Long-term anti-proteinuric effect of Losartan in renal transplant recipients treated for hypertension

Jesús Calviño, Xose M. Lens, Rafael Romero and Domingo Sánchez-Guisande

Division of Nephrology, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain

Correspondence and offprint requests to: Jesús Calviño, Division of Nephrology, Complexo Hospitalario Universitario de Santiago, C/ Galeras s/n, E-15705 Santiago de Compostela, Spain.



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Hypertension is common after renal transplantation. Angiotensin II type 1 receptor antagonists are a new class of agents that, without the side-effects mediated by kinins, have shown their efficacy in the treatment of hypertension and heart failure. The aim of the study was to assess the efficacy and safety of Losartan for the treatment of hypertension and to evaluate its long-term effect on graft function in a group of stable renal transplant patients.

Methods. Eighteen non-diabetic renal transplant recipients evaluated at our unit for more than 1 year after transplantation (13–155 months) were enrolled. Losartan was administered for a period of 14.2±6.86 (6–28) months at a dose of 25–100 mg/day depending on the antihypertensive response obtained.

Results. Losartan satisfactorily lowered systemic blood pressure. Overall graft function remained stable and a significant reduction in proteinuria was observed throughout the period on Losartan (1.0±0.87 vs 0.4±0.83 g/l, P=0.003). No serious side-effects were reported except for a significant reduction in the mean haemoglobin concentration (from 13.5±1.74 g/dl to 12.2±2.19 g/dl; P=0.001).

Conclusions. A satisfactory antihypertensive effect was observed with long-term therapy with Losartan. A significant reduction in proteinuria without adversely affecting graft function was the main beneficial effect observed. Losartan was generally well tolerated and a decrease in haemoglobin was the major side-effect.

Keywords: Losartan; hypertension; renal transplantation; proteinuria; anaemia



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Dramatic improvements in the first year survival of renal allografts have occurred during the last decade. This is mainly due to improved immunosuppresive regimens, especially the introduction of cyclosporin A (CsA) in the early 1980s [1]. However, despite these impressive results the rate of late renal allograft failure has remained relatively unchanged. Chronic CsA nephrotoxicity and cardiovascular risk factors such as hypertension have been suggested to play a role in this phenomenon [1,2].

The benefits of angiotensin-converting-enzyme (ACE) inhibitors in the treatment of hypertension and renal diseases have been widely reported. In contrast to other antihypertensive drugs, ACE inhibitors lower both systemic and intraglomerular pressure, which is translated into a decrease in glomerular hypertension, a reduction in proteinuria and an increase in renal functional reserve [3]. In renal transplantation, intraglomerular hypertension can contribute to the development of renal failure. The increase of this pressure may result from an increase in systemic blood pressure in conjunction with a reduction in functioning renal mass secondary to repeated renal rejection episodes, cyclosporin nephrotoxicity, small renal size and glomerulonephritis [4]. On the basis of these pathophysiological considerations the use of ACE-inhibitors in hypertensive renal transplant patients has also been recommended. Moreover, recent data support an in vitro decrease in TGF ß-induced fibrosis after angiotensin blockade in a chronic CsA nephrotoxicity model [5]. Clinical trials, except for those regarding post-transplant erythrocytosis [6], are scant since ACE-inhibitors can induce a decline in glomerular filtration rate when renal artery stenosis is present, as well as exacerbate type IV renal tubular acidosis induced by CsA [4]. These are probably the main clinical arguments that explain why many physicians avoid this kind of therapy in hypertensive renal transplant patients.

Angiotensin II type I receptor antagonists represent a new class of drugs that may have the benefits of ACE inhibitors without the adverse effects induced by bradykinins [7]. In renal transplantation, recent reports have documented a decrease in haemoglobin concentration with angiotensin II type I receptor antagonists [8,9], but their long-term effect on blood pressure and renal function have not been analysed.

