki K, Kobayashi S. Yagi Y, Morimoto S, Takeda R, Murakami M: The effect of mercuric, chloride, of bilateral ureteral ligation and of bilateral nephrectomy on plasma renin substrate concentration in rats. Jap Circ J 32: 1591, 1968. Sokabe H, Shibayama BP, Mizogami S, Sakai F: Cardiovascular reactivity after bilateral nephrectomy in rats. Jap Heart J 6: 233, 1965. Montague D: Kinetics of renin-angiotensin reaction in plasma of normal and nephrectomized rats. Amer J Physiol 215: 78, 1968. Carretero 0, Gross F: Renin substrate in plasma under various experimental conditions in the rat. Amer J Physiol. 213: 695, 1967. Carretero 0. Gross F: Evidence for humoral factors participating in the renin-substrate reaction. Circ Res 20-21 (suppl I I): 115, 1967. Merrill JP, Schupak E: Mechanisms of hypertension in renoprival man. Canad Med Ass J 90: 328,1964. Hirasawa K: Studies on renin-angiotensin system. I. Studies on angiotensinase activity in liver diseases. Jap Circ J 32: 407, 1968. Laragh H, Cannon PJ, Ames RP: Interaction between aldosterone secretion, sodium and potassium balance, and angiotensin activity in man: Studies in hypertension and cirrhosis. Canad Med Ass J 90: 248, 1964. Gunnells JC, Stickel DL. Robinson RR: Episodic hypertension associated with positive renin assays after renal transplantation. New Eng J Med 274: 543, 1966. Abbrecht PH, Turcotte JG, Vander AJ: Plasma erythropoietin and renin activity after canine renal allotransplantation. J Lab Clin Med 71: 766, 1968. Abbrecht PH, Vander AJ, Turcotte JG: Effects of saline loading on the renin, erythropoietin. and blood pressure responses to canine renal allotransplantation. Circ Res 25: 99, 1969.
The American
Journal of Medicine
Volume 54
43
FRANKLIN LEONARD JEREMIAH
D. MCDONALD, A. BRENNAN, G. TURCOTTE,
M.D.* M.D.t M.D.
Ann Arbor, Michigan
From the Departments of Internal Medicine, Physiology and Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48104. This study was supported by a grantin-aid from The American Heart Association, a grant from The Michigan Kidney Foundation and U.S. Public Health Service Grant No. 5MOlR142-12. Send requests for reprints to Dr. Franklin D. McDonald, Renal Section, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48104. Manuscript received October 18, 1971. *Present address: Nephrology Division, Wayne State University School of Medicine, Hutzel Hospital, 432 East Hancock Avenue, Detroit, Michigan 48201. TFormer Fellow of The Michigan Kidney Foundation. Present address: The Mayo Clinic and Foundation. Rochester, Minnesota.
Acute, severe hypertension was observed immediately after the transplantation of the kidneys of a “hepatorenal donor” into two anephric patients. Extremely high levels of plasma renin activity were found in both recipients. The transplantation of “high renin kidneys” into high substrate circulations likely explains this observation. It is viewed as the human counterpart of the increased sensitivity of anephric animals to injected renin. Despite minimal and inconsistent pathologic abnormalities of the kidney [l-4], patients with severe liver disease often have progressive, oliguric renal failure [5-121. It has been suggested that this “hepatorenal syndrome” is the result of a functional and reversible abnormality of renal hemodynamics [10,13]. The reversibility has been confirmed by the successful functioning of kidneys from “hepatorenal” donors after homotransplantation [14]. None of the recipients became severly hypertensive after the transplant, but only one had been nephrectomized beforehand [15]. We observed two patients who were anephric five and eight weeks, respectively, before receiving the kidneys of a “hepatorenal” donor. Acute, severe hypertension developed in each after the vascular clamps were removed. The plasma renin activity levels in both were markedly elevated at this time. We will show how the dynamics of the renin-angiotension system in the and in the nephrectomized human “hepatorenal syndrome” help to explain these observations. MATERIAL AND METHODS Renin activity was determined in peripheral venous plasma samples by rat bioassay. Concentration and purification of the samples were carried out as described by Brubacher and Vander [16]. The normal values for volunteers, fasted in the morning and after at least 30 minutes of quiet sitting, are 4.3 f 0.33 (standard error of the mean [SEMI) ng/ml after three to four days on a 120 meq sodium diet and 9.4 f 1.1 ng/ml after seven days on a 9 meq sodium diet. Other chemical determinations were performed using the AutoanalyzeP (Technicon).
