The benefits of renin–angiotensin blockade in renal transplant recipients with biopsy-proven allograft nephropathy

Jeffrey S. Zaltzman, Michelle Nash, Rick Chiu and Ramesh Prasad

Renal Transplant Program, Division of Nephrology, St Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence and offprint requests to: Dr Jeffrey S. Zaltzman, Director of Renal Transplantation, Division of Nephrology, Dept of Medicine, University of Toronto, St Michael's Hospital, 30 Bond St, Toronto, Ontario, Canada M5B 1W8. Email: jeffrey.zaltzman{at}utoronto.ca



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Allograft nephropathy, regardless of aetiology, leads to progressive renal injury and eventual graft loss. In native kidney disease, treatment of hypertension, in particular with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has proven beneficial in retarding renal function decline. In the present study, we reviewed the clinical course of a renal transplant recipient cohort that was prescribed either an ACEi or ARB for biopsy-proven allograft nephropathy.

Methods. Patients were followed from the time of post-biopsy initiation of ACEi/ARB and were stratified based on biopsy findings. Outcomes of interest included safety, allograft survival, renal function and change in slope of renal function pre- and post-ACEi/ARB.

Results. The 5 year allograft survival after biopsy diagnosis of allograft nephropathy was 83%. Serum creatinine was 191±97 (86–377) µmol/l at the time of biopsy and 228±102 (102–575) µmol/l at last follow-up. The slopes of reciprocal creatinine vs time were used to calculate the decline in renal function and were compared pre- and post-ACEi/ARB. The mean slope±SD was –0.06±0.21 l/µmol x 10–3 per month in the 12 months prior to therapy and –0.03±0.09 l/µmol x 10–3 per month following therapy. The absolute difference in slopes was 0.03 (P =<0.0001).

Conclusions. Treatment with ACEi/ARB may be beneficial in the management of allograft nephropathy.

Keywords: allograft nephropathy; angiotensin-converting enzyme inhibitors; angiotensin receptor antagonists



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Angiotensin-converting enzyme inhibitors (ACEi) retard the progression of both diabetic [1] and non-diabetic [2] native kidney disease. This observation has been extended to angiotensin-II receptor antagonists (ARB), at least in type 2 diabetics [35]. However, these drugs are still not widely used in renal transplant recipients due to fears of precipitating hyperkalaemia, anaemia and decline in renal function [6], despite previous studies that have demonstrated their safety and efficacy [7]. While they are known to be effective for post-transplant hypertension [8], it is not known if ACEi and ARB have the potential long-term benefit in slowing the progressive deterioration of renal function that occurs in established allograft nephropathy. The current study reviews the long-term effect of administering ACEi and/or ARB on the rate of decline in function of renal allografts following diagnostic biopsy for progressive renal allograft dysfunction.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We reviewed the charts of all adult single-organ renal transplant recipients transplanted at our centre between 1981 and 1998 and identified the subset prescribed an ACEi or an ARB. Our experience with respect to both safety and efficacy in this population has been reported previously [7]. From this group, we identified a cohort that had been prescribed either agent only after a renal biopsy was performed for progressive allograft dysfunction based on deteriorating renal function and characterized as having allograft nephropathy. For study purposes, biopsy specimens were defined as having chronic allograft nephropathy (CAN) if there was a primary immunological component or allograft damage in the absence of recurrent or de novo glomerular disease or calcineurin-inhibitor toxicity. This latter group was designated as ‘Other’. CAN was further subdivided into grade 1 or mild, characterized by mild interstitial fibrosis (ci1) and tubular atrophy or loss (ct1); grade 2 or moderate, defined by moderate interstitial fibrosis (ci2) and tubular atrophy or loss (ct2); and grade 3 or severe, characterized by marked interstitial fibrosis (ci3) and severe tubular atrophy or loss (ct3). Since the study was conducted retrospectively, the pathologist interpreting the biopsy results was blinded to the patient's outcome. Patients were included if there were at least two serum creatinine (SCr) measurements in the 18 months prior to ACEi or ARB therapy and a 3–5 year follow-up post-ACEi or ARB initiation or allograft loss. Patients were excluded from the study if the biopsy specimen contained evidence of acute rejection or if there was a clinical suspicion of acute rejection prior to the biopsy. Demographic characteristics, patient and graft survival, renal function, serum potassium, haemoglobin, 24 h proteinuria and interval blood pressure were collected by chart review.

