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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2018  |  Volume : 29  |  Issue : 3  |  Page : 637-642
Early initiation of angiotensin-converting enzyme inhibitors in postrenal transplant period: A study from a state-run tertiary care center


Department of Nephrology, Institute of Nephro-Urology, Victoria Hospital Campus, Bengaluru, Karnataka, India

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Date of Submission28-Jun-2017
Date of Acceptance26-Jul-2017
Date of Web Publication28-Jun-2018
 

   Abstract 

Angiotensin-converting enzyme inhibitors (ACEi) comprise a drug class, which are potent antihypertensives with renoprotective effects but are grossly underutilized in renal transplant recipients. These drugs have been reported to cause elevated potassium and creatinine levels in some renal transplant patients. There have been no reports of prospective studies on use of ACEi in renal transplant patients in the early post-transplant period. The purpose of this study is to assess the safety of an ACEi, when started in the early post-transplant period. In this prospective observational study, we reviewed 78 kidney transplant recipients during the period of January 2012 to March 2017 at our institution. Sixty-four patients were initiated on ACEi therapy within a month of transplantation, while 14 were initiated after one-month post-transplant; the latter was classified as late initiation group. Patients were enrolled when they met the following criteria: declining serum creatinine, improving urine output, and serum potassium <5.5 mEq/L. Exclusion criteria included anaphylaxis to ACEi, use of ACEi or angiotensin receptor blocker for the treatment of post-transplant erythrocytosis, and serum potassium >5.5 mEq/L. Sixty-four patients were studied, 53 (83%) were male and 11 (17%) were female. Mean age was 32 ± 15 years (12-56). Minimum duration of follow-up was six months. For each patient, hemoglobin, serum creatinine, and potassium levels were tested at the beginning of ACEi and at the end of the first, third, and the sixth month. The average potassium and hemoglobin levels did not differ significantly between the groups and were within the normal clinical ranges. While incidence of graft failure did not differ, death with functioning graft was lower in the ACEi group. ACEi can successfully be used in postrenal transplant with beneficial long-term impact on renal function. However, here is a need for further randomized controlled studies to validate this observation.

How to cite this article:
Sreeadhara C G, Narayanaswamy R, Lingaraju U, Leelavathi V, Shivaprasad S M. Early initiation of angiotensin-converting enzyme inhibitors in postrenal transplant period: A study from a state-run tertiary care center. Saudi J Kidney Dis Transpl 2018;29:637-42

How to cite this URL:
Sreeadhara C G, Narayanaswamy R, Lingaraju U, Leelavathi V, Shivaprasad S M. Early initiation of angiotensin-converting enzyme inhibitors in postrenal transplant period: A study from a state-run tertiary care center. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Nov 13];29:637-42. Available from: http://www.sjkdt.org/text.asp?2018/29/3/637/235185

   Introduction Top


Renal transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD) and is associated with significant improvements in survival and quality of life. Despite improvement in patient and graft survival, transplant recipients continue to die prematurely due to cardiovascular disease. The graft and patient survival has improved considerably during the last decade, but the longterm results have not been as encouraging. It is not very clear whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) are harmful or helpful for postrenal transplant patients. Many may wish to treat post-transplant patients with an ACEi or an ARB for compelling indications, and the known cardio and renoprotective effects of these agents in native kidneys may also exist in transplanted allografts.[1] On the other hand, these drugs can cause increase in serum creatinine and potassium levels, which could be mistaken for acute rejection or expose a patient to additional testing and therapy. Therefore, prospective controlled trials to guide practitioners on the use of these agents and provide perspective on the potential risks and benefits in these patients are clearly needed. In patients with stable graft function, it appears that early use of an ACEi is not associated with early deleterious effects on serum crea-tinine or potassium, and these medications may also retain their beneficial effects on reducing left ventricular hypertrophy and proteinuria. ACEi inhibits the effects of angiotensin II by blocking its synthesis. ACEi is grossly underutilized in renal transplant recipients. There have been only a few reports of the use of ACEi in renal transplant patients in the early post-transplant period.[2] There have been no prospective studies on the use of ACEi in renal transplant patients in the early post-transplant period. Hence, we felt there is a need to assess the safety of an ACEi, when started early in post-transplant period.


