The renin–aldosterone axis in kidney transplant recipients and its association with allograft function and structure
Authors: Naim Issa, Fernando Ortiz, Scott A Reule, Aleksandra Kukla, Bertram L Kasiske, Michael Mauer, Scott Jackson, Arthur J Matas, Hassan N Ibrahim, Behzad Najafian
Journal: Kidney International (2013)

The level of the renin–angiotensin–aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with glomerular filtration rate (GFR) change, interstitial expansion, and end-stage renal disease (ESRD), we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria, or interstitial expansion. Losartan use (hazard ratio (HR) 0.48 (95% confidence interval (CI) 0.21–1.0), insignificant) and Caucasian donor (HR 0.18 (95% CI 0.07–0.4) significant) were associated with less doubling of serum creatinine, death, or ESRD. Hypertension, <3 human leukocyte antigen matches, the combination of tacrolimus–rapamycin, and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD (HR 1.01 (95% CI 1.00–1.02)). Thus, systemic RAAS is not overly activated in kidney transplant recipients, but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD. The level of the renin–angiotensin–aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with glomerular filtration rate (GFR) change, interstitial expansion, and end-stage renal disease (ESRD), we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria, or interstitial expansion. Losartan use (hazard ratio (HR) 0.48 (95% confidence interval (CI) 0.21–1.0), insignificant) and Caucasian donor (HR 0.18 (95% CI 0.07–0.4) significant) were associated with less doubling of serum creatinine, death, or ESRD. Hypertension, <3 human leukocyte antigen matches, the combination of tacrolimus–rapamycin, and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD (HR 1.01 (95% CI 1.00–1.02)). Thus, systemic RAAS is not overly activated in kidney transplant recipients, but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD. The benefits of suppressing the renin–angiotensin–aldosterone system (RAAS) is generally considered to extend beyond their antihypertensive properties, and RAAS blockers are the preferred agents in established chronic kidney disease, particularly in those with proteinuria.1.Lewis E.J. Hunsicker L.G. Bain R.P. et al.The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (5018) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. 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: 851-860Crossref PubMed Scopus (5040) Google Scholar, 3.Turner J.M. Bauer C. Abramowitz M.K. et al.Treatment of chronic kidney disease.Kidney Int. 2012; 81: 351-362Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Ameliorating hyperfiltration that is mainly driven by the rise in the intraglomerular pressure has been suggested as a central pathway by which these agents could convey their renoprotection. Their benefit in the setting of kidney transplantation, a possibly more pure form of hyperfiltration considering the reduced renal mass, has been suggested but is far from established.4.Hiremath S. Fergusson D. Doucette S. et al.Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence.Am J Transplant. 2007; 7: 2350-2360Crossref PubMed Scopus (147) Google Scholar We recently tested whether angiotensin II (AII) blockade, compared with placebo, would retard the development of interstitial fibrosis or graft loss when given for the first 5 years after transplant.5.Ibrahim H.N. Jackson S. Connaire J. et al.Angiotensin II blockade in kidney transplant recipients.J Am Soc Nephrol. 2013; 24: 320-327Crossref PubMed Scopus (76) Google Scholar The result was not statistically significant, raising the question of whether RAAS is stimulated in this setting. To address this possibility, we measured plasma renin activity (PRA) and plasma aldosterone levels (Paldo) at baseline and annually in participants of the Angiotensin II Blockade in Chronic Allograft Nephropathy (ABCAN) Trial, Clinical Trials.Gov (NCT 01467895). We assessed predictors of their levels and their responsiveness to AII blockade. We hypothesized that RAAS is not overly activated in kidney transplant recipients, and that losartan at 100mg/day would effectively suppress this hormonal axis. We also examined whether higher PRA and Paldo would be associated with inferior allograft function and structure. At 58±34 days after kidney transplantation, a total of 153 kidney recipients were randomized to placebo (n=76) or 100mg of losartan daily (n=77). Mean age was 48.7±12.4 years, most recipients were White, had received a kidney from a live donor (71%), and one-third had diabetes. The characteristics of participants are described in detail in Table 1.Table 1Recipient characteristics at randomization (n=153)VariableMean (s.d.) or N (%)Age (years)48.7 (12.4)Female recipient59 (38.6)Cause of kidney disease Diabetes mellitus57 (37.3) Hypertension10 (6.5) Polycystic kidney disease23 (15.0) Other63 (41.2)BMI (kg/m2)26.4 (5.1)HLA matches <379 (51.6)SBP (mmHg)130.5 (18.3)DBP (mmHg)73.5 (10.7)Donor age (years)40.3 (12.1)Female donor83 (54.3)Deceased donor45 (29.4)Induction immunosuppression Interleukin-2 antagonist27 (17.6) Antithymocyte globulin126 (82.3)Immunosuppression Tacrolimus + rapamycin21 (13.7) Tacrolimus + MMF34 (22.2) Tacrolimus + MMF + Pred.15 (9.8) CSA40 (26.1) CSA + MMF + Pred.26 (17.0) Other17 (11.1)Loop diuretics39 (25.5)Thiazide diuretics12 (7.8)ACR (mg/g creatinine)75.5 (157.3)Iothalamate GFR (ml/min)56.1 (17.0)Abbreviations: ACR, albumin–creatinine ratio; BMI, body mass index; CSA, cyclosporine; DBP, diastolic blood pressure; GFR, glomerular filtration rate; HLA, human leukocyte antigen; MMF, mycophenolate mofetil; Pred., prednisone; SBP, systolic blood pressure. Open table in a new tab Abbreviations: ACR, albumin–creatinine ratio; BMI, body mass index; CSA, cyclosporine; DBP, diastolic blood pressure; GFR, glomerular filtration rate; HLA, human leukocyte antigen; MMF, mycophenolate mofetil; Pred., prednisone; SBP, systolic blood pressure. Baseline PRA was 0.99±1.37ng/ml/h and Paldo was 136±9.18pg/ml in the group as a whole. In the losartan group, they were 0.91±1.11 and 138.1±92.8, whereas in the placebo group they were 1.07±1.59 and 134.1±91.4, respectively (P-values not significant). The mean 24-h urinary sodium and potassium excretion rates were comparable between the two groups: 171.3±94.3 and 49.5±26.1mEq/day in the losartan group and 183±99.2 and 53.2±26.4mEq/day in the placebo group, respectively. Baseline Paldo was 43.4pg/ml (P=0.049) lower in living donor transplant recipients, and 117.1pg/ml higher in those with hyperlipidemia (P=0.04; Table 2 and Appendix 1). Increased urine sodium excretion rate was associated with decreased Paldo (P=0.01). Female recipients had a lower PRA but, interestingly, those with a kidney from a female donor had PRA levels 0.67ng/ml/h higher than those with a kidney from a male donor (P=0.01). Increased donor age was associated with lower baseline PRA (P=0.01). There was no statistically significant difference in Paldo for those on losartan versus placebo at any time point. Those on losaratan had significantly higher PRA levels than those on placebo at each annual time point after transplant in years 1–4 losartan was discontinued 1 month before the year 5 visit (Figure 1a and b). Interestingly, 138/153 (90.2%) and 61/76 (80.3%) of participants had PRA and Paldo values that were within the normal range (≤300pg/ml and ≤5ng/ml/h, respectively) at these time points (Figure 2a and b).Table 2Predictors of plasma renin activity (ng/ml/h) and plasma aldosterone (pg/ml)VariableOR (95% CI)P-valueVvInt/C doubling or ESRD from IF/TA Plasma aldosterone1.01 (1, 1.01)0.21 Plasma renin activity0.91 (0.49, 1.7)0.77 Female recipient0.36 (0.12, 1.08)0.07 Acute rejection4.62 (1.8, 11.83)<0.01 <3 HLA matches3.13 (1.08, 9.11)0.04 Tacrolimus + rapamycin3.32 (0.98, 11.27)0.05VvInt/C doubling or any ESRD Plasma aldosterone1.01 (1, 1.02)0.08 Plasma renin activity0.47 (0.17, 1.27)0.14 Female recipient0.37 (0.12, 1.08)0.07 DBP (mmHg)0.85 (0.73, 1)0.05 Hypertension11.99 (1.9, 75.59)0.01 Acute rejection8.14 (2.04, 32.38)<0.01 <3 HLA matches6.17 (1.37, 27.74)0.02 Losartan0.24 (0.08, 0.76)0.02 Loop diuretics3.64 (0.96, 13.77)0.06 CSA + MMF0.06 (0.01, 0.59)0.02 CSA + MMF + Pred.0.13 (0.02, 1.06)0.06Creatinine doubling, ESRD, or death Plasma aldosterone1 (0.99, 1)0.39 Plasma renin activity0.92 (0.57, 1.47)0.73 SBP (mmHg)1.04 (1, 1.09)0.05 Hypertensive2.07 (1.03, 4.18)0.04 Acute rejection2.66 (1.36, 5.18)<0.01 <3 HLA matches1.66 (0.9, 3.04)0.10 Caucasian donor0.37 (0.19, 0.73)<0.01 Losartan0.5 (0.27, 0.91)0.02 Iothalamate GFR1.04 (1.01, 1.08)0.02Abbreviations: CI, confidence interval; CSA, cyclosporine; DBP, