Suppression of plasma renin activity by cyclosporine

Suppression of Plasma Renin Activity by Cyclosporine

JOHN P. BANTLE, M.D. ROBERT J. BOUDREAU, M.D., Ph.D. THOMAS F. FERRIS, M.D. Minneapolis,

Minnesota

From the Department of Medicine and the Division of Nuclear Medicine, University of Minnesota, Minneapolis, Minnesota. This work was supported by Grant HL-17871 and General Clinical Research Center Grant R&400, both from the National Institutes of Health, Bethesda, Maryland, and by a grant-in-aid from Sandoz, Inc., East Hanover, New Jersey. Requests for reprints should be addressed to Dr. John P. Bantle, Box 504 UMHC, University of Minnesota, Minneapolis, Minnesota 55455. Manuscript submitted October 2, 1986, and accepted January 13, 1987.

Cyclosporine treatment is associated with hypertension and suppression of plasma renin activity, the causes of which are unclear. To determine whether suppressed plasma renin activity is due to extracellular fluid volume expansion, 10 cyclosporine-treated renal transplant recipients were compared with 10 azathioprine-treated renal transplant recipients and seven patients with renal insufficiency. Glomerular filtration rate and effective renal plasma flow were significantly lower in cyclosporine-treated patients than in azathioprine-treated patients. Upright plasma renin activity was suppressed in cyclosporine-treated patients (cyclosporine 2.9 f 0.9, azathioprine 4.7 f 0.9, renal insufficiency 5.2 f 1.9 rig/ml/hour) but could be stimulated by a four-day period of dietary sodium restriction and diuretic administration (cyclosporine 15.8 f 4.4 rig/ml/hour). Extracellular fluid volume tended to be higher in cyclosporine-treated patients (cyclosporine 30.7 f 2.3, azathioprine 26.7 f 2.5, renal insufficiency 25.5 f 1.4 percent lean body mass), although the difference between cyclosporine-treated and azathioprine-treated patients did not attain statistical significance. There were no differences in the urinary excretion of prostaglandin E2 or 6-keto prostaglandin F,, between the two groups of renal transplant recipients. It is concluded that suppresslon of plasma renin activity by cyclosporine is physiologic and may reflect expansion of extracellular fluid volume, which can be reversed by sodium depletion. Cyclosporine is a fungal peptide with potent immunosuppressant properties that has proved to be of considerable utility in organ transplantation [I]. The immunosuppressant capabilities of the drug have also been employed in the treatment of a variety of diseases including type I diabetes mellitus [2], systemic lupus erythematosus [3], resistant uveitis [4], aplastic anemia [5], and thrombocytopenic purpura [6]. However, important side effects of cyclosporine therapy are hypertension [7,8] and decreased renal function [l ,&lo], with increased serum creatinine concentration [7,8,11], decreased glomerular filtration rate [8], decreased renal plasma flow [8], and hyperkalemia [ 121 all occurring with administration of the drug. In a previous study, we reported that renal transplant recipients treated with cyclosporine demonstrated suppressed plaSma renin activity and impaired urinary potassium excretion when compared with azathioprine-treated transplant recipients [ 131. Suppressed plasma renin activity in the cyclosporine-treated patients was accompanied by hypertension, but its cause was unclear. In the present study, we attempted to determine if the suppression of plasma renin activity observed in renal transplant recipients treated with cyclosporine was due to a vasculotoxic effect of the drug on the renal juxtaglomerular

July

1987

The American

Journal

of Medicine

Volume

83

59

CYCLOSPORINE

SUPPRESSION

OF PLASMA

RENIN

ACTIVITY-BANTLE

ET AL

apparatus impairing synthesis or secretion of renin or, rather, a physiologic response to sodium retention. Also, since renal prostaglandin synthesis is an important determinant of renin secretion, we assessed the effects of cyclosporine on urinary excretion of prostaglandin Es (PGEp) and 6-keto prostaglandin F,, (6-keto PGF,,), a major metabolite of prostaglandin I2 (PC+). The results obtained in cyclosporin-e-treated renal transplant recipients were compared with those in azathioprine-treated renal transplant recipients and patients with renal insufficiency not undergoing transplantation.