   Subjects and Methods Top


Aim

The purpose of this study is to assess the safety of an ACEi class, when started in early post-transplant period.

Materials and methods

This is a prospective observational study. We reviewed 78 kidney transplant patients during the period of January 2012 to October 2016 at our institution. Sixty-four patients were initiated on ACEi therapy within four weeks of post-transplant. Fourteen patients were started on calcium channel blocker (CCB) and ACEi was started after a month of post-transplant. They were classified as late initiation group. Minimum duration of follow-up was six months. A patient was considered to be enrolled in the study on the 1st day following transplantation if the following inclusion criteria were met: (a) declining serum creatinine, (b) improving urine output and (c) serum potassium <5.5 mEq/L. The exclusion criteria were: (a) evidence of transplant renal artery stenosis, (b) serum potassium >5.5 mEq/L, (c) anaphylaxis to ACEì and (d) use of ACEi or ARB for treatment of post-transplant erythrocytosis.

Immunosuppression in all patients consisted of calcineurin inhibitor tacrolimus, mycophe-nolate mofetil and prednisone. All patients received one single-strength trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis. The time points for data analysis were day 0 (day of enrollment), one-month and three, six, and nine months, post-enrollment. All data were obtained from the patient's transplant inpatient file and data sheet.

Outcomes

Primary outcomes were hyperkalemia and graft dysfunction. Secondary outcomes were graft loss and death with or without graft loss.


   Statistical Analysis Top


Values are given as means ± standard deviation. For comparison between two groups (early ACEi group and late initiation group), the Student' s t-test assuming equal variance of the mean was used to determine statistical significance. P <0.05 was chosen to represent significant differences using Mann-Whitney test.


   Results Top


Study characteristics

[Table 1] summarizes the baseline characteristics of both groups. The mean age was 32 ± 15 years (12-60) [Figure 1]. The sample size was 78 cases. The duration of the study varied from two days to five years and included only those who completed six months of follow-up. ACEi used was benazepril, ramipril, or enalapril.
Figure 1: Age distribution of the study.

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Table 1: Baseline study characteristics of the two groups of patients.

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Graft and patient survival

While the incidence of graft failure did not differ in the ACEi group, death with functioning graft was lower although it was not statistically significant (P = 0.09) [Table 2].
Table 2: Results of various parameters in the two groups of patients.

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Renal function

The study showed that the change in glo-merular filtration rate (GFR; serum creatinine estimation) was not significant when compared between early ACEi and late ACEi groups [Table 2].

Blood pressure

The data showed that there was no difference in the blood pressure (BP) between the two groups.

Anemia

The study showed that the change in hemoglobin after ACEi therapy in early initiation group and late initiation was not statistically significant [Table 2]. There was no use of erythropoiesis-stimulating agents in either of the groups.

Potassium

The mean baseline serum potassium level was higher in the late ACEi group compared to early initiation group, but on follow-up, the trend reversed. The values were statistically insignificant [Table 2]. We had one patient with hyperkalemia in the early initiation group, who was found to have tacrolimus toxicity after evaluation, and the hyperkalemia subsided once tacrolimus dose was adjusted.


   Discussion Top


The benefit of renin–angiotensin system blockade has been definitely demonstrated in nontransplant populations with increased cardiovascular (CV) risk,[3],[4],[5],[6] including patients with proteinuric and non-proteinuric CKD.[7],[8],[9],[10] In contrast, there are no studies on a long-term CV or renal outcomes in kidney transplant recipients treated with ACEi or ARBs. A few prospective randomized trials comparing ACEi/ ARB therapy to either a different class of anti-hypertensive agents or placebo have been reported.[11] However, these trials are with small sample sizes and/or very limited follow-up periods.[12],[13],[14],[15],[16],[17],[18]