The aim of this preliminary study was to evaluate the long-term effect of Losartan on blood pressure, proteinuria, and renal function in a group of hypertensive renal transplant patients.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Eighteen non-diabetic and non-nephrectomized, cadaveric renal transplant recipients with hypertension, 11 males and 7 females aged 47±12.4 (28–67) years, treated at our unit for more than 1 year after transplantation (13–155 months) were enrolled. Hypertension was defined as an increase in blood pressure exceeding either a systolic level of 140 mmHg and/or a diastolic level of 90 mmHg in the previous three visits at the transplant clinic. All routine biochemical and haematological parameters performed during these visits were stable in all the cases. Overt proteinuria (>0.3 g/l) was present in 11 patients before beginning the study. Losartan was added as a new antihypertensive agent for a period of 14.2±6.86 (6–28) months at a dose of 25–100 mg/day depending on the antihypertensive response obtained. Serum creatinine and potassium concentrations were determined 1 week later in order to evaluate any acute nephrotoxic effect of Losartan. None of the patients had previously been on ACE inhibitors nor concurrently treated with more than two antihypertensive drugs.

Parameters were measured at the outpatient clinic initially and at the end of the follow up period or before Losartan withdrawal. The biochemical and haematological parameters, haemoglobin, haematocrit and leukocyte count, serum creatinine, potassium, lipid profile (total cholesterol and triglycerides), aminotransferases and uric acid concentration, were measured by conventional laboratory techniques. Proteinuria was measured in overnight urine samples at 3 months and at the end of the follow-up. Fasting CsA levels were measured by fluorescence polarization assay (Abbott Laboratories). Body weight and blood pressure were also determined at the beginning and at the end of the study. Arterial blood pressure was measured by a mercury manometer after 5 min of sitting. The first and fifth Korotkoff sounds were used as indications for systolic and diastolic blood pressure. Mean arterial blood pressure was calculated as diastolic plus one third of pulse pressure.

Statistical analysis was carried out using Student's paired t-test and a Pearson's correlation analysis. Data are reported as mean±standard deviation unless otherwise stated. We considered P<0.05 as statistically significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics are summarized in Table 1Go. Maintenance of immunosuppression was achieved with CsA in 14 patients (78%) and azathioprine in four (22%). Patients were studied at a mean of 76 months after transplantation, 60% of them being hypertensive prior to transplantation. Sixteen patients (90%) were concurrently treated with other antihypertensive drugs, with nifedipine being the most frequent choice (44%). Five patients (28%) were on diuretics and six on combinations.


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Table 1. Patient demographics
 
The effects of Losartan on blood pressure, renal function and cyclosporin are displayed in Table 2Go. Despite hypertension being quite severe in our group of patients, a significant decrease in systolic (161±16.4 vs 144±16.5 mmHg, P<0.001), mean (115±9.1 vs 105±9.4 mmHg, P=0.001) and diastolic blood pressure levels (92±8.6 vs 86±8.2 mmHg, P=0.035) was observed. After 2 and 3 months of therapy, concurrent antihypertensive therapy could be even withdrawn in two patients. Hypotension was not documented.


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Table 2. Effects of Losartan on blood pressure, renal function and cyclosporin concentration
 
No acute renal function impairment was observed after initiation of Losartan. In three patients with a pre-treatment plasma creatinine level above 3 mg/dl, a progressive deterioration of renal function was observed and Losartan was withdrawn after 10, 11 and 15 months, respectively. Renal arteriography did not demonstrate significant stenosis in any of these cases. Despite including these patients in the analysis, mean serum creatinine did not significantly increase after a mean follow up period of 14.2±6.86 (6–28) months in our group of patients (2.0±0.98 vs 2.2±1.42 mg/dl, P NS).

Potassium concentration remained statistically unchanged throughout the treatment period. However, Losartan was withdrawn from one patient because of threatening hyperkalaemia (6 mM/l) after 9 months of therapy.

In 11 patients with overt proteinuria, mean proteinuria significantly decreased after Losartan therapy (1.0±0.87 vs 0.4±0.83 g/l, P=0.003). This reduction was already observed after 3 months on Losartan (to 0.6±1.0 g/l, P=0.01). There was no correlation between the reduction in proteinuria and serum creatinine nor with the decrease in mean blood pressure (Figure 1Go). CsA concentrations as well as daily dosages were also not statistically different from the mean pre-treatment level.