Donor For six years prior to his death, the donor (V.M.S., AAVAH No. 38407-18-14) a 53 year old white male alcoholic, had been treated with diuretics because of edema associated with hepatic cirrhosis. He
January 1973
The American
Journal of Medicine
Volume 54
39
HYPERTENSION
FOLLOWING
TRANSPLANTATION
Methyldapa25CImgI.v.
1
;! 60
L
20 t
Dlazaxlde150mgI v rMethyldopo 500mg I.v
iVessels Unclamped
tv
? 2
OF “HEPATORENAL
6 8 IO HOURS AFTER INDUCTIONOF ANESTHESIA
12
Figure 1. Case 1. Changes in blood pressure and shortly after transplant procedure.
during
entered
Hospi-
the Ann
Arbor
tal on September cites
and
found
to
omas,
edema have
massive
Veterans’
13, 1970, resistant scleral ascites
Administration
because to diuretic
icterus, and
of increasing therapy.
cutaneous peripheral
as-
He was
spider edema,
angiand
a
venous pattern. The blood urea nitrogen level was 71 mg/lOO ml, serum creatinine 2.6 mg/lOO ml, serum bilirubin 3.7 mg/lOO ml and the serum glutamic oxaloacetic transaminase (SGOT) 102 U/ml. Despite vigorous treatment with diuretics and fluid and sodium restriction, his urinary output decreased and his mental status deteriorated. He vomited blood and became comatose. Two days before his death the urinary output was less than 200 ml/day. The blood urea nitrogen was 139 mg/lOO ml, serum creatinine 7.4 mg/lOO ml and serum bilirubin 12 mg/ 100 ml. The urine specific gravity was 1.040. He died on October 9, and his kidneys were donated to the patients to be described. Postmortem examination confirmed the diagnosis of cirrhosis and, in addition, a previously unsuspected focus of hepatocellular carcinoma wasdound. prominent
abdominal
Recipients Case 1. This patient (H.H., UMMC No. 1183126) was a 27 year old white woman with a history of hypertension during each of her four pregnancies within the previous nine years. In 1969, at the time of a therapeutic abortion, her renal function was said to be normal despite a blood pressure of 200/150 mm Hg. In April 1970, she was admitted elsewhere with fatigue, nausea, vomiting and dyspnea. The blood pressure was 220/160 mm Hg and fell to 200/120 mm Hg with hydralazine therapy. The blood urea nitrogen level rose from 83 to 115 mg/lOO ml during her hospitalization. She was transferred to The University of Michigan Medical Center on May 9, 1970. Her blood pressure was 220/125 mm Hg. Physical ‘examination showed cardiomegaly, a protodiastolic gallop, papilledema,
40
January
1973
The American Journal of Medicine
DONOR”
KIDNEYS-MCDONALD
ET AL.
scattered wheezes throughout the lungs, a slightly enlarged liver and a trace of pedal edema. Serum creatinine was 20.7 mg/lOO ml. She was treated with peritoneal dialysis, methyldopa, hydrochlorothiazide and hydralazine. She was discharged, improved, on May 27 with a standing blood pressure of 140/105 mm Hg. Symptomatic uremia and hypertension persisted despite intensive therapy, and she had a weight loss of 20 pounds over the next two months. Plasma renin activity on August 28 was 19.8 ng/ml. On September 2 a bilateral nephrectomy was performed without complications. Her blood pressure was then easily controlled and the plasma renin activity fell to 0.35 ng/ml. On October 9 she received a kidney from the donor described. During induction of anesthesia her blood pressure rose to 190/130 mm Hg but shortly after the procedure was begun it fell to 140/100 mm Hg without specific therapy. Immediately after the vascular anastomosis was completed, there was an acute and persistent elevation in the blood pressure (Figure 1). Ventricular tachycardia developed and was successfully reverted to sinus rhythm with the intravenous administration of lidocaine. Within three hours of the vascularization of the transplant plasma renin activity was 86.3 ng/ml. The blood pressure was lowered by intravenous administration of diazoxide and methyldopa. Hemodialysis was continued intermittently and was terminated 19 days after the transplant at which time renal function was satisfactory. Initially daily administration of methyldopa, 500 mg orally, was necessary to control the blood pressure, but as renal function improved this was discontinued and the blood pressure remained in the normal range. A percutaneous renal biopsy specimen obtained on November 10 showed glomerular sclerosis and periglomerular fibrosis. At this time plasma renin activity was 3.7 ng/ml. The patient was