Suwelack et al studied 96 non-diabetic-hypertensive patients, who were randomized to receive either atenolol or quinapril within three-months post-transplant. The study with a follow-up of five years showed similar effects on BP and graft function between groups at five years and atenolol-treated patients showed a significant increase in proteinuria compared with those receiving quinapril.[18] However, in the above study, graft and patient survival were not reported. The largest study to report graft and patient survival included 502 transplant recipients (10% were diabetic) within 10-year post-transplant, randomized to receive either candesartan or placebo.[17] When with the placebo group, the candesartan group was associated with lower BP, lesser proteinuria, and higher serum creatinine and potassium levels. The primary end point of graft survival, CV mortality, and all-cause mortality was similar between the two groups at 23 months.

Ibrahim et al conducted a study involving 154 patients (37% were diabetic) within three months of post-transplant, who were randomized to receive losartan or placebo.[14] The primary end point of graft loss because of a doubling of the fraction of renal cortical volume occupied by the interstitium or biopsy-proven interstitial fibrosis/tubular atrophy occurred in six of 47 losartan-treated patients versus 12 of 44 receiving placebo (P = 0.08) at five years. There was no difference in time to ESRD or death between the groups.

Two systematic meta-analyses also have been attempted to consolidate these data. Hiremath et al identified 21 randomized trials of three databases spanning 1966–2007 involving 1549 patients with the use of ACEi/ARBs.[19] At 27-month median follow-up time, the use of ACEi/ARBs was associated with significant reductions in proteinuria (–0.47 g/d), in glomerular filtration rate (GFR: −5.8 mL/min), and hematocrit (−3.5%) without a significant effect on potassium levels. Due to insufficient data, the effects on patient, and graft survival were not assessed. Cross et al reported a Cochrane Database systematic review two years later, which included seven studies comparing a group receiving ACEi with CCBs with 405 patients and 10 studies comparing a group on ACEi with placebo with 445 patients.[20] Compared with CCBs, the use of ACEi was associated with a significant reduction in proteinuria (–0.28 g/d), GFR (–11.49 mL/min), and hemoglobin (–1.3 g/dL), with a 2.74-fold elevated relative risk of hyperka-lemia. Again, data on graft loss and patient survival were not reported.

Even though results from prospective trials have not provided sufficient data regarding the effects on graft and patient survival, many large retrospective database analyses have offered some insight. Using the Austrian Dialysis and Transplant Registry and Eurotransplant data-bases, Heinze et al studied 2031 patients receiving kidney transplant at a single center between 1990 and 2003.[21] Compared with no ACEi/ARB therapy, any documented ACEi/ARB use was associated with improved 10-year graft survival (59% versus 41%, P = 0.002) and patient survival (74% versus 53%, P <0.001). However, another retrospective analysis, the Collaborative Transplant Study of 17,209 patients transplanted between 1995 and 2004, was unable to show a difference in graft survival at six years in patients either on or off ACEi/ARB therapy at one-year post-transplant including subpopulations of diabetic patients and patients at higher pretransplant CV risk.[22]

Therefore, definitive evidence for the benefit of ACEi/ARB therapy in transplant recipients is lacking. Although ACEi/ARB therapy is associated with reduced GFR, anemia, and hyperkalemia, these drugs are effective in reducing hypertension and proteinuria. An ongoing prospective, double-blinded, randomized control trial of 500 at-risk post-transplant recipients involving 11 Canadian transplant centers will evaluate the effectiveness of ramipril versus placebo on a composite end point of doubling of serum creatinine, ESRD, or death and will add crucial insight into this controversial and unresolved clinical dilemma.[23]

Our study is the first prospective study from India on the use of ACEi in early posttrans-plant period, which showed no significant difference in BP, serum creatinine, hemoglobin level, and graft survival when compared with the late initiation of ACEi.


   Conclusion Top


ACEi can be used successfully postrenal transplant with beneficial long-term impact on renal function. There is a need for further randomized controlled studies to see the effect of ACEi on graft function and its survival.

Conflict of interest: None declared.

