Blockade of the renin–angiotensin system increases graft survival in patients with chronic allograft nephropathy

Marika A. Artz1, Luuk B. Hilbrands1, George Borm2, Karel J. M. Assmann3 and Jack F. M. Wetzels1

1 Department of Nephrology, 2 Department of Epidemiology and Biostatistics and 3 Department of Pathology, University Medical Center St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands

Correspondence and offprint requests to: M. A. Artz, MD, University Medical Center Nijmegen, Department of Nephrology, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Email: m.artz{at}nier.umcn.nl



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Chronic allograft nephropathy (CAN) is the leading cause of late allograft failure, with only limited treatment options. Blockade of the renin–angiotensin system (RAS) decreases progression in diabetic and non-diabetic renal disease, but the effect on CAN is as yet unclear. Therefore, we have studied retrospectively the effect of RAS blockade on renal survival in patients with biopsy-proven CAN.

Methods. The medical records of 72 patients with biopsy-proven CAN were evaluated with regard to time course of graft function, proteinuria, blood pressure, and antihypertensive and immunosuppressive treatment. Cox's proportional hazards model was used for analysing renal graft survival after the index biopsy.

Results. On univariate analysis, histological determinants influencing renal survival were the chronic interstitial and chronic tubular score, and clinical parameters were the serum creatinine level at the time of the biopsy, the relative change in serum creatinine level between 12 months post-transplantation and at the time of the biopsy, mean systolic and diastolic blood pressure after the biopsy, and RAS blockade by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. On multivariate analysis, graft outcome was influenced by the relative change in serum creatinine level between 12 months post-transplantation and the time of the index biopsy, the urinary protein excretion, the mean diastolic blood pressure after the index biopsy, and RAS blockade. Renal graft survival after treatment with RAS blockade was 6.3 (0.9–10.9) years as opposed to 1.8 (0.1–6.7) years in untreated patients (P = 0.003).

Conclusion. RAS blockade increases graft survival in CAN. In view of the limited treatment options for CAN, this finding is of importance and needs confirmation by a prospective randomized trial.

Keywords: chronic allograft nephropathy; prognosis; renal transplantation; renin–angiotensin system



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Although the recent introduction of newer immunosuppressive drugs has resulted in an impressive reduction in the rate of acute rejections after renal transplantation, the impact of these agents on long-term graft survival is less well established. Chronic allograft nephropathy (CAN) is still the leading cause of late allograft failure. Both immunological and non-immunological factors are involved in the pathogenesis of CAN and contribute to chronic tubulo-interstitial, glomerular and vascular injury [1]. There is no evidence-based treatment of CAN. Most studies focus on limiting or avoiding the use of calcineurin inhibitors, the use of lipid-lowering or antihypertensive drugs, or the application of agents with antifibrogenic and antiproliferative properties [2,3]. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are of special interest in this respect, since these drugs attenuate the decline of renal function in patients with diabetic and non-diabetic renal diseases [4,5]. Although these studies provide arguments for the use of ACE inhibitors in patients with CAN, firm proof of their benefits is lacking. Moreover, the use of ACE inhibitors may pose specific problems, especially in renal transplant recipients. In the case of transplant renal artery stenosis or severe arteriolar intimal fibrosis, acute worsening of graft function can occur after ACE inhibition. Furthermore, in a rat model of CAN, the use of an ACE inhibitor attenuated the development of focal segmental glomerulosclerosis, but worsened intimal hyperplasia [6]. Finally, blockade of the renin–angiotensin system (RAS) has been associated with anaemia and hyperkalaemia. Although Stigant et al. have suggested that both ACE inhibitors and ARBs are generally well tolerated in renal transplant recipients with well functioning grafts [7], side effects may be more prominent in patients with renal failure. We have studied retrospectively the effect of RAS blockade on the rate of progression of histologically confirmed CAN.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
From all patients who received a renal allograft at the University Medical Center Nijmegen in the period from December 1974 until January 1997, we selected those patients with a diagnosis of CAN in a graft biopsy taken >1 year after transplantation. Graft biopsies were taken between October 1980 and April 1999. Patients with documented renal graft artery stenosis or ureteral obstruction were excluded. In our centre, renal allograft biopsies are only performed on clinical grounds (either deteriorating graft function or proteinuria exceeding 1 g/24 h). All selected graft biopsies were reviewed by one renal pathologist and evaluated according to the Banff 1997 criteria for chronic allograft nephropathy [8]. A total of 141 patients were identified initially. Twenty-seven patients were excluded because the biopsy did not meet the minimal criteria, i.e. containing at least seven glomeruli and one artery. Patients were also excluded when the graft biopsy showed signs of co-existing pathology that could influence renal survival (acute rejection in 35 patients, and recurrence of the original renal disease in seven patients). Finally, 72 patients with histologically confirmed CAN could be evaluated. The medical records of these patients were analysed with regard to the following variables: age, original renal disease, donor age and gender, human leukocyte antigen (HLA) mismatches, delayed graft function, immunosuppressive treatment, incidence of acute rejections, blood pressure, antihypertensive treatment, serum creatinine levels and urinary protein excretion.

Statistical analysis
Values are given as mean±SD in the case of normal distribution or otherwise as median and range. Statistical analysis was performed using the Statistical Product and Services Solutions (SPSS) package, version 11.0 (Chicago, IL). Continuous values were analysed using Student's t-test or Mann–Whitney U-test when appropriate. Categorical values were analysed using the {chi}2 test or Fisher's exact test when appropriate.

Cox's proportional hazard model was used for survival analysis. Analysis of the incidence of graft failure was censored for death of the patient. Both backward and forward selection were used, with P<0.05 and P<0.10 for retaining/inclusion and removal of variables, respectively. As the number of variables was too high for straightforward backward selection, a preliminary selection was carried out and variables that showed poor univariate association with survival (P>0.15) were excluded. When necessary, parameters were normalized by logarithmic or square-root transformation. Sensitivity analyses were carried out in order to evaluate the robustness of the final model. In these analyses, the impact of the choice of the criterion for retaining/inclusion and removal of the variables, the choice of transformation and the influence of collinearity were evaluated. Kaplan–Meier analysis was used to estimate median survival. A P-value of <0.05 (two-sided) was considered statistically significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The patients (45 males and 27 females) received a kidney graft at an age of 37±16 years. The donor (39 males and 33 females) age was 34±19 years. Initial immunosuppressive treatment included a calcineurin inhibitor in 45 patients. Twenty-five (34.7%) patients remained free of acute rejection, 34 (47.2%) had one acute rejection, 10 (13.9%) had two, and three (4.2%) had three acute rejection episodes. At 12 months after transplantation, the serum creatinine level was 124 (67–245) µmol/l.

The index biopsy was taken at 3.3 (1.1–14.0) years after transplantation. The indication for taking a biopsy was deteriorating graft function in 42 (58%) patients, proteinuria in 11 (15%) patients, and both in 19 (26%) patients. At the time of biopsy, the serum creatinine level was 189 (100–501) µmol/l, and 61 (85%) patients had proteinuria (≥0.2 g/10 mmol creatinine). The median urinary protein excretion in these patients was 3.3 (0.2–16.8) g/10 mmol creatinine. Systolic and diastolic blood pressure at the time of biopsy were 155±24 and 89±11 mmHg, respectively. At the time of the biopsy, 29 patients were taking a calcineurin inhibitor. Follow-up time after the index biopsy was 1.8 (0.1–13.6) years.

On univariate analysis (Table 1), histological determinants that significantly influenced graft survival were the chronic interstitial and chronic tubular score. Clinical and laboratory factors that significantly influenced graft survival were: the serum creatinine level at the time of the biopsy, the relative change in the creatinine level between 12 months post-transplantation and at the time of the biopsy, mean systolic and diastolic blood pressure during the first year after the biopsy (determined with intervals of 3 months) and RAS blockade after the biopsy. The urinary protein excretion at the time of the biopsy showed a strong tendency to influence renal survival after the biopsy. The use of a calcineurin inhibitor at the time of biopsy did not influence graft survival. In seven out of 29 patients using a calcineurin inhibitor at the time of the biopsy, the calcineurin inhibitor was withdrawn. This withdrawal did not affect graft survival. The use of other antihypertensive drugs such as calcium channel blockers and ß-blockers did not affect graft survival.


