The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA

Alice Schmidt, Ursula Gruber, Georg Böhmig, Elke Köller and Gert Mayer

Division of Nephrology and Dialysis, Department of Medicine III, University of Vienna, Vienna, Austria



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The angiotensin II (AT II) type I receptor antagonist losartan has been reported to increase urinary uric acid and potassium excretion. These effects might be beneficial in cyclosporin (CsA)-treated renal transplant recipients, who frequently suffer from hyperuricaemia and hyperkalaemia.

Methods. In this prospective, open, randomized, two-way cross-over study we included 13 hypertensive CsA-treated patients after renal transplantation and administered either the angiotensin-converting enzyme (ACE) inhibitors enalapril or losartan. Laboratory parameters, 24-h urinary protein excretion, and mean 24-h arterial blood pressure (MAP) were checked after 3 weeks treatment with enalapril, after a wash-out period of 2 weeks, and before and after a 3-week treatment course with losartan.

Results. Both drugs slightly reduced MAP (losartan from 97±6 to 94±9 and enalapril to 93±8 mmHg). Serum potassium levels significantly increased during enalapril therapy (from 4.3±0.5 to 4.8±0.4 mmol/l, P<0.05), as did, although not significantly, uric acid concentrations (from 7.8±1.9 to 8.2±1.8 mg/dl, P=0.5). Losartan, on the contrary, only mildly affected serum potassium (4.3±0.5 vs 4.5±0.5 mmol/l, P=0.25) and serum uric acid decreased (from 7.8±2.4 to 7.3±1.8 mg/dl, P=0.6). Serum aldosterone and urinary aldosterone excretion were significantly reduced only during ACE inhibitor treatment, which might explain the variable effects on potassium homeostasis.

Conclusion. Losartan may be a useful agent to reduce blood pressure and serum uric acid levels in renal transplant recipients treated with CsA. Furthermore, in this high-risk population, the effects on serum potassium levels are less marked with losartan than with enalapril.

Keywords: ACE inhibitors; angiotensin II receptor antagonists; CsA; renal transplantation; serum potassium; serum uric acid



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Chronic renal transplant failure (CRTF) is one of the leading causes of terminal renal insufficiency [1]. Approximately 20% of patients entering maintenance dialysis do so because their allograft has failed. The pathogenesis of CRTF is multifactorial with immunological as well as non-immunological factors contributing [2]. Attempts to improve transplant function in patients with CRTF by increasing immunosuppressive medication have been largely unsuccessful. Furthermore, although cyclosporin A (CsA) has had a major impact on renal allograft survival by reducing early graft loss due to acute rejection, it does not affect the incidence of CRTF [3].

Several studies have been performed using therapeutic strategies, which have been proved beneficial in chronic native kidney disease, a disorder that, at least in some respects, shares some remarkable similarities with CRTF [4,5]. One of these strategies has been blockade of the renin–angiotensin–aldosterone system (RAAS). In chronic native kidney disease the administration of an angiotensin-converting enzyme (ACE) inhibitor has been shown to slow progression of the disease [68], probably by protecting remaining nephrons after the loss of a critical amount of renal mass. CRTF definitely represents a state of reduced nephron number and therefore ACE inhibitors might exert positive effects on excretory allograft function, although definite proof for this hypothesis is still lacking [9]. Nonetheless, as in native kidney disease, ACE inhibitors reduce proteinuria and stabilize glomerular permselective function [10,11]. Similar effects might be seen when angiotensin II (AT II) type 1 receptor antagonists are used.

Hypertension, hyperuricaemia, and hyperkalaemia are frequent complications of CsA therapy in patients after kidney transplantation. The incidence of hyperuricaemia in one study was 84% in those treated with CsA vs 30% in those treated with azathioprine and prednisone, and may be due to a decrease of glomerular filtration and/or an impairment of tubular secretion [12]. CsA may also reduce potassium excretion both by decreasing the activity of the RAAS and by impairing tubular responsiveness to aldosterone [13]. Concomitant administration of an ACE inhibitor, which also diminishes aldosterone release, may lead to life-threatening hyperkalaemia. Losartan, a selective AT II type 1 receptor antagonist, has been shown to increase uric acid as well as potassium excretion in healthy subjects [14]. In a large cohort of 112 patients, presenting with mild to end-stage renal disease, who completed 12 weeks of active treatment with losartan, only one patient discontinued the study due to hyperkalaemia [15]. Furthermore, a uricosuric activity was described recently in heart-transplant recipients [16].