discharged on November 15 on an immunosuppressive program, but she was rehospitalized in December 1970, for treatment of thrombophlebitis. In March 1971, an emergency laparotomy and repair of a perforated gastric ulcer were performed. In the postoperative period bilateral staphylococcal pneumonia developed which was treated with vancomycin. A spontaneous pneumothorax necessitated placement of a chest tube. Upper gastrointestirial bleeding recurred and the patient died on April 6, 1971. At autopsy the kidneys microscopically showed evidence of moderate cellular rejection in addition to the findings already described. The renal vessels were patent and the anastomosis uncompromised. 2. This patient was a 51 year old black man (D.R., UMMC No. 1182792) with a 10 year history of untreated hypertension. He had been hospitalized elsewhere in February 1970 for symptoms of peripheral edema and dyspnea. At that time his blood pressure was 210/150 mm Hg. Cardiomegaly, peripheral edema, ascites and bilateral pulmonary rales were found. He was treated with digitalis, diuretics and antihypertensives. His condition improved and he was discharged with a serum creatinine value of 8.3 mg/ Case
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100 ml and a blood urea nitrogen level of 96 mg/lOO ml. In April a peritoneal dialysis was performed. Two months later he was admitted to The University of Michigan Medical Center with symptoms of uwmia. His blood pressure was 240/120 mm Hg lying and 220/110 mm Hg standing. Physical examination disclosed hypertensive retinopathy, cardiac enlargement and peripheral sensory neuropathy. The hematocrit was 20 per cent, blood urea nitrogen 135 mg/lOO ml, serum creatinine 18 mg/lOO ml and the urine culture was negative. A 24-hour creatinine clearance was 3 ml/minute. On June 23, a regular program of hemodialysis was begun. Hypertension was no problem once regular hemodialysis was started. On July 19 a bilateral nephrectomy was performed and the patient received a cadaver kidney. On August 14 the transplanted kidney had to be removed because of deteriorating function and hemodialysis was restarted. On October 9 he received one of the kidneys of the donor described. Shortly after the vascular clamps were removed and the circulation to the transplant was begun there was an acute elevation of the blood pressure (Figure 2). Within three hours of the transplant, the plasma renin activity was 91 ng/ml. The hypertension responded well to the intramuscular administration of hydralazine. Although the blood pressure level remained moderately elevated for three days, no further treatment was required. Regular hemodialysis was continued and the urinary output increased. On October 25 the immunosuppressive program was stopped when a pneumonia developed which did not respond to antibiotic therapy. At this time the plasma renin activity was 3.9 ng/ml of plasma. Aerobatter aerogenes and Pseudomonas aeruginosa were cultured from the sputum. Renal function deteriorated thereafter and on November 16, the patient died. Postmortem examination revealed bilateral pneumonitis with cavitation and abscess formation. Cytomegalovirus was cultured from both lungs. The kidney showed marked interstitial edema with early fibrosis and a marked interstitial infiltrate composed of lymphocytes, plasma cells and polymorphonuclear leukocytes. No compromise of the vascular anastomosis or renal arteries was seen. COMMENTS the histologic lesions of the kidneys of patients with renal failure accompanying severe liver disease may be characteristic [l-3], they are neither specific nor universal. It is difficult then to ascribe to them critical pathogenetic significance. It is, however, widely accepted that renal blood flow and glomerular filtration rate are reduced in the “hepatorenal syndrome” [5-l 31 and systemic blood pressure tends to be low terminally [12]. Variable results are reported for plasma volume [7-9,121, blood volume [17] and cardiac output [5,7,11]. Certainly these data cannot be marshalled in a universal explanation of the altered Although
OF “HEPATORENAL
DONOR”
KIDNEYS-MCDONALD
Hydmlozlne20mg Iim
I” 240 r
LVessek
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g w
40
ET AL.
Unclamped
t
kzo;,.,,...,.,.,,..,. 2 HOURS AFTER
3
INDUCTION
4 OF ANESTHESIA
Figure 2. Case 2. Changes in blood pressure and shortly after transplant procedure.
