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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 6  |  Page : 1128-1132
Safety and efficacy of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in chronic allograft injury


1 Department of Nephrology and Clinical Transplantation, Laboratory Medicine, Transfusion Services and Immunohematology, Institute of Kidney Diseases and Research Center, Institute of Transplantation Sciences (IKDRC-ITS), Ahmedabad, Gujarat, India
2 Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, Institute of Kidney Diseases and Research Center, Institute of Transplantation Sciences (IKDRC-ITS), Ahmedabad, Gujarat, India

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Date of Web Publication8-Nov-2011
 

   Abstract 

Angiotensin II plays a crucial role in the development of chronic allograft injury (CAI). Clinical experience with angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockade (ARBS) in CAI has unfortunately been limited. We carried out a prospective one year single center case controlled study to analyze the effect of ACEI /ARBS on the progression of CAI and in decreasing proteinuria. One hundred patients with CAI were evaluated. Of the 100 patients, 50 were selected to receive ACEI/ ARBS (group 1) and 50 managed without ACEI/ARBS (group 2). Their remaining management was similar in both the groups. Patients with hyperkalemia, history of allergic reactions, ACEI/ARBS intake and pregnancy were excluded. Average time for development of CAI was 19.6 ± 12.7 months in group 1 vs. 20.8 ± 12.8 in group 2. In group 1, mean systolic/diastolic BP was 136/82 mmHg at the time of establishment of CAI and 124/76 mmHg at the end of one year, and in group 2, it was 138/86 mmHg vs. 126/80 mmHg, respectively. Mean glomerular filtration rate (GFR) was 48.78 ± 13.4 in the former vs. 44.23 ± 8.14 in the latter. ACEI/ARBS administration was associated with stabilization of serum creatinine. GFR was maintained up to one year after CAI. Group 1 had a decrease in proteinuria by 1.41 g/day as compared with group 2 with proteinuria of 0.83 g/day. ACEI/ARBS administration is beneficial in CAI for BP control and significant decrease in proteinuria along with the stabilization of graft function.

How to cite this article:
Shah P R, Kute V B, Saboo D S, Goplani K R, Gumber M R, Vanikar A V, Patel H V, Trivedi H L. Safety and efficacy of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in chronic allograft injury. Saudi J Kidney Dis Transpl 2011;22:1128-32

How to cite this URL:
Shah P R, Kute V B, Saboo D S, Goplani K R, Gumber M R, Vanikar A V, Patel H V, Trivedi H L. Safety and efficacy of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in chronic allograft injury. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2017 Nov 24];22:1128-32. Available from: http://www.sjkdt.org/text.asp?2011/22/6/1128/87206

   Introduction Top


Chronic allograft injury (CAI), the entity encompassed by the previous descriptive term "chronic allograft nephropathy" (CAN), has been defined as progressive renal dysfunction (at least three months post-transplant) independent of acute rejection (AR), drug toxicity, and recurrent/de novo nephropathy with histological changes of vascular intimal hyperplasia, tubular atrophy, interstitial fibrosis, and chronic transplant glomerulopathy. [1] The pathophysiology of CAI is complex and multi-factorial. Both alloantigen dependent factors like acute rejection (AR), human leukocyte antigen (HLA) matching, ABO incompatibility, donor-specific antibodies (DSA), inadequate immunosuppression, and allo-antigen independent factors like donor age, living-related/deceased donor, ischemia-reperfusion injury, injuries associated with calcineurin inhibitors (CNI), virus related injuries, hypertension, hyperlipidemia, and diabetes mellitus, etc. are involved in its causation. [2],[3],[4] The immune involvement and factors responsible for CAI are yet undefined although it remains the major cause of renal allograft failure. [5],[6]

Both, renal function [7] and histology [8] correlate with the ultimate prognosis of the graft. CAI index at two years correlates with transplant function at six years associated with eventual graft failure despite improvement in immunosuppression regimes. Current therapeutic strategies for patients with CAI involve minimization/elimination of CNI, good blood pressure (BP) control, blood sugar control, treatment for dyslipidemia, and use of sirolimus. Angiotensin II plays a crucial role in pathologenesis of CAI. Systemic and glomerular hypertension with proteinuria occurs in CAI under conditions of juxtaglomerular hypertrophy with up-regulated renin-angiotensin (RAS) activity in the renal allograft. These represent independent risk factors for rapid progression of renal allograft failure. The clinical experience with RAS blockade in CAI has unfortunately been limited. Angiotensin-converting enzyme inhibitors (ACEI) are as effective as calcium-channel blockers in controlling BP and preserving glomerular filtration rate (GFR). [9] ACEI retard the progression of both diabetic [2] and non-diabetic [3] native kidney diseases. This observation has been extended to angiotensin-II receptor antagonists (ARB), at least in type 2 diabetics. [4],[5] However, these drugs are still not widely used in renal transplant recipients due to fear of precipitating hyperkalaemia, anemia, and decline in renal function. [10]