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Fig. 1. Correlation between the reduction in proteinuria and the changes in mean BP.

 
A significant reduction in the mean haemoglobin concentration and haematocrit was observed after Losartan therapy (Table 3Go). These reductions occurred in all but two patients, none of them had erythrocytosis. Average haemoglobin level decreased by 1.3 g/dl (range 3.7–2 g/dl), from 13.5±1.74 g/dl to 12.2±2.19 g/dl (P=0.001). Likewise the mean haematocrit decreased by 4% (range 13–5%), from 41±5.6 to 37±6.4% (P=0.002). There was no correlation between the reduction in haemoglobin and serum creatinine nor between the decrease in haemoglobin and body weight.


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Table 3. Effects of Losartan on haematological parameters
 
Additional laboratory results, namely white blood cell count, uric acid, lipid profile (total cholesterol and triglycerides) and aminotransferases, were unaffected after Losartan therapy. Angio-oedema and cough were not reported.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Hypertension is a frequent complication after renal transplantation. This condition may result in an increased risk for cardiovascular morbidity and mortality as well as contribute to the progression of renal insufficiency [10]. ACE inhibitors have been widely used in the treatment of hypertension, heart failure and renal diseases but their role in renal transplantation is incompletely defined. These drugs effectively lower blood pressure and animal experimentation suggests they may have a beneficial effect against chronic CsA nephrotoxicity [5]. Nevertheless, clinical trials are generally limited to those regarding post-transplant erythrocytosis although in hypertensive renal transplant patients, a significant reduction in proteinuria without adversely affecting graft function has also been reported [11,12].

Losartan is the first of a number of non-peptide selective blockers of angiotensin II binding to type 1 angiotensin receptors on the cell membrane, thereby inhibiting the action of angiotensin II [7]. This agent has primarily been evaluated for the treatment of hypertension and appears to have an effect similar to that seen with ACE inhibitors [13]. In renal transplantation, experimental data have shown a reduction of TGF ß-induced fibrosis either with Losartan or Enalapril in a chronic CsA nephrotoxicity model [5]. As with ACE inhibitors, human data is mainly focused on erythrocytosis [8,9], and its long-term effect on blood pressure, renal function and proteinuria has still not been assessed.

In the present study, despite hypertension being so severe to require two antihypertensive drugs in six patients, Losartan effectively reduced blood pressure in all cases and baseline antihypertensive therapy could be even withdrawn in two patients. It was well tolerated and orthostatic hypotension was not reported.

In addition to its systemic antihypertensive effect, there is conflicting data on whether Losartan has the same favourable effects on glomerular haemodynamics, i.e, a reduction in intraglomerular hypertension, hyperfiltration and proteinuria as ACE-inhibitors because it does not increase kinins [7]. In fact, bradykinin has been shown to have beneficial effects associated with the release of nitric oxide and prostacyclin, which may contribute to the haemodynamic effects of ACE-inhibitors [13]. However, most of the data indicate that bradykinins play a minor role [14], and some studies have failed to show any differences in urinary albumin excretion when treating hypertensive patients with or without chronic renal failure either with Enalapril or with Losartan [15,16].

In our group of patients, 11 had overt proteinuria before beginning the study and in all these cases either a reduction or a stabilization in urinary protein excretion was detected at the end of the follow-up. This effect was already observed after 3 months on Losartan. Moreover, new onset of proteinuria was not documented during the period on Losartan in any of the non-proteinuric cases. These results might be in agreement with the report of Traindl et al. [11] who describe a significant reduction in proteinuria of hypertensive renal transplant patients treated with the ACE inhibitor, Lisinopril, and the one of Martinez-Castelao et al. [17] who found a more effective antiproteinuric effect in patients on Enalapril than in those on Verapamil or Doxazosin. Although we did not analyse any glomerular haemodynamic parameters, the decrease in proteinuria in our group of renal transplant recipients might be the consequence of a fall in intraglomerular pressure and/or changes in the glomerular basement membrane [15]. Furthermore, no correlation was found between the reduction in proteinuria and the decrease in mean arterial blood pressure, suggesting that the antiproteinuric effect of Losartan was independent of blood pressure changes.