Renal function was estimated both by SCr and Cockcroft–Gault [9] estimation of the creatinine clearance (ClCr). However, data on weight was not available at all time points, therefore, the rate of decline in renal function both pre- and post-initiation of ACEi or ARB therapy was estimated by plotting the slope (m) of the reciprocal SCr vs time. By definition, a less negative slope indicated a slowing in the decline in renal function. Slopes were compared by the Wilcoxon signed rank test. Graft survival in recipients with and without CAN was plotted using Kaplan–Meier methodology with comparisons made by the log-rank test. A two-tailed P-value of <0.05 was considered significant for all analyses. Renal function analysis included only those patients with a functioning allograft at last follow-up. The Friedman test for non-parametric repeated measures was used for comparisons of mean arterial pressures. The Statistical Package for the Social Sciences (SPSS®; Chicago, IL, USA) was used for most analyses except slope analysis, which was done with the Statistical Analysis System (SAS®; Cary, NC, USA).



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
There were 642 patients who received a renal transplant at our centre between 1981 and 1998. The safety and efficacy of ACEi and ARB use has previously been reported in this population [7]. Of the 177 patients from that cohort, 56 (32%) (study cohort) were prescribed either agent following an allograft biopsy diagnosis of CAN (n = 40): CAN grade 1 (n = 15), CAN grade 2 (n = 15), CAN grade 3 (n = 10), recurrent glomerular disease (n = 7), calcineurin-inhibitor toxicity (n = 2) or an undetermined/mixed chronic aetiology (n = 7). The demographics of this cohort are provided in Table 1. At the time of ACEi/ARB initiation, 39 patients were on cyclosporin microemulsion, four on tacrolimus, 47 on prednisone, 36 on azathioprine, four on mycophenolate mofetil (MMF) and two on sirolimus. During the follow-up period, six patients were switched from cyclosporin to tacrolimus and five were switched from azathioprine to MMF. Twenty-five patients were given enalapril, 14 ramipril, nine other ACEi, seven losartan and in three patients an ACEi was later switched to losartan. There were neither any patients on both an ACEi and an ARB during the period of follow-up or any patients who crossed over from ARB to ACEi therapy.


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Table 1. Baseline demographics

 
Graft survival was 83% at 5 years, with no difference in survival by histopathological diagnosis as the reason for chronic renal allograft dysfunction (Figure 1). There were 12 graft losses in all, with 10 losses occurring in the CAN group (event rate 10/40, 25%). By subgroup, there were 4/15 (26.6%) allografts lost in CAN grade 1, 3/15 (20.0%) losses in CAN grade 2 and 3/10 (30.0%) lost in those with CAN grade 3. There were 2/16 (12.5%) allografts lost in the non-CAN or ‘other’ group. None of these differences reached statistical significance. In addition, there was no survival difference between recipients of living donors vs those of cadaveric donors (data not shown). SCr was 191±97 (86–377) µmol/l at the time of biopsy and 228±102 (102–575) µmol/l at last follow-up. The change in SCr by subgroup for those with functioning allografts at follow-up is illustrated in Table 2. There was a trend towards improvement in SCr for the subgroup with CAN grade 1, with a statistical rise in SCr for CAN grade 2 and ‘other’ biopsy diagnoses.



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Fig. 1. Allograft survival. The proportion of allografts surviving vs time is illustrated. CAN is shown by the dashed line and the solid line illustrates ‘other’ biopsy diagnosis. These were not significantly different.

 

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Table 2. Renal function by biopsy diagnosis

 
The calculated ClCr was 57±23 ml/min at ACEi/ARB initiation, 58±24 ml/min at 1 year, 55±21 ml/min at 2 years, 55±23 ml/min at 3 years, 50±29 ml/min at 4 years and 48±31 ml/min at 5 years.

Figure 2 illustrates the change in renal function pre- and post-ACEi/ARB. The mean slope±SD was –0.06±0.21 l/µmol x 10–3 per month in the 12 months prior to therapy and –0.03±0.09 l/µmol x 10–3 per month following therapy. The absolute difference in slopes was 0.03 (P =<0.0001).



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Fig. 2. Slope of reciprocal serum creatinine. Change in renal function both pre- and post-initiation of ACEi/ARB is depicted. The mean slope±SD was –0.06±0.21 l/µmol x 10–3 per month in the 12 months prior to therapy and –0.03±0.09 l/µmol x 10–3 per month following therapy. The absolute difference in slopes was 0.03 (P =<0.0001).

 
The improvement in glomerular filtration rate (GFR) with ACEi/ARB was independent of blood pressure, as the mean arterial pressure (MAP) did not change over the course of the study. The MAP was 106.6±7.8 mmHg at 6 months pre-ACEi/ARB, 110.0±16.6 mmHg at time 0, 103.7±12.5 mmHg at 6 months post-therapy, 110.3±8.1 mmHg at 24 months, 108.0±5.4 mmHg at 48 months and 100.6±8.1 mmHg at 60 months post-ACEi/ARB. None of these differences were statistically different.

In this cohort there were seven patients with proteinuria >2 g/day. The mean proteinuria was 3.4±0.5 g/day pre-ACEi/ARB and decreased to 1.7±0.4 g/day at last follow-up. Although a positive trend, the numbers were too small to achieve statistical significance.

At baseline, the [K+] was 4.4±0.6 mEq/l and it was 4.6±0.6 mEq/l at the end of the study. Haemoglobin at baseline was 124±27 mg/dl and was 122±19 mg/dl at study end. Neither of these differences reached statistical significance.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This retrospective cohort study of the effects of long-term ACEi and ARB administration to a group of renal transplant recipients demonstrates that renin–angiotensin system (RAS) blockade can slow the rate of progression of established chronic renal allograft dysfunction and is also associated with excellent long-term graft function and survival. To date this is the longest reported follow-up of patients with allograft nephropathy prescribed specific treatment for this condition. Despite the presence of biopsy-proven allograft nephropathy and suboptimal renal function at baseline, the 83% overall 5 year allograft survival compares favourably with the survival of renal allografts in general. At our centre, 5 year allograft survival following the first year post-transplant is 86%. The improvement in slope of the rate of decline in renal function associated with RAS inhibition was both clinically and statistically significant. Moreover, although patients with CAN demonstrated a trend towards greater allograft loss over the follow-up period than those with other chronic conditions in the allograft, the benefits of RAS inhibition were seen in both groups. Importantly, the improvement in GFR was independent of blood pressure control as there was no sustained blood pressure improvement with ACEi/ARB. The stable blood pressure in this subgroup is in contrast to what we have described previously in the larger cohort of 177 patients prescribed ACEi/ARB [7].

Our findings must be interpreted in the context of the design of the study. First, these data were collected retrospectively and exclude those patients who lost their allografts very early on post-ACEi/ARB initiation. Second, patients who could not tolerate ACEi/ARB were also excluded from this analysis. In our previously published report, ~25% of patients had to discontinue ACEi/ARB therapy for a variety of reasons [7]. Third, while there was no ‘control group’, the design of the study allowed each patient to serve as his/her own control, with 18 month data pre-ACEi/ARB and the benefit of a 60 month follow-up. A proper randomized control trial with ACEi or ARB with an endpoint of renal allograft survival in recipients with CAN would require between 150 and 250 patients per group, depending on the magnitude of the difference and the length of follow-up. It is unlikely that such a trial would be feasible. In addition to the initiation of ACEi/ARB, there were a number of immunosuppressive changes made following the biopsy diagnosis. The overall net benefit of immunosuppressant change could not be determined in this study. With respect to immunosuppression, while calcineurin inhibitors have the greatest negative impact on renal function, in none of our patients were calcineurin inhibitors discontinued. Thus, the benefit seen in improvement in GFR could not be attributed to the calcineurin effect.

This report extends the published experience with ACEi and ARB in slowing the decline of renal function to the transplant population. The benefit of RAS inhibition in ameliorating CAN has been shown previously in animal models [10]. ACEi have been shown to reduce leukocyte infiltration, inhibit growth factor mRNA and reduce proteinuria in a rat model [11]. In the Fisher into Lewis rat model of CAN, angiotensin-II blockade prevents glomerulosclerosis, although graft vascular intimal hyperplasia was induced [12]. Using a similar model, Noris et al. [13] showed that the combination of MMF and losartan was effective in preventing chronic rejection. The clinical experience with RAS blockade in CAN has, unfortunately, been limited. ACEi are at least as effective as calcium-channel blockers in controlling blood pressure and preserving GFR, although one randomized clinical trial demonstrated a better GFR with a calcium-channel blocker at 2 years [14]. Differing intrarenal haemodynamics between these two classes of drugs [8], similar to that seen in native kidneys, might explain these results. Furthermore, despite the different levels of GFR, differences in graft survival have not been shown to date. A previous study demonstrated a 50% increase in baseline SCr in 19% of an ACEi/ARB-treated group at 27 months, compared with 39% in a group not on either agent [15]. Several groups have demonstrated a reduction in proteinuria in ACEi- and ARB-treated patients [7,16,17].

ACEi and ARB may be used safely when used according to guidelines that are now emerging [7,8]. The control of renal allograft nephropathy is becoming especially important with the suppression of acute rejection rates and wider cadaveric donor acceptance from donor supply–recipient demand mismatch [18]. Although our study is limited by lack of randomization to type of therapy and the absence of a control group, it seems reasonable to propose that ACEi and ARB may be used in the long term in patients with established chronic renal allograft dysfunction with excellent results. Due to the extreme difficulty inherent in performing trials with sufficient power to prove their benefit prospectively [19], we might be limited to similar evidence for the foreseeable future. We, as well as others, have suggested that these drugs be considered as a mainstay of therapy post-renal transplantation [2022]. Certainly, a proactive approach to retarding progression of CAN that includes RAS inhibition is warranted.

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: 23. 5.03
Accepted in revised form: 1.10.03





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