   Material and Methods Top


This study was conducted as a prospective single center case controlled study. We enrolled 100 non-diabetic patients from October 2006 through January 2008 with biopsy findings of CAI associated with minimum rise in serum creatinine (SCr) of >10% from baseline. All patients had interstitial fibrosis with tubular atrophy without C4d staining on kidney biopsy. Exclusion criteria were hyperkalemia with serum potassium levels >5.5 mEq/dL, history of allergic reaction to ACEI/ARBS, pregnancy, and patients already on ACEI/ARBS. In addition, those with renal allograft biopsies with primary immunological component/recurrent or de novo glomerular disease or CNI toxicity were also excluded from the study. Patients were divided into two groups; 50 in each group. ACEI/ARBS were administered in group 1; and group 2 did not receive it. The remaining management was similar in both the groups. All patients were on cyclosporine-A (CSA) and CSA levels were within the acceptable range and comparable between the two groups. The baseline immunosuppression and dietary potassium intake were unaltered in both the groups; stringent BP control, dyslipidemia control by diet adjustment, and necessary drug therapy if required were given.

The study and written informed consent forms were approved by the Institutional Review Board.

Once CAI was established, each patient was followed up for one year; weekly in the first month, fortnightly for next two months, monthly for next six months, and thereafter once every three months. During every visit, detailed clinical history and physical examination with special emphasis on BP and body weight was carried out. Laboratory evaluation included hemogram, SCr, blood urea, fasting and post-prandial blood sugar, urine routine and microscopy, electrolytes, and lipid profile.

Group 1 was administered ACEI/ ARBS, starting at 50 mg/day for losartan or 2.5 mg/day of ramipril and after evaluating for side-effects and tolerance, gradually doses were increased to 100 mg/day for losartan and 10 mg/day for ramipril. Outcome of interest was safety, allograft survival, and decrease in proteinuria, BP control, changes in lipid profile and SCr preand post-ACEI/ARBS administration. Group 2 was studied similarly.

The Modification of Diet in Renal Disease (MDRD) method was used to estimate creatinine clearance on each visit. Patients were excluded from the study if the biopsy (when performed for acute graft dysfunction) revealed evidence of AR.


   Results Top


In both the groups, chronic glomerulonephritis (CGN) was the most common native kidney disease followed by chronic tubulo-interstitial nephritis (CIN) due to reflux nephropathy or posterior urethral valves, urinary tract obstructtion; and these were also comparable in both the groups. Mean age was 38 years (range: 18-67 years) in group 1; and 31 years (range: 18-70 years) in group 2. The average time for development of CAI after transplantation was 19.6 ± 12.68 months in group 1, vs. 20.82 ± 12.80 in group 2. In both the groups, 11 patients received deceased donor organ transplants. Thirty patients in group 1 and thirty one in group 2 had developed AR before enrollment.

In the first group, mean systolic/diastolic BP was 136/82 mmHg at time of establishment of CAI and 124/76 mmHg at the end of one year; and in second group, it was 138/86 mmHg vs. 126/80 mmHg, respectively.

First drug used for control of blood pressure was ACEI/ARBS. Calcium channel blocker and centrally acting drug clonidine, respectively, were the second and third drugs to be used. In both the groups, patient required two to three drugs to control the blood pressure.

Mean SCr in group 1 was 1.97 ± 0.25 mg/dL at the time of development of CAI vs. 1.96 ± 0.22 mg/dL in group 2. At the end of one year mean SCr was 2.10 ± 0.36 mg/dL vs. 2.35 ± 0.38 mg/dL in group 2. Mean SCr was 2.04 ± 0.26 after six months of CAI in the ACEI and ARBS group, while it was 2.16 ± 0.28 in the other group. At six months of CAI, difference in the average SCr rise between the two groups was 0.13 mg%. Average SCr rise in ACEI and ARBS was 0.07 mg%, while it was 0.2 mg% in the other group. At one year of CAI, difference in the average SCr rise between the two groups was 0.26 mg%. Average SCr rise in ACEI and ARBS was 0.13 mg%, while it was 0.39 mg% in the other group. Difference in SCr between the two groups at six months and at one year was statistically significant.

