No Improvement of Patient or Graft Survival in Transplant Recipients Treated with Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Type 1 Receptor Blockers: A Collaborative Transplant Study Report
Gerhard Opelz*,
Martin Zeier,
Gunter Laux*,
Christian Morath and
Bernd Döhler*
Departments of * Transplantation Immunology and Nephrology, University of Heidelberg, Heidelberg, Germany
Address correspondence to: Prof. Gerhard Opelz, Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany. Phone: +49-6221-56-4013; Fax: +49-6221-56-4200; gerhard.opelz{at}med.uni-heidelberg.de
Received for publication May 31, 2006.
Accepted for publication August 27, 2006.
It was reported recently that treatment of kidney transplantrecipients with angiotensin-converting enzyme inhibitors (ACEI)or angiotensin II type 1 receptor blockers (ARB) is associatedwith strikingly improved long-term graft and patient survival.This finding has important implications for future posttransplantationtherapy recommendations. In an analysis of 17,209 kidney and1744 heart transplant recipients, an association of treatmentwith ACEI/ARB with improved transplant outcome could not beconfirmed. It is concluded that recommendations for a widespreaduse of ACEI/ARB treatment in transplant recipients are unwarranted.
Research in clinical kidney transplantation is increasinglyfocusing on long-term outcome. A recent publication by Heinzeet al. (1), based on an analysis of 2031 patients, receivedmuch attention because it showed that treatment with angiotensin-convertingenzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers(ARB) resulted in strikingly better long-term graft and patientsurvival as compared with patients who did not receive suchtreatment. Patient survival was approximately 20% and graftsurvival was approximately 30% better at 5 yr in patients whoreceived ACEI or ARB treatment, a result that is nothing lessthan spectacular. A lower rate of cardiovascular death was identifiedas the main treatment benefit. Consequently, the authors recommendedmore frequent use of these medications in kidney transplantrecipients. If confirmed, then treatment with ACEI or ARB wouldrepresent the most powerful hitherto documented means by whichlong-term graft and patient survival can be improved. Becauseof the far-reaching implications of this important finding,potentially beyond the field of renal transplantation, we conductedan analysis of ACEI/ARB in kidney and heart transplant recipientswho were reported to the Collaborative Transplant Study (CTS)(2).
All recipients of a first kidney transplant that was performedfrom 1995 through 2004, who had a functioning graft 1 yr aftertransplantation, and for whom information was available on treatmentor the absence of treatment with an ACEI or ARB were includedin this analysis. Information on treatment with ACEI or ARBwas requested on the CTS (2) questionnaires from 1995 onwardat yearly intervals after transplantation and typically wasprovided by centers that use ACEI/ARB in some of their patients.A total of 107 of 299 kidney transplant centers that participatedin CTS provided data on ACEI/ARB use, which is part of the nonmandatory"extended follow-up" CTS study questionnaire (2). Of centersthat provided information on extended follow-up, the part ofthe questionnaire on ACEI/ARB use was completed for 85.1% ofpatients followed. A parallel analysis was performed in recipientsof cardiac transplants who were reported to the CTS registryby 36 centers.
Graft and patient as well as death-censored graft survival ratescommencing 1 yr after transplantation (the first data pointat which treatment with ACEI/ARB was recorded) were computedaccording to the Kaplan-Meier method (3), and the log rank testwas used to estimate statistical significance. MultivariateCox regression analysis (4) was performed using the covariablesyear of transplantation, donor relationship (deceased, HLA-identicalsibling, HLA haplotype-matched related, other living donor),recipient geographic origin (continent), original disease thatled to ESRD, duration of pretransplantation dialysis, recipientand donor gender, race and age, number of HLA mismatches, preformedpanel-reactive lymphocytotoxic antibodies, cold ischemia timein hours, and indication of increased pretransplantation cardiovascularrisk, as well as the following variables that were recordedat 1 yr after transplant: Systolic BP, treatment for hypertensionother than diuretics, immunosuppression with calcineurin inhibitoror not, treatment for rejection during first posttransplantationyear, and serum creatinine. Confounder variables were categorizedsuitably for Cox regression analysis, and interaction termswere considered appropriately. P < 0.05 was taken to indicatestatistical significance.