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Table 1. Cox proportional hazards analysis of factors influencing graft failure

 
Since ACE inhibitors and ARBs might have been avoided in patients with a rapidly deteriorating graft function, we also investigated the effects of these drugs in the subset of patients who had a functioning graft for at least 6 months after biopsy (n = 60). Because this analysis yielded the same results as the initial analysis including all 72 patients, the multivariate analysis was performed subsequently in all 72 patients.

Upon multivariate analysis (Table 1), the factors that influenced graft outcome were: the relative change in the creatinine level between 12 months post-transplantation and at the time of the biopsy, the urinary protein excretion at the time of the biopsy, the mean diastolic blood pressure during the first year after the index biopsy, and the use of an ACE inhibitor or ARB after the biopsy. The histological parameters did not independently influence graft outcome.

Twenty-three patients of our study cohort were treated with an ACE inhibitor (n = 21) or an ARB (n = 2). Four patients started prior to the biopsy, and 19 patients after a median interval of 3 (1–39) months following the graft biopsy. The ACE inhibitors or ARBs were used during 28 (5–77) months. The year of transplantation and the clinical characteristics of these patients did not differ from those that were never treated with RAS blockade (Table 2). In the latter group, the graft biopsy was taken 3 years earlier and in the graft biopsy more severe chronic tubular lesions were seen. Initial immunosuppression after transplantation and immunosuppressive treatment at the time of the index biopsy did not differ between both groups (Table 3).


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Table 2. Characteristics of patients with or without RAS blockade

 

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Table 3. Immunosuppressive and antihypertensive medication in patients with and without RAS blockade

 
Haemoglobin level decreased after initiation of RAS blockade, from 7.4±1.0 mmol/l at baseline to 7.0± 1.3 mmol/l at 1 month (P < 0.05), and 6.7±1.5 mmol/l at 6 months (P < 0.01). RAS blockade was stopped in one patient after using an ACE inhibitor for 6 months because of anaemia. In the patients not on RAS blockade, the haemoglobin level also decreased, from 7.0±1.2 mmol/l at the time of biopsy, to 6.5± 1.4 mmol/l 6 months later (P < 0.01). At 1 month after initiation of RAS blockade, the serum potassium level increased from 4.1±0.6 to 4.6±0.6 mmol/l (P < 0.01), and remained stable thereafter. In none of the patients did RAS blockade have to be stopped due to hyperkalaemia.

At the time of the index biopsy, the number of antihypertensive drugs was not different for either group (1.7±1.1 for the RAS blockade group vs 1.4±0.9, NS). In the RAS blockade group, the number of antihypertensive drugs increased to 1.9± 1.1 at 6 months, 2.3±0.7 at 1 year and 2.4±0.7 at 2 years. In the patients not receiving RAS blockade, the number of antihypertensive drugs also increased, but to a lesser extent, to 1.9±0.8 at 1 year and 1.9±1.0 at 2 years after the biopsy. This resulted in a higher total number of antihypertensive drugs in the patients on RAS blockade 2 years after the index biopsy. The number of patients using ß-blockers, calcium channel blockers, diuretics and other antihypertensive drugs was not different between patients using RAS blockade and patients not on RAS blockade (Table 3).

Baseline systolic blood pressure was 158±19 mmHg in patients starting on RAS blockade. At 1 and 6 months after initiation of RAS blockade, systolic blood pressure was 150±23 and 152±28 mmHg, respectively (no significant differences compared with baseline). Baseline diastolic blood pressure was 90±9 mmHg in patients starting on RAS blockade. At 1 and 6 months after initiation of RAS blockade, diastolic blood pressure was 87±7 and 88±13 mmHg, respectively (no significant differences compared with baseline). There was no difference in time course of systolic and diastolic blood pressure between patients on RAS blockade and patients not treated with RAS blockade, during 2 years after the index biopsy (P = 0.18 and P = 0.34, respectively).