 
   References Top

1.
Remuzzi G, Perico N. Routine renin-angiotensin system blockade in renal transplantation? Curr Opin Nephrol Hypertens 2002;11:1-0.  Back to cited text no. 1
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2.
Midtvedt K, Hartmann A, Foss A, et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril. Transplantation 2001;72:1787-92.  Back to cited text no. 2
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3.
Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 2002;359:995-1003.  Back to cited text no. 3
    
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Fox KM, EURopean Trial On Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8.  Back to cited text no. 4
    
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Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 2002;359:1004-10.  Back to cited text no. 5
    
6.
Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53.  Back to cited text no. 6
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Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in protei-nuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997; 349:1857-63.  Back to cited text no. 7
    
8.
Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs. amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial. JAMA 2001;285:2719-28.  Back to cited text no. 8
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9.
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9.  Back to cited text no. 9
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Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60.  Back to cited text no. 10
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11.
Salzberg DJ, Karadsheh FF, Haririan A, Reddivari V, Weir MR. Specific management of anemia and hypertension in renal transplant recipients: Influence of renin-angiotensin system blockade. Am J Nephrol 2014;39:1-7.  Back to cited text no. 11
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12.
Andrés A, Morales E, Morales JM, Bosch I, Campo C, Ruilope LM; Valsartan in Renal Transplantation Group. Efficacy and safety of valsartan, an angiotensin II receptor antagonist, in hypertension after renal transplantation: A randomized multicenter study. Transplant Proc 2006;38:2419-23.  Back to cited text no. 12
    
13.
Formica RN Jr., Friedman AL, Lorber MI, Smith JD, Eisen T, Bia MJ. A randomized trial comparing losartan with amlodipine as initial therapy for hypertension in the early post-transplant period. Nephrol Dial Transplant 2006;21:1389-94.  Back to cited text no. 13
    
14.
Ibrahim HN, Jackson S, Connaire J, et al. Angiotensin II blockade in kidney transplant recipients. J Am Soc Nephrol 2013;24:320-7.  Back to cited text no. 14
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Iñigo P, Campistol JM, Lario S, et al. Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients. J Am Soc Nephrol 2001;12:822-7.  Back to cited text no. 15
    
16.
Martínez-Castelao A, Hueso M, Sanz V, et al. Double-blind, crossover, comparative study of doxazosin and enalapril in the treatment of hypertension in renal transplant patients under cyclosporine immunosuppression. Transplant Proc 2002;34:403-6.  Back to cited text no. 16
    
17.
Philipp T, Martinez F, Geiger H, et al. Candesartan improves blood pressure control and reduces proteinuria in renal transplant recipients: Results from SECRET. Nephrol Dial Transplant 2010;25:967-76.  Back to cited text no. 17
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18.
Suwelack B, Kobelt V, Erfmann M, et al. Long-term follow-up of ACE-inhibitor versus beta-blocker treatment and their effects on blood pressure and kidney function in renal transplant recipients. Transpl Int 2003;16:313-20.  Back to cited text no. 18
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19.
Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA. Renin angiotensin system blockade in kidney transplantation: A systematic review of the evidence. Am J Transplant 2007;7:2350-60.  Back to cited text no. 19
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20.
Cross NB, Webster AC, Masson P, O'Connell PJ, Craig JC. Antihypertensive treatment for kidney transplant recipients. Cochrane Database Syst Rev 2009;3:CD003598.  Back to cited text no. 20
    
21.
Heinze G, Mitterbauer C, Regele H, et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol 2006;17:889-99.  Back to cited text no. 21
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22.
Opelz G, Zeier M, Laux G, Morath C, Döhler B. 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. J Am Soc Nephrol 2006;17:3257-62.  Back to cited text no. 22
    
23.
Knoll GA, Cantarovitch M, Cole E, et al. The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation - Study design. Nephrol Dial Transplant 2008;23:354-8.  Back to cited text no. 23
[PUBMED]    

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Correspondence Address:
Umesh Lingaraju
Department of Nephrology, Institute of Nephro-Urology, Victoria Hospital Campus, Bengaluru, Karnataka
India
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DOI: 10.4103/1319-2442.235185

PMID: 29970741

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