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
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Abstract |
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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 (0.910.9) years as opposed to 1.8 (0.16.7) 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; reninangiotensin system
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Introduction |
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Subjects and methods |
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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 MannWhitney U-test when appropriate. Categorical values were analysed using the 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. KaplanMeier analysis was used to estimate median survival. A P-value of <0.05 (two-sided) was considered statistically significant.
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Results |
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The index biopsy was taken at 3.3 (1.114.0) 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 (100501) 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 (0.216.8) 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 (0.113.6) 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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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 (139) months following the graft biopsy. The ACE inhibitors or ARBs were used during 28 (577) 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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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 (0.19.3) g/10 mmol creatinine. After initiation of RAS blockade, proteinuria decreased to 1.1 (0.14.3) g/10 mmol creatinine at 3 months (P = 0.021) and 1.2 (0.16.5) 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 (121306) µmol/l. After using RAS blockade for 1 month, serum creatinine had increased to 210 (128365) 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 (0.910.9) years, as opposed to 1.8 (0.16.7) 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 (0.910.9) years] and patients not treated with RAS blockade [2.2 (0.513.6) 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) 0.682.97; P = 0.35], or between baseline and 6 months after initiation of RAS blockade [exp(B) = 1.07, 95% CI 0.651.78; 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 0.971.01; P = 0.33].
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Discussion |
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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 ischaemiareperfusion 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.
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References |
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