Median baseline proteinuria in patients starting on RAS blockade was 2.1 (0.1–9.3) g/10 mmol creatinine. After initiation of RAS blockade, proteinuria decreased to 1.1 (0.1–4.3) g/10 mmol creatinine at 3 months (P = 0.021) and 1.2 (0.1–6.5) g/10 mmol creatinine at 6 months (P = 0.086). In the patients not treated with RAS blockade, proteinuria did not change during 2 years after the index biopsy.

Median baseline serum creatinine level in patients starting on RAS blockade was 191 (121–306) µmol/l. After using RAS blockade for 1 month, serum creatinine had increased to 210 (128–365) µmol/l (P = 0.051). At 3 months after initiation of RAS blockade, no difference in serum creatinine level compared with baseline was found.

In patients using an ACE inhibitor or ARB, the median graft survival time following the biopsy was 6.3 (0.9–10.9) years, as opposed to 1.8 (0.1–6.7) years in patients not treated with RAS blockade (P = 0.003, Figure 1). When analysing only the patients with a follow-up of at least 6 months after the index biopsy (n = 60), the difference in renal survival between patients treated with RAS blockade [6.3 (0.9–10.9) years] and patients not treated with RAS blockade [2.2 (0.5–13.6) years] was still significant (P = 0.02). In the group of patients treated with RAS blockade, the risk of graft failure was not influenced by the change in proteinuria between baseline and 3 months [exp(B) = 1.42, 95% confidence interval (CI) 0.68–2.97; P = 0.35], or between baseline and 6 months after initiation of RAS blockade [exp(B) = 1.07, 95% CI 0.65–1.78; P = 0.78]. Also, the rise in serum creatinine level at 1 month after initiation of RAS blockade did not influence graft survival [exp(B) = 0.99, 95% CI 0.97–1.01; P = 0.33].



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Fig. 1. Graft survival in patients on RAS blockade (dotted line) vs patients not on RAS blockade (solid line).

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In this retrospective study in patients with biopsy-proven CAN, we demonstrate that RAS blockade results in increased graft survival. The effect of treatment with an ACE inhibitor or ARB in our study is consistent and strong. Exclusion of patients with loss of graft function within 6 months after the biopsy did not alter the results. Moreover, baseline clinical characteristics of patients treated with RAS blockade, including blood pressure, urinary protein excretion and presence of diabetes, were not different from those of the patients not treated with these drugs. The only observed differences between both groups were the score for chronic tubular damage, and the year of biopsy. The latter differed by merely 3 years, while the time interval between transplantation and biopsy was similar in both groups. Moreover, in multivariate analysis, neither the histological score nor the year of biopsy influenced graft survival. Taken together, although we have to admit that the retrospective nature of the study may have biased the results in some way, we feel that it is unlikely that selection bias can fully explain the observed benefit of RAS blockade. Our study thus strengthens the conclusion of Lin et al. [9]. In a retrospective analysis in renal transplant patients with biopsy-proven CAN, these authors observed a trend towards slowing the progression of renal insufficiency in patients using either an ACE inhibitor or an ARB. In Lin's study, CAN was graded mild in ~50% of cases, and ~40% of patients also showed signs of acute rejection in the biopsy, which may explain the more moderate efficacy of RAS blockade in their patients.

Our data support that RAS blockade can be safely used in renal transplant patients, even when moderate renal insufficiency is present. Unexpected rises of serum creatinine, anaemia and hyperkalaemia were not a major problem, a conclusion also drawn by Stigant et al. who have evaluated RAS blockade in patients with well preserved graft function [7].

We did not observe a difference in blood pressures after renal biopsy in the two patient groups, although the patients on RAS blockade used more antihypertensive drugs than patients not treated with RAS blockade. It is therefore unlikely that the beneficial effect of RAS blockade was largely mediated by blood pressure reduction. Nevertheless, we found that the level of blood pressure per se was a predictor of renal function deterioration. This is in agreement with studies demonstrating that hypertension is an independent risk factor for CAN [3]. Also, hypertension is an independent risk factor for cardiovascular disease, which is the leading cause of death in renal transplant recipients [10]. Treatment of hypertension therefore is important, not only for maintaining graft function, but also for reducing cardiovascular morbidity.