In total, 17,209 kidney transplant recipients were includedin this analysis. Approximately one third (33.5%) of the patientswere on treatment with an ACEI or ARB 1 yr after transplantation.The fraction of recipients who were receiving ACEI/ARB increasedfrom 17% in 1996 to 28% in 2000 and further to 46% in patientswho received a transplant in 2004. Using treatment with ACEIor ARB 1 yr after transplantation as an indicator, we foundno evidence for improved graft or patient survival during thesubsequent 5 yr in patients who received treatment (Figure 1).The graft survival rates at 6 yr for patients with or withoutACEI/ARB treatment were 82.5% (SE 0.8%) and 83.7% (SE 0.5%;P = 0.40), and the corresponding patient survival rates were91.1% (SE 0.6%) and 92.0% (SE 0.4%), respectively (P = 0.32).Neither was there a difference in death-censored graft survival:89.4% (SE 0.7%) versus 89.5% (SE 0.4%), respectively (P = 0.72).Multivariate Cox regression analysis considering multiple confoundersconfirmed this result; associated risk ratios (RR) for importantpotential confounders are listed in Table 1. The Cox regressionresult suggests that confounding background factors were notresponsible for our inability to detect an advantage of ACEI/ARBtreatment (graft survival: risk ratio RR 1.05 [95% confidenceinterval (CI) 0.94 to 1.17; P = 0.42]; patient survival: RR1.01 [95% CI 0.86 to 1.18; P = 0.90]). Neither was a beneficialeffect of treatment demonstrable when recipients of grafts fromdeceased donors or living donors were analyzed separately (Figure 2).The rate of cardiovascular death in patients with or withoutACEI/ARB treatment was virtually identical, showing a negligibledifference of 0.4% (P = 0.66).
Figure 1. Graft (left) and patient (right) survival rates of kidney transplant recipients either on treatment with angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers (ACEI/ARB) 1 yr after transplantation (+ACEI/ARB) or not treated with ACEI/ARB (–ACEI/ARB). Numbers of patients studied and percentage of survival are indicated at bottom. There was no significant difference in survival between patients who did or did not receive ACEI/ARB treatment.
Table 1. Risk ratios for confounders in Cox regression analysis for graft survival from 2 to 6 yr: First kidney transplants performed 1995 through 2004a
Figure 2. Comparison of graft survival in recipients of kidney transplants from deceased donors (left) or living donors (right). Treatment with ACEI/ARB showed no significant influence on graft survival.
Because this finding was in stark contrast to the publicationof Heinze et al. (1), we performed additional analyses to testthe robustness of our data. We limited the analysis to recipientsof deceased-donor transplants and examined first whether the1-yr indicator point might have been insufficient for identifyingpatient subgroups with sufficient ACEI/ARB exposure. Therefore,we analyzed patients who were known to have received ACEI/ARBat 1, 2, and 3 yr and compared them with patients who did notreceive treatment at 1, 2, and 3 yr. Analysis of graft survivalfor the subsequent 3 yr showed no difference between the twogroups (Figure 3). Neither was there a difference in patientor functional survival. We were able to observe 1519 patientsafter 5 yr of follow-up, 491 of whom were recorded to have beentreated at each yearly interval from 1 to 5 yr with ACEI/ARBand 1028 of whom were never treated. Subsequent follow-up wastoo short for meaningful survival computations. However, thetwo groups of patients had a virtually identical distributionof serum creatinine values at 5 yr: 53.0% of patients on continuousACEI/ARB treatment had a creatinine of <130 µmol/L,44.4% had 130 to 259 µmol/L, 2.0% had 260 to 400 µmol/L,and 0.6% had >400 µmol/L. The corresponding valuesfor patients who never received ACEI/ARB were 51.8% with <130µmol/L, 44.0% with 130 to 259 µmol/L, 3.3% with260 to 400 µmol/L, and 0.9% with >400 µmol/L(Mantel-Haenszel test: P = 0.37). In the absence of detaileddata on posttransplantation cardiovascular comorbidity, we focusedon subgroups of patients who could be presumed to be at increasedcardiovascular risk: Patients with diabetic or hypertensivenephropathy, patients who were categorized by the transplantcenters before transplantation to be at increased cardiovascularrisk, patients who were older than 60 yr, patients with a 1-yrsystolic BP of 140 mmHg, patients with a total serum cholesterolat 1 yr of 200 mg/dl, and patients with a 1-yr serum creatinineof 130 µmol/L. In none of these patient subsets coulda significant advantage of treatment with ACEI/ARB be demonstrated(Table 2). The result comparing graft outcome in patients withor without ACEI/ARB treatment in relation to systolic BP suggeststhat treatment with ACEI/ARB does not exert a BP-independentbeneficial effect. Figure 4 illustrates that the widely knowndeleterious effect of posttransplantation hypertension on kidneygraft survival (5) was determined by the extent to which BPwas controlled, irrespective of whether patients were treatedwith ACEI/ARB. We next examined whether treatment with ACEI/ARBmight affect the survival rate of heart transplant recipients.As shown in Figure 5, no significant treatment benefit was found(RR 0.88; 95% CI 0.63 to 1.23; P = 0.46).