However, no formal comparison of the effects of losartan with those of ACE inhibitors has been reported in renal transplant recipients. As losartan might be an interesting therapeutic agent in CsA-treated patients, we performed this prospective randomized cross-over study to compare the effects of losartan with those of the ACE inhibitor enalapril on serum uric acid levels as well as potassium homeostasis.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Thirteen renal transplant recipients (12 male, one female, mean age 58±12 years) receiving CsA-based immunosuppression were recruited from our outpatients clinic. Additional therapy included prednisolone in 12 (2.5–7.5 mg/day; mean 4.4±1.6 mg/day), azathioprine in six (50–100 mg/day; mean 69±22 mg/day), and mycophenolate mofetil in four patients (1–2 g/day; mean 1.6±1.5 g/day). All patients had been transplanted for at least one year and showed stable excretory allograft function for at least 6 months with serum creatinine levels below 2 mg% and urinary protein excretion below 1 g/day. Before the start of the treatment, renal transplant artery stenosis was ruled out by colour-coded duplex sonography. Eight days prior to the start of therapy the patients were put on a moderately salt-restricted diet (8 g/day) containing 0.8 g protein/kg/day.

Study design
The study was performed on an outpatients basis and patients were randomly assigned to receive either losartan 50 mg or enalapril 10 mg for a period of 3 weeks according to a two-way cross-over design with a wash-out period of 2 weeks in between.

All patients showed mild hypertension defined as a systolic blood pressure between 140 and 159 mmHg and a diastolic blood pressure between 90 and 99 mmHg. Concomitant antihypertensive therapy (which was unchanged during the study) included calcium antagonists in seven, ß-blocking agents in five, {alpha}-blockers in two, and diuretics in four patients.

Methods
Laboratory parameters were measured before and after each treatment phase and included plasma renin and aldosterone concentrations, plasma ACE activity, urinary aldosterone excretion, and serum uric acid, potassium, creatinine, bicarbonate and CsA trough levels and 24-h urinary protein excretion.

Blood samples were drawn carefully, nonetheless three serum potassium measurements (one losartan baseline, one enalapril baseline, and one enalapril final measurement) were excluded from our calculation because there were signs of haemolysis. Blood samples for determination of plasma renin activity (PRA), ACE activity, and aldosterone levels were drawn after a resting period of 2 h in a supine position, before drug administration.

Blood pressure was evaluated by ambulatory blood pressure monitoring before the start of the study and after each treatment period of 3 weeks. Eleven patients completed the 9 weeks of the study period. Two patients dropped out, one due to non-compliance, the other developed an exanthema after 3 days of enalapril treatment. All patients tolerated 50 mg losartan without side-effects, the enalapril dose had to be reduced to 5 mg/day in four subjects because of orthostatic side-effects.

The study was approved by the local human ethics committee and written informed consent was obtained from every patient before the study.

Statistical methods
All values are given as mean±1 SD. Statistical analysis was done by ANOVA and post hoc testing was performed by Fisher's least squares test using Bonferronis correction for multiple analysis. A P value <0.05 was considered significant.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Both losartan and enalapril decreased blood pressure, although the reduction was not statistically significant. As can be seen from Table 1Go, both drugs were equally effective when mean 24-h, day-time, or night-time bloodpressure values were analysed separately. Mean systolic blood pressure decreased from 130±8 to 127±11 mmHg after losartan, and to 127±13 mmHg after enalapril; mean diastolic pressure showed a decrease from 79±7 to 77±9 mmHg after losartan and to 76±9 mmHg after enalapril.


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Table 1. Twenty-four-hour blood pressure measurement in renal transplant recipients treated for 3 weeks with either losartan or enalapril

 
CsA trough levels, serum creatinine, and venous plasma bicarbonate concentrations were stable during the study period (see Table 2Go). Urinary protein excretion was reduced by both drugs to the same extent. Serum potassium levels did not exceed 5.5 mmol/l in any patient at any time and increased after 3 weeks enalapril treatment significantly from 4.3±0.5 to 4.8±0.4 mmol/l (P<0.05), whereas 3 weeks of losartan therapy induced only a slight increase from 4.3±0.4 to 4.5±0.5 mmol/l (P=0.25). Serum uric acid levels increased slightly during enalapril therapy from 7.8±1.9 to 8.2±1.8 mg/dl (P=0.5), whereas losartan induced a decrease of serum uric acid level from 7.8±2.4 to 7.3±1.8 mg/dl, although statistical significance was not reached (P=0.6).