GFR was measured on each visit, at the time of CAI, six months and one year after CAI. Mean GFR was 49.33 ± 12.1 (mL/min/1.73 m 2 ) after six months of CAI in the ACEI and ARBS group, while it was 46.36 ± 10.2 (mL/min/1.73 m 2 ) in the other group. At one year after development of CAI in the ACE and ARBS groups, mean GFR was 48.78 ± 13.4, while it was 44.23 ± 8.14 in the other group.

At six months of CAI, difference in the average GFR decrease between the two groups was 4.84 mL/min/1.73 m 2 . Average GFR decrease in ACEI and ARBS was 0.74 mL/min/ 1.73 m 2 , while it was 5.58 mL/min/1.73 m 2 in the other group. At one year of CAI, difference in the average GFR decrease between the two groups was 6.42. Average GFR decrease in ACEI and ARBS was 1.29 (mL/min/1.73 m 2 ), while it was 7.71 (mL/ min/1.73 m 2 ) in the other group. Like the difference in SCr between the two groups, the difference in GFR between the two groups at six months and at one year was statistically significant. Thus, this study shows that the use of ACEI and ARBS was associated with stabilization of SCr and GFR which was still being maintained up to one year after CAI.

Proteinuria

A total of 33 patients in ACEI and ARBS group had proteinuria. The mean proteinuria in these 33 patients' was 2.45g/day which decreased to 1.04 g/day one year after CAI after using ACEI/ARBS. In the non ACEI and ARBS group, 31 patients had proteinuria; the mean proteinuria in these 31 patients was 2.665 g/day which decreased to 1.83 g/day one year after CAI. Patient in first group had decrease in proteinuria by about 1.41 g/day, while in second group, it was 0.83 g/day only and the difference was statistically significant.

Losartan as ARB was used in 14 patients in dose of 100 mg per day and ACEI (ramipril in the dose of 10 mg per day maximum) was used in 36 patients in the first group. As cough was noted in five patients in one month, it was replaced with losartan.

There were no patients on both ACEI and ARB during the period of follow-up. Drop in hemoglobin was present in eight patients by >2gm%, but did not require change in the drug usage. Increase in serum potassium (Se K+) was seen in 20 patients with a rise of >1 meq/L, but none with >5.5 meq/L, so the drug was continued with close watch on Se K + level.


   Discussion Top


Philip Halloran et al [11] have suggested the injury triangle in pathogenesis of CAI. There is interplay between immune recognition, inflammation, and injury/stress. CAI is the main cause of returning to dialysis after kidney transplantation. [2],[3],[4],[5] In CAI, both renal function [7] and histology [8] correlate with the ultimate prognosis of the graft. The benefit of RAS inhibition in ameliorating CAI has been shown previously in animal models. [12] ACEi have been shown to reduce leukocyte infiltration, inhibit growth factor mRNA, and reduce proteinuria in a rat model. [13] ACEi are safe and efficient antihypertensives with renoprotective effects in patients with CAI. Favorable response to ACEi has been reflected in diminished proteinuria, slow increase of creatinine, regulation of arterial hypertension, and better long-term survival of patients and kidney allografts. [14] El-agroudy et al [15] have shown that ARB significantly decreases the plasma levels of IGF-ß, uric acid, and proteinuria. Their results could play an important and decisive role in the treatment and prevention of chronic allograft injury.

Creatinine and effect on protienuria in various studies [Table 1]

Ten-year survival rates were74% in the ACEI/ ARB group, but only 53% in the no ACEI/ARB group (P<0.001). [16] Stabilization of renal function may be due to better control of blood pressure along with decrease in protienuria and by direct effect of drug on decreasing intraglomerular pressure and decreasing the level of TGFß. Calvino et al [17] have suggested that a significant reduction in proteinuria without adversely affecting allograft function was the main beneficial effect observed in their study of eighteen non-diabetic renal transplant recipients evaluated at their unit. Lin et al [18] have shown that use of ACEI or ARBs is well tolerated in renal allograft recipients with CAI. It is associated with trend of slowing renal insufficiency as well as a significant survival benefit in the combined endpoint of allograft failure or death. [18],[19] In our study, a patient, in whom we have used ACEI or ARBS, had SCr of 1.97 ± 0.25 at the time of CAI, which was 2.10 ± 0.36 at the follow up of one year duration, while in the other group in whom we have not used the drug had SCr of 1.96 ± 0.22 at the time of CAI, which at the follow up was 2.35 ± 0.38 mg% and the difference was statistically significant.
Table 1: Table comparing the effect of ACEI and ARBS on serum creatinine and proteinuria in various series
including ours.