Overall graft function was not influenced during the long-term observation period. No acute renal function derangement was observed after the initiation of Losartan. In three patients with a baseline plasma creatinine level above 3 mg/dl, serum creatinine gradually increased throughout the treatment period despite a drop in urinary protein excretion. Renal arteriography failed to find any significant lesion in any of these cases. Despite Losartan withdrawal after 10, 11 and 15 months of therapy, respectively, renal function continued to deteriorate and was attributed to chronic allograft rejection. Furthermore, in our cohort, potassium levels did not significantly change and hyperkalaemia was not a serious side-effect except in one patient concurrently treated with a potassium-sparing diuretic. In this case, after 9 months of therapy, both Losartan and potassium-sparing diuretic withdrawal resulted in quick normalization of serum potassium.

In fact, the most commonly observed side effect was a decrease in haemoglobin concentration. Several studies have previously documented ACE inhibitor-related anaemia in patients with normal renal function, renal disease and in renal transplant recipients without polycythaemia [6]. Recent reports have shown a similar effect in dialysis populations treated with `sartanes' [18], and a beneficial effect has also been documented in the treatment of post-transplant erythrocytosis [8,9]. The mechanism why these agents induce anaemia is still unclear. As ACE-inhibitors, angiotensin II type I receptor antagonists may cause anaemia either by a direct inhibition of erythropoietin production or insulin like growth factor-1 or via an indirect mechanism (improvement of renal perfusion followed by a subsequent decrease of oxygen consumption) [19]. Moreover, a negative effect on haematopoiesis at the bone marrow level has also been suggested since angiotensin II type I receptors have been recently identified on erythroid progenitors [20]. Interestingly, in our study, the reduction in haemoglobin concentration was observed in a group of renal transplant patients without erythrocytosis. The effect of Losartan on haemoglobin concentration was consistently present in all but two patients. Moreover, overall graft function remained stable throughout the study and no correlation was found between the reduction in haemoglobin and serum creatinine. The decline in haemoglobin level remained statistically significant even when excluding the three cases where serum creatinine gradually increased. Furthermore, the absence of a significant correlation between weight gain and haemoglobin concentration argues against haemodilution as a causative factor for anaemia in our group of patients.

ACE inhibitors have been associated with leukopenia and agranulocytosis, especially in immunosuppressed patients with collagen vascular diseases and renal insufficiency [6]. In our study, white blood cell count remained stable and neutropenia was not observed in any of the patients. Lipid profile (total cholesterol and triglycerides) and CsA concentrations did not significantly change after Losartan therapy. Although hepatotoxicity has occasionally been reported in conjunction with Losartan therapy [21], aminotransferases were not affected during the treatment period, in our group of patients. The slight fall in plasma uric acid levels described with Losartan in hypertensive patients [7] was not observed in our group of renal transplant recipients. We failed to find a reasonable explanation for this fact except that the enhanced uric acid excretion attributed to this drug was probably impaired by the concurrent use of diuretics in some of the patients. Moreover, plasma CsA concentrations did not significantly change throughout the period on Losartan.