Initiation of RAS blockade was followed by a firm reduction of proteinuria of >50%. Comparable degrees of reduction of proteinuria have been observed in other studies addressing the antiproteinuric effects of ACE inhibitors, especially in patients with secondary forms of focal segmental glomerulosclerosis [11]. The large effect of RAS blockade on graft survival, with graft half-life increasing almost 3-fold, may seem rather incredible. However, similar renoprotective effects have been reported in patients with IgA nephropathy (end-point reached in 13 vs 57%) [12] and in the GISEN study in patients with non-diabetic proteinuric renal diseases (relative risk reduction 2.32) [13]. Although high levels of proteinuria were associated with reduced graft survival, we could not demonstrate a relationship between the decrease in proteinuria after the start of RAS blockade and graft survival. This could be related to lack of power.

Although the magnitude of the protective effect of RAS blockade in our patients must be interpreted with caution in view of the retrospective nature of the study, it is safe to conclude that RAS blockade, in particular ACE inhibition, which we mainly have used, does not exert any untoward effect in patients with CAN, as might have been anticipated based on some animal and human data. In a study investigating the effect of ACE inhibitors or ARBs in a rat model of CAN, chronic RAS blockade by both drugs resulted in preservation of glomerular morphology in the absence of proteinuria, but intimal hyperplasia was enhanced, especially when the RAS blockade was initiated early after transplantation [6]. In human studies, ACE inhibitors increased the risk of re-stenosis after coronary stent implantation, especially in patients with the DD genotype for the angiotensin I converting enzyme deletion allele polymorphism [14]. These observations suggest that during repair of the endothelium, shortly after an insult such as recent ischaemia–reperfusion injury or after recent stenting, blockade of the formation of angiotensin II might have unwanted effects on the vascular patency. During rejection episodes, donor endothelium is replaced by endothelial cells of the recipient [15]. Apparently, recovery of endothelial injury in patients with CAN is not negatively influenced by administration of ACE inhibitors at the indicated time periods.

The mechanisms of the renoprotective effects of ACE inhibitors and ARBs are debated. Possible mechanisms include a reduction of intraglomerular capillary pressure due to efferent arteriolar vasodilation, a decreased production and/or expression of growth factors such as transforming growth factor (TGF)-ß [16] or a reduction of the activity of the plasminogen activator inhibitor type I (PAI-I), a fibrogenic and fibrinolytic mediator that has been associated with the occurrence and rate of progression of CAN [17]. Although the renoprotective effects of both ACE inhibitors and ARBs are mainly achieved by their shared antiproteinuric effect, their mechanism of action is not entirely similar. ACE inhibitors block the formation of angiotensin II, thereby blocking the stimulation of both the AT1 and AT2 receptor (angiotensin II receptor type 1 and 2). ARBs result in blockade of the AT1 receptor, whereas the AT2 receptor can still be stimulated. Stimulation of the AT2 receptor by angiotensin II counteracts many effects of the AT1 receptor, and may be beneficial for the prevention of re-stenosis after coronary angioplasty [18]. Furthermore, angiotensin II stimulates the release of PAI-I. Treatment with the ACE inhibitor ramipril resulted in a sustained reduction of the plasma level of PAI-I, whereas losartan only caused a temporary reduction [19]. The clinical significance of these differences has not been fully elucidated, but the renoprotective effect of ACE inhibitors and ARBs in non-diabetic renal disease and in type 2 diabetes with incipient nephropathy is considered to be comparable [20].

In contrast to others [2], we did not find an improvement of the course of renal function upon discontinuing the use of calcineurin inhibitors. This lack of effect might be related to limited power, since discontinuation of calcineurin inhibitors was only performed in seven patients.

In summary, our data indicate that RAS blockade by an ACE inhibitor or ARB in biopsy-proven CAN results in increased graft survival. In view of the limited treatment options for CAN, this finding is of importance and needs confirmation by a prospective randomized trial.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 27. 2.04
Accepted in revised form: 19. 7.04