Click here to view


In conclusion, our study shows that the use of ACEI or ARBS is beneficial in patients with post transplant CAI by stabilization of graft function, good control of blood pressure, and significant decrease in protienuria.

 
   References Top

1.Jevnikar AM, Mannon RB. Late kidney allograft loss: What we know about it, and what we can do about it. Clin J Am Soc Nephrol 2008; 3:S56-7.  Back to cited text no. 1
    
2.Koskinen P, Lemstrom K, Hayry P. Chronic rejection. Curr Opin Nephrol Hypertens 1996; 5:269-72.  Back to cited text no. 2
    
3.Azuma H, Tilney NL. Immune and non immune mechanisms of chronic rejection of kidney allografts. J Heart Lung Trnasplant 1995;14:S136-42.  Back to cited text no. 3
    
4.Matas AJ, Burke JF Jr, De Vault GA Jr, Monaco A, Pirsch JD. Chronic rejection. J Am Soc Nephrol 1994;4:S23-9.  Back to cited text no. 4
    
5.Paul LC. Chronic renal transplant loss. Kidney Int 1995;47:1491-9.  Back to cited text no. 5
    
6.Kasiske BL. Clinical correlates to chronic allograft rejection. Kidney Int1997;52:S71-4.  Back to cited text no. 6
    
7.Hunsicker LG, Held PJ. The role of HLA matching for cadaveric renal transplants in the cyclosporine era. Semin Nephrol 1992;12:293-303.  Back to cited text no. 7
    
8.Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: Risk factors and implications for renal allograft survival. Transplantation 1997;63:968-74.  Back to cited text no. 8
    
9.Kasiske BL, Heim Duthoy KL, Tortorice KL, Rao KV. The variable nature of chronic declines in renal allograft function. Trnasplantation 1991;51:330-4.  Back to cited text no. 9
    
10.Hume DM, Merrill JP, Miller BF, Thorn GW. Experiences with renal homotransplantations in the human: Report of nine cases. J Clin Invest 1955;34:327-82.  Back to cited text no. 10
    
11.Halloran PF, MelkA, Barth C. Rethinking chronic allograft nephropathy. J Am Soc Nephrol 1999;10:167-81.  Back to cited text no. 11
    
12.Porter KA, Dossetor JB, Marachioro TL, et al. Human renal transplants. I. Glomerular changes. Lab Invest 1967;16:153-81.  Back to cited text no. 12
    
13.Zollinger HU, Moppert J, Thiel G, Rohr HP. Morphology and pathogenesis of glomerulopathy in cadaver kidney allografts treated with anti-lymphocyte globulin. Curr Top Pathol 1973; 57:1-48.  Back to cited text no. 13
    
14.Tesi RJ, Elkhammas EA, Davies EA, Henry ML, Ferguson RM. Renal transplantation in older people. Lancet 1994;343:461-4.  Back to cited text no. 14
    
15.El-Agroudy AE, Hassan NA, Foda MA, et al. Effect of angiotensin II receptor blocker on plasma levels of TGF- ß1 and interstitial fibrosis in hypertensive kidney transplant patients. Am J Nephrol 2003;23:300-6.  Back to cited text no. 15
    
16.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(3):889-99.  Back to cited text no. 16
    
17.Calvino J, Lens XM, Romero R, et al. Longterm antiproteinuric effect of losartan in renal transplant recipients treated for hypertension. Nephrol Dial Transplant 2000;15:82-6  Back to cited text no. 17
    
18.Lin J, Valeri AM, Markowitz GS, DAgati VD, Cohen DJ, Radhakrishnan J .Angiotensin converting enzyme inhibition in chronic allograft nephropathy. Transplantation 2002;73:783-8.  Back to cited text no. 18
    
19.BarnasU, SchmidtA, HaasM, OberbauerR, MayeG. The effects of prolonged angiotensin-converting enzyme inhibition on excretory kidney function and proteinuria in renal allograft recipients with chronic progressive transplant failure. Nephrol Dial Transplant 1996;11:1822-4.  Back to cited text no. 19
    

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Correspondence Address:
P R Shah
Department of Nephrology and Clinical Transplantation, Institute Of Kidney Diseases & Research Centre - Institute Of Transplantation Sciences (IKDRC-ITS), Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat
India
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PMID: 22089769

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