Figure 3. Analysis of patients who were treated with ACEI/ARB 1, 2, and 3 yr after transplantation with patients who were not receiving treatment at 1, 2, and 3 yr. Graft survival during the subsequent 3 yr was not significantly different (P = 0.14).
Figure 4. Graft survival rates in patients with or without ACEI/ARB treatment according to systolic BP 1 yr after transplantation. A deleterious effect of hypertension on graft survival was noted regardless of whether patients were treated with ACEI/ARB (regression P < 0.001 in both patient groups shown). Outcome was related to the degree of BP control and not to treatment with ACEI/ARB. In none of the BP subgroups was the difference in graft survival between patients with or without ACEI/ARB statistically significant.
Figure 5. Survival of heart transplants in patients with or without ACEI/ARB treatment 1 yr after transplantation. No significant difference in long-term survival was observed.
On the basis of favorable results that were obtained in studiesof nontransplantation patients who were at high cardiovascularrisk (6–8), it was a reasonable hypothesis to proposea beneficial effect of treatment with ACEI/ARB in kidney transplantrecipients. ACEI/ARB treatment reduces myocardial infarction,stroke, and cardiovascular death in nontransplant populations(6–8). Cardiovascular death is a main cause of death inkidney recipients (9). We are unaware of large, prospectivestudies aimed at the evaluation of ACEI/ARB treatment in transplantrecipients. However, off-label treatment of transplant patientswas initiated in the mid-1990s in the hope that the rate ofcardiovascular death might be lowered. Furthermore, the provenefficacy of treatment with ACEI/ARB on progression of nativerenal disease (10,11) led to speculation that long-term graftfunction also might benefit. These expectations were substantiatedby the recent report of Heinze et al. (1), which showed thattreatment with ACEI/ARB indeed was associated with a strikingimprovement of posttransplantation graft and patient survival.The graft survival rate was approximately 30% higher at 5 yrin patients who were receiving treatment compared with patientswho were not receiving treatment, and the corresponding differencein patient survival was equally impressive: Approximately 20%at 5 yr (1). However, in our analysis of 17,209 kidney recipientswho were reported to the CTS, we were unable to confirm a positiveeffect of treatment with ACEI/ARB.
The contrasting results that were obtained in the two studiesask for critical examination. Whereas Heinze et al. excludedthe first 90 d after transplantation from analysis, we excludedthe first posttransplantation year. The difference in methodshould not affect the ability to detect a qualitative differencein long-term outcome between groups of patients with or withoutACEI/ARB treatment. Heinze et al. reported a 5-yr patient survivalrate in patients who did not receive ACEI/ARB of approximately70% (1). This result is highly unusual. Even in the era from1985 through 1990, before ACEI/ARB was used in any kidney transplantrecipients, the CTS data show an overall patient survival ratefor recipients of diseased donor kidneys of 83% at 5 yr. Heinzeet al. excluded mortality during the first 90 d and includedan unspecified fraction of living donors, which makes the lowpatient survival rate that was obtained in their analysis evenmore unusual. The authors stated that they separated their patientsinto those who never used ACEI/ARB and those who ever used ACEI/ARB(1). Although the exact method of how this was done was notdescribed, the procedure conceivably led to an artificiallyinflated success rate for patients who were receiving ACEI/ARB.For example, a patient who did not receive treatment duringthe first 3 yr but was put on ACEI/ARB from 3 yr onward couldnot possibly have failed before year 3. By this definition,patients who never received ACEI/ARB had a possibility of failureat any time after transplantation, whereas patients in whomtreatment was initiated several years after transplantationhad a possibility of failure only subsequent to the first treatmentwith ACEI/ARB. We believe that categorization of patients accordingto treatment at a given point in time (e.g., 1 yr after transplantation)and analysis according to the "intention to treat" principleis appropriate for studying treatment effects of ACEI/ARB onlong-term outcome. A possible shortcoming of this approach isthat we cannot exclude the possibility that a patient may havebeen receiving ACEI/ARB at 1 yr and removed from treatment afew months later. Heinze et al. counted such patients in the"treated" group, and this uncertainty therefore is irrelevantfor explaining the difference between the results that wereobtained in the two studies. Our subanalysis comparing patientswho were receiving ACEI/ARB treatment at 1, 2, and 3 yr withpatients who did not receive ACEI/ARB at 1, 2, and 3 yr likelycompared a group in which most patients were on continuous treatmentwith another group in which most patients were not treated atall; this subanalysis also failed to show a treatment benefit(Figure 3). The results that were obtained in various patientrisk categories shown in Table 2, as well as the result thatwas obtained in heart transplant recipients (Figure 5), ledus to conclude that treatment with ACEI/ARB is not associatedwith noticeably improved graft or patient survival in transplantrecipients.