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Table 2. Serum potassium, uric acid, and creatinine concentrations, and 24-h urinary protein excretion in renal transplant recipients treated for 3 weeks with either losartan or enalapril

 
As expected ACE activity decreased significantly after 3 weeks of enalapril therapy but remained unaffected by the AT II type 1 receptor blockade. PRA rose after both treatments, but plasma aldosterone activity decreased markedly only after 3 weeks of enalapril whereas it remained stable after losartan treatment. Aldosterone excretion also was reduced significantly only after enalapril therapy (Table 3Go).


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Table 3. Serum ACE, PRA, and aldosterone concentrations, as well as 24-h urinary aldosterone excretion in renal transplant recipients treated for 3 weeks with either losartan or enalapril

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Whether AT II type 1 receptor antagonists are as effective as ACE inhibitors in slowing the progression of chronic renal disease is still unclear and remains to be established in prospective studies. However, it is generally accepted that hypertension is a major renal and cardiovascular risk factor in renal transplant recipients. Recently it was shown that losartan effectively and safely lowered blood pressure in renal transplant patients [17]. ACE inhibitors additionally have been shown to reduce urinary protein excretion in native kidney disease as well as in renal transplants, and AT II receptor antagonists are known to reduce proteinuria also, at least in native kidney disease [18]. Especially CsA-treated allograft recipients frequently develop hyperuricaemia and hyperkalaemia. Uric acid accumulation may lead to gout, whereas hyperkalaemia may be exacerbated by the administration of ACE inhibitors via reduction of aldosterone production.

It was the aim of this study to determine whether losartan, an AT II type 1 receptor antagonist, might reduce serum uric acid levels, as it has been shown in patients with normal renal function where losartan, but not the active metabolite E-3174, competitively inhibits urate reabsorption in the renal proximal tubule [19]. A uricosuric action was described in healthy volunteers [14,19] and Minghelli et al. [16] recently described a significant decrease in serum uric acid levels and a significant increase in urinary uric acid:creatinine ratio mainly in the first 4 h after drug intake in heart-transplant recipients.

In agreement with these results, uric acid levels decreased during losartan therapy in our renal transplant recipients too, whereas there was a small, although non-significant, rise during enalapril administration. Unfortunately in our study we were not able to demonstrate a significant decrease of serum uric acid during the treatment phase with a losartan dose 50 mg. It is likely that the uricosuric effect would have been more marked using a higher losartan dose, as it is known from studies with healthy volunteers that the urinary excretion of uric acid is dose dependent [20].

Interestingly, potassium excretion has also been shown to increase after losartan therapy and hyperkalaemia was a very infrequent finding in a large study in patients with chronic renal disease treated with this compound [15]. Nonetheless, the exact mechanism that would explain why losartan would affect serum potassium levels to a smaller extent than an ACE inhibitor is still unclear. In our study, serum potassium levels increased significantly only after enalapril therapy, whereas the small elevation noted during AT II type 1 receptor blockade was not significant. This difference was observed despite equivalent reduction of blood pressure, as measured by 24-h ambulatory blood-pressure measurement. Renal excretory function, at least as far as assessed by serum creatinine concentration, remained stable during both drug administration periods. Therefore, differences in renal function are an unlikely explanation. Surprisingly, serum aldosterone levels and urinary aldosterone excretion declined significantly only during enalapril therapy, whereas losartan had a much smaller effect. Comparable results have been observed in healthy volunteers with losartan doses between 10 and 40 mg/day [17] and recently in patients with native kidney disease treated with valsartan [21]. The blockade of the RAAS seems to be less marked with losartan than with enalapril. This difference may well explain the differing effects on potassium homeostasis.

In summary, losartan as well as enalapril therapy lower 24 h blood pressure in patients after renal transplantation using CsA based immunosuppression. Losartan additionally lowered serum uric acid concentrations and furthermore induced less hyperkalaemia than ACE inhibition in this high-risk population.



   Acknowledgments
 
This work was supported by a scientific grant of MSD, Austria.



   Notes
 
Correspondence and offprint requests to: Alice Schmidt MD, Division of Nephrology and Dialysis, Department of Medicine III, University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 8. 8.00
Revision received 24.11.00.