In conclusion, long-term therapy with Losartan was safe and effective in our group of renal transplant recipients. A satisfactory reduction in blood pressure was achieved and overall graft function remained stable. A significant decrease in proteinuria was the most beneficial effect observed. Whether these effects might protect the graft and, thus, prevent the progression of renal disease requires further randomized investigation. Losartan was generally well tolerated and a decrease in haemoglobin concentration was the main side-effect observed.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Peeters J, Roels L, Vanrenterghem Y. Chronic renal allograft failure: Clinical overview. Kidney Int 1995; 48 [Suppl 52]: S97–S101[ISI]
  2. Raine AEG. Does antihypertensive therapy modify chronic allograft failure? Kidney Int 1995; 48 [Suppl 52]: S107–S111[ISI]
  3. Rosenberg ME, Lawrence JS, Correa-Rotter R, Hostetter TH. The paradox of the renin angiotensin system in chronic renal disease. Kidney Int 1994; 45: 403–410[ISI][Medline]
  4. Curtis JJ, Luke RG, Whelchel JD, Diethelm AG, Jones P, Dustan HP. Inhibition of angiotensin converting enzyme in renal transplant recipients with hypertension. N Engl J Med 1983; 308: 377–381[ISI][Medline]
  5. Shihab FS, Bennett WM, Tanner AM, Andoh TF. Angiotensin II blockade decreases TGF-ß1 and matrix proteins in cyclosporine nephropathy. Kidney Int 1997; 52: 660–673[ISI][Medline]
  6. Vlahakos DV, Canzanello VJ, Madaio MP, Madias NE. Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis 1991; 17: 199–205[ISI][Medline]
  7. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996; 334: 1649–1654[Free Full Text]
  8. Ducloux D, Saint-Hillier Y, Chalopin JM. Effect of Losartan on haemoglobin concentration in renal transplant recipients – a retrospective analysis. Nephrol Dial Transplant 1997; 12: 2683–2686[Abstract]
  9. Klaassen RJL, Van Gelder T, Rischen-Vos J, Deinum J, Man in't Veld AJ, Weimar W. Losartan, an angiotensin-II receptor antagonist, reduces hematocrits in kidney transplant recipients with postransplant erythrocytosis. Transplantation 1997; 64: 780–782[ISI][Medline]
  10. Curtis JJ. Hypertension following kidney transplantation. Am J Kidney Dis 1994; 23: 471–475[ISI][Medline]
  11. Traindl O, Falger S, Reading S et al. The effects of lisinopril on renal function in proteinuric renal transplant recipients. Transplantation 1993; 55: 1309–1313[ISI][Medline]
  12. Bochicchio T, Sandoval G, Ron O, Perez-Grovas H, Bordes J, Herrera-Acosta J. Fosinopril prevents hyperfiltration and decreases proteinuria in post-transplant hypertensives. Kidney Int 1990; 38: 873–879[ISI][Medline]
  13. Pitt B, Segal R, Martinez FA et al., on behalf of the ELITE Study Investigators. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of losartan in the elderly study, ELITE). Lancet 1997; 349: 747–752[ISI][Medline]
  14. Nabokov A, Amann K, Gassmann P, Schwarz U, Orth SR, Ritz E. The renoprotective effect of angiotensin-converting enzyme inhibitors in experimental chronic renal failure is not dependent on enhanced kinin activity. Nephrol Dial Transplant 1998; 13: 173–176[Abstract]
  15. Gansevoort RT, de Zeevw D, Jong PE. Is the proteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? Kidney Int 1994; 45: 861–867[ISI][Medline]
  16. Nielsen S, Dollerup J, Nielsen B, Jensen H&Aelig;, Mogensen CE. Losartan reduces albuminuria in patients with essential hypertension. An enalapril controlled 3 months study. Nephrol Dial Transplant 1997; 12 [Suppl 2]: 19–23[Free Full Text]
  17. Martinez-Castelao A, Hueso M, Sanz V, Rejas J, Alsina J, Grinyó JM. Treatment of hypertension after renal transplantation: long-term efficacy of verapamil, enalapril, and doxazosin. Kidney Int 1998; 68 [Suppl]: 130–134
  18. Schwarzbeck A, Wittenmeier KW, Hällfritzsch U. Anaemia in dialysis patients as a side-effect of sartanes. Lancet 1998; 352: 286[ISI][Medline]
  19. Morrone LF, di Paolo S, Logoluso F, Schena A, Stallone G, Giorgino F, Schena P. Interference of angiotensin-converting enzyme inhibitors on erythropoiesis in kidney transplant recipients. Transplantation 1997; 64: 913–918[ISI][Medline]
  20. Mrug M, Stopka T, Julian BA, Prchal JF, Prchal JT. Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 1997; 100: 2310–2314[Abstract/Free Full Text]
  21. Nygaard B, Strandgaard S. Marked hepatotoxicity associated with losartan treatment. Blood Press 1996; 5: 190–191[Medline]
Received for publication: 22.12.98
Accepted in revised form: 3. 9.99