A limitation of our study is that information on posttransplantationcardiovascular risk factors was not available, because one wouldexpect any treatment benefits of ACEI/ARB to be pronounced inpatients who are at increased cardiovascular risk. As an approximation,we analyzed subgroups of patients who can be assumed to havebeen at increased cardiovascular risk: Patients with diabeticor hypertensive nephropathy, patients who were categorized beforetransplantation by the transplant centers to be at increasedcardiovascular risk, patients who were older than 60 yr at thetime of transplantation, patients with posttransplantation hypercholesteremia,and patients with posttransplantation hypertension. In addition,we examined 1744 heart transplant recipients. In none of thesepatient subgroups was a beneficial effect of ACEI/ARB treatmenton graft or patient survival demonstrable.
One must consider the possibility that patients who were treatedwith ACEI/ARB may have been deemed high risk on the basis ofvarious clinical parameters and that the equivalent graft andpatient survival rates that were observed in patients with orwithout treatment therefore may reflect a positive effect ofACEI/ARB in high-risk patients. In the absence of prospectivetrial data, however, such argumentation would be speculative.The strikingly higher graft and patient survival rates thatwere reported by Heinze et al. (1) were not confirmed in ouranalysis. On the basis of the currently available evidence,we believe that recommendations for the liberal treatment oftransplant recipients with ACEI/ARB are premature.
Acknowledgments
The generous support of staff members at the following 107 kidneyand 36 heart transplant centers who provided data for this studyis gratefully acknowledged: Kidney transplant centers: Aachen,Adelaide, Ankara, Antalya, Belfast, Belo Horizonte (2 centers),Berlin, Bern, Botucatu, Brisbane, Bristol, Budapest, Cape Town(2 centers), Caracas, Christchurch, Cincinnati, Cologne, Cordoba,Duesseldorf, Durban, Edmonton, Erlangen-Nuernberg, Florence,Frankfurt, Freiburg, Fulda, Geneva, Giessen, Glasgow, Goettingen,Grand Rapids, Guadalajara, Halle, Hamilton, Hann-Muenden, Hawthorne,Heidelberg, Homburg, Hong Kong (2 centers), Innsbruck, Izmir,Jena, Kaiserslautern, Katowice, Kaunas, Kermanshah, Leicester,Leuven, Liege, Lima, Linz, Ljubljana, Luebeck, Maceio, Manila,Mannheim, Maracaibo, Marburg, Martin, Medellin, Mexico City,Milan, Muenster, Nancy, Newcastle, Novara, Oviedo, Pamplona,Panama, Pato Branco, Pecs, Perth, Poitiers, Prague, Quebec,Regensburg, Reims, Rio de Janeiro, Rostock, Santander, Sao Paulo(2 centers), Seoul, Shreveport, St. Gallen, Strasbourg, Sydney(2 centers), Szeged, Tehran, Tel Aviv, Toulouse, Tuebingen,Turin, Ulm, Uppsala, Valdivia, Valencia (2 centers), Vilnius,Winnipeg, Wuerzburg, Zagreb, and Zurich. Heart transplant centers:Aachen, Auckland, Brisbane, Charleston, Columbus, Dallas, Duesseldorf,Edmonton, Essen, Giessen, Graz, Hamburg, Heidelberg, Helsinki,Hershey, Jena, Kansas City, Lausanne, Leuven, Liege, Loma Linda,Loyola, Manchester, Medellin, Miami, Milwaukee, Montreal, Nancy,Papworth-Cambridge, Paris, Quebec, Sheffield, Tucson, Turin,Vancouver, and Zurich.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
140 mmHg, patients with a total serum cholesterol at 1 yr of 