6
0
IO
during
renal hemodynamics. The concept of reduced effective plasma volume has been introduced to explain these [4], but this, too, does not enjoy universal acceptance [18]. Schroeder et al. [lo] studied the clearance and extraction of paraaminohippurate (PAH) in patients with this syndrome. They suggested that there is a decrease in blood flow to the renal cortex and perhaps an increase in medullary flow. Epstein et al. [13] confirmed the reduction in cortical blood flow rate and distribution by application of the 133Xenon washout technic. Indeed, there was a clear inverse correlation between the percentage of flow to the cortical zone and the severity of renal functional impairment. Further, two lines of evidence suggest that the renal hemodynamic abnormalities identified are both functional and reversible: (1) Angiographic abnormalities observed in these patients were not present when the studies were repeated postmortem, and (2) there was marked hemodynamic instability in this group suggested by continually changing disappearance rates during the 133Xenon curves. Finally, it was suggested that the hemodynamic abnormalities identified in their study were the result of active vasoconstriction, but failure to reverse them with intrarenal arterial infusion of phentolamine diminished the likelihood of a participation in this of the sympathetic nervous system or circulating catecholamines. The reversible nature of the renal hemodynamic and functional abnormalities is confirmed by the successful function of transplants taken from “hepatorenal” donors in the hands of Koppel et al. [14] as well as our experience with patient H.H. (Case 1). In our patient D.R. (Case 2) renal function also seemed to be improving when his immunosuppressive agents were radically modified in an attempt to treat his pneumonia. Hartroft and Hartroft [I91 showed that in patients with cirrhosis and ascites the juxtaglomerular index is higher
January 1973
The American Journal of Medicine
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HYPERTENSION FOLLOWING TRANSPLANTATION OF “HEPATORENAL DONOR” KIDNEYS-MCDONALD
than that in normal subjects. Ayers [20] has shown that the plasma renin activity level of such patients is about fourfold higher and the renin substrate concentration about 50 per cent lower than in control subjects. These findings were confirmed by Schroeder et al. [17], who also found a correlation between plasma renin activity and the severity of renal functional impairment. It has been known that the nephrectomized animal has an increased sensitivity to injected renin [21-281, but not to angiotension nor norepinephrine [24,28]. Blaquier et al. [24] showed that the response was not only greater but also more prolonged and associated with a higher plasma angiotension Ii level. Also, when the plasma of a nephrectomized animal was given to a normal animal, the blood pressure response to a dose of renin was greater than when the plasma of a normal rat was given beforehand [24]. Confirmation of a humoral factor responsible for this came from the studies of Bing and Magill [28], which showed that the normal and nephrectomized rats of a cross-circulated pair had similarly increased sensitivity to injected renin and increased in vitro angiotension generation after addition of exogenous renin to the plasma. When plasma from nephrectomized animals was given to normal rats their response to exogenous re,nin was greater than when they were given plasma from normal rats. It is now well accepted that the plasma renin activity is lower and the plasma renin substrate concentration is 5 to 15 times higher within a few hours of nephrectomy in experimental animals and man [22,25,26,29-391. It is generally agreed that the augmented pressor response to renin injection in animals under these circumstances is accounted for, at least in part, by the high plasma substrate concentration [25,27,35,36]. However, considerable debate continues regarding whether or not this augmentation is modified either by a decrease in plasma angiotensinase after nephrectomy [22,24,29], or by a change in the velocity of the renin-substrate reaction [24-26,36,38]. With this background we ought to be able to offer an explanation for the acute, severe hypertension observed in our patients immediately after the transplanted kidneys became part of the general circulation. The donor surely had the “hepatorenal syndrome.” It is almost certain then that he had high plasma [17,20] and renal renin
ET AL
levels [19]. We are unable to decide to what extent the elevated plasma angiotensinase level described by Hirasawa [40] and suggested by Laragh et al. [41] contributed to his hypotension. The recipients, on the other hand, had been nephrectomized five and eight weeks before the transplant. In only patient H.H. (Case 1) was plasma renin activity measured between nephrectomy and transplant. It is likely that the level was quite low in both and that both had rather high renin substrate levels. We postulate that what followed the transplants was an exact human counterpart of the experiments described herein, in which exogenous renin given to nephrectomized animals, causes severe hypertension. Here, “high renin kidneys” were placed into “high substrate circulations.” The extremely high plasma renin activity values in each patient within a few hours after the transplant support this hypothesis. Within 24 hours the transplanted kidney can secrete renin [42,43]. Further, the levels seen with early rejection [31,32,43,44] or acute tubular necrosis [31] after transplantation are not of the magnitude seen in our two patients. Indeed, neither of these phenomena is necessarily associated with augmented plasma renin activity [32]. Finally, it is not possible to explain the acute hypertension in these patients on the basis of administration of pressor agents since they received none. Nor can it be explained by inappropriate blood or fluid replacement during the procedure. We are most conservative with fluid replacement during surgery in these patients until it becomes clear whether or not renal function has been established. Also, the central venous pressure and body weight failed to rise. The present observation of acute severe hypertension immediately after vascular anastomosis in two anephric patients who received the kidneys of a “hepatorenal” donor should not deter the use of this source of kidney donors. One should be prepared for this complication which did result in a potentially fatal arrhythmia in one of our patients and could result in acute heart failure. Early treatment should control the hypertension and prevent the latter two complications. ACKNOWLEDGMENT We gratefully acknowledge the editorial advice of Drs. John M. Weller, Richard Malvin and Paul Churchill and the secretarial assistance of Mrs. Elizabeth Cord.
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42
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Blaquier P, Hoobler SW, Schroeder J, Gomez A, Kreulen T: Effect of bilateral nephrectomy and pressor response to renin. Amer J Physiol 203: 339, 1962. Blaquier P: Kinetic studies on renin-angiotensinogen reaction after nephrectomy. Amer J Physiol 208: 1083, 1965. Blaquier P, Basso N. de la Riva I: Kinetics of reninrenin substrate. Circ Res 20-21 (suppl II): 109, 1967. Bing J: Mechanism of the increased sensitivity to renin in nephrectomized animals. Acta Path Microbial Stand 60: 311,1964. Bing J, Magill F: Potentiation of sensitization to renin in normal rats by cross circulation with nephrectomized. Acta Path Microbial Stand 59: 485, 1963. Blair-West Jr, Coghlan JP, Denton DA, Scoggins BA, Wintour M, Wright RD: The renin angiotensin aldosterone system in sodium depletion. Med J Aust 2: 290, 1967. Haber E; Recent developments in pathophysiologic studies of the renin-angiotensin system. New Eng J Med 280: 148, 1969. West TH. Turcotte JG, Vander A: Plasma renin activity, sodium balance, and hypertension in a group of renal transplant recipients. J Lab Clin Med 73: 564, 1969. Blaufox MD, Birbari AE, Hickler RB, Merrill JP: Peripheral plasma renin activity in renal-homotransplant recipients. New Eng J Med 275: 1165, 1966. Vertes V, Cangiano JL, Berman LB, Gould A: Hypertension in end stage renal disease. New Eng J Med 280: 978, 1969. Hirasawa K. Yamamoto H, Matsui A, Shinozaki K, Kobayashi S. Yagi Y, Morimoto S, Takeda R, Murakami M: The effect of mercuric, chloride, of bilateral ureteral ligation and of bilateral nephrectomy on plasma renin substrate concentration in rats. Jap Circ J 32: 1591, 1968. Sokabe H, Shibayama BP, Mizogami S, Sakai F: Cardiovascular reactivity after bilateral nephrectomy in rats. Jap Heart J 6: 233, 1965. Montague D: Kinetics of renin-angiotensin reaction in plasma of normal and nephrectomized rats. Amer J Physiol 215: 78, 1968. Carretero 0, Gross F: Renin substrate in plasma under various experimental conditions in the rat. Amer J Physiol. 213: 695, 1967. Carretero 0. Gross F: Evidence for humoral factors participating in the renin-substrate reaction. Circ Res 20-21 (suppl I I): 115, 1967. Merrill JP, Schupak E: Mechanisms of hypertension in renoprival man. Canad Med Ass J 90: 328,1964. Hirasawa K: Studies on renin-angiotensin system. I. Studies on angiotensinase activity in liver diseases. Jap Circ J 32: 407, 1968. Laragh H, Cannon PJ, Ames RP: Interaction between aldosterone secretion, sodium and potassium balance, and angiotensin activity in man: Studies in hypertension and cirrhosis. Canad Med Ass J 90: 248, 1964. Gunnells JC, Stickel DL. Robinson RR: Episodic hypertension associated with positive renin assays after renal transplantation. New Eng J Med 274: 543, 1966. Abbrecht PH, Turcotte JG, Vander AJ: Plasma erythropoietin and renin activity after canine renal allotransplantation. J Lab Clin Med 71: 766, 1968. Abbrecht PH, Vander AJ, Turcotte JG: Effects of saline loading on the renin, erythropoietin. and blood pressure responses to canine renal allotransplantation. Circ Res 25: 99, 1969.
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