blocker. The blood pressure values reported are the mean of four readings obtained from each patient on days 2 and 3 (when patients were not receiving diuretics or antihypertensive medications) and on days 6 and 7 (following sodium depletion). The research protocol was reviewed and approved by the University of Minnesota committee on the use of human subjects in research. Written informed consent was obtained from all participants. Serum electrolytes, serum urea nitrogen, and serum and urine creatinine were measured in the chemistry laboratories of University of Minnesota Hospitals by automated methods. Plasma renin activity was determined by measurement of the generation of angiotensin I by the method of Haber et al [ 141. Plasma and urine aldosterone concentrations were determined by radioimmunoassay. Urinary PGE:, and 6-keto PGF,, values were also determined by radioimmunoassay as previously described in a report from our laboratory [ 151. Extracellular fluid volume and glomerular filtration rate were determined after intravenous injection of 1.0 mCi of ggmTc-DTPA. Duplicate blood samples were obtained 120, 160, 200, and 240 minutes after injection. Formed elements were removed, and samples were then ultrafiltered using Amicon Centrifree Micropartition Systems (Amicon Corporation, Danbers. Massachusetts) to remove any protein-bound ggmTc. Samples were assayed for activity along with standards prepared from a dilution of the injected solution. The data were plotted, and linear regression was used to fit logI counts/ml of the samples versus time. The following formulas were used to calculate extracellular fluid volume (ECFV) and glomerular filtration rate (GFR): ECFV = VI, = D/Co, where VI, = volume of distribution gQmT~-DTPA, D = activity gQmTc-DTPA injected, and Co = extrapolated counts when time equals zero; GFR = MCR = VoX where MCR = metabolic clearance rate QgmTc-DTPA and x = fractional removal rate (0.693/t& as estimated from the plot of loglo counts ggmTc-DTPA/ml versus time. A comparison between glomerular filtration rates as determined by QQmT~-DTPA and endogenous creatinine clearance is shown in Figure 1. Effective renal plasma flow was estimated following intravenous injection of 50 &i of 13%hippuran. Duplicate blood samples were removed between 40 and 50 minutes after injection. Plasma samples and standards were subsequently counted. Effective renal plasma flow was calculated from the regression equations established by Tauxe and co-workers [ 161. The gQmT~-DTPA and 13’1-hippuran were injected sequentially on the same morning. Different counting windows were used for each isotope. Filtration fraction was calculated as glomerular filtration rate divided by effective renal plasma flow. Creatinine clearance, glomerular filtration rate, and effective renal plasma flow were corrected to a surface area of 1.72 m2 for each subject. Lean body mass was calculated for each subject from urinary creatinine excretion (average of two values) according to the formula of Forbes and Bruining [ 171. Comparisons between the cyclosporine group and the other two patient groups were made by the Student t test when the data were normally distributed and by Wilcoxon’s two-sample rank sum test when they

PATIENTS AND METHODS Ten renal transplant recipients treated with cyclosporine were compared with 10 renal transplant recipients treated with azathioprine and seven patients with chronic renal insufficiency who were not receiving either cyclosporine or azathioprine. All renal transplant recipients underwent transplantation at least three months prior to evalution and were receiving stable doses of cyclosporine or azathioprine. Patients with edema were excluded as were patients in whom temporary discontinuation of antihypertensive therapy was not throught to be justifiable. Research subjects were hospitalized in the General Clinical Research Center at the University of Minnesota and given a diet containing 120 meq of sodium and 80 meq of potassium for three days. Blood samples for measurement of serum electrolytes, urea nitrogen, and creatinine were obtained before breakfast on days 2. 3, and 4. On day 3, after two hours of upright posture, blood samples were obtained for measurement of plasma renin activity and plasma aldosterone. Also on day 3, 24hour urine collections for measurement of creatinine, aldosterone, PGEp, and 6-keto-PGF,, were obtained. On day 4, extracellular fluid volume, glomerular filtration rate, effective renal plasma flow, and filtration fraction were determined following intravenous injection of technetium 99m-labeled diethylenetriaminepenta-acetic acid (ggmT~-DTPA) and iodine 131labeled otthoiodohippurate (13’1-hippuran). After the isotopic determinations were obtained, renal transplant recipients received a 15 meq sodium diet and 40 mg of furosemide daily. The patients with renal insufficiency did not participate in this part of the study. On day 7 (the fourth day of the low-sodium diet and furosemide administration), repeated 24-hour urine collections for measurement of creatinine, aldosterone, PGE*, and bketo PGFI, were obtained. On day 8, repeated samples for measurement of plasma renin activity and plasma aldosterone were obtained after two hours of upright posture. All patients who were taking diuretics discontinued their use one week before admission. All antihypertensive medications except beta blockers were discontinued the day prior to admission. Patients taking beta blockers (eight in the cyclosporine group, four in the azathioprine group, and three in the group with renal insufficiency) received half of their usual dose on the day prior to admission and discontinued beta blocker use on the day of admission. Two patients whose diastolic blood pressure exceeded 110 mm Hg during the period of study each received one dose of a beta

60

July

1667

The American

Journal

of Medicine

Volume

63

CYCLOSPORINE

were not. One-tailed t tests were used to determine if extracellular fluid volume was increased in cyclosporinetreated patients. Group data are presented as the mean f SEM unless otherwise stated. The General Clinical Research Center CLINFO computer system was used for all data analyses.

SUPPRESSION

OF PLASMA

RENIN

ACTIVITY-BANTLE

ET AL

120 l Cyclosporine-treated 0 Azathioprine-treated

2 100 E 1 .5 E 0

RESULTS

?

The characteristics of the three patient groups are presented in Table 1. The mean number of months from renal transplantation to study was less for the cyclosporinetreated patients than for the azathioprine-treated patients. None of the azathioprine-treated patients was receiving or had received cyclosporine. The daily dosages of prednisone being taken by the cyclosporine-treated and azathioprine-treated patients were similar. Although both systolic and diastolic blood pressure were greater in the cyclosporine-treated patients than in the patients in the other two groups, the difference did not achieve statistical significance. Serum sodium and potassium levels were similar in the three groups. Azathioprine-treated patients had significantly higher glomeru!ar filtration rates than did the cyclosporine-treated patients who, in turn, had significantly higher values than did the patients with renal insufficiency. During the third day of a diet containing 120 meq of sodium and 80 meq of potassium, upright plasma renin activity was significantly lower in cyclosporine-treated patients than in azathioprine-treated patients (Table II). Although the differences in upright plasma aldosterone between the cyclosporine-treated group and the other two groups were not significant, urine aldosterone excretion was marginally lower in the cyclosporine-treated group. After sodium depletion with a 15 meq sodium diet and 40 mg of furosemide daily for four days, mean weight loss was significantly less in the cyclosporine-treated patients than in the azathioprine-treated patients (1.4 f 0.2 versus 2.7 f 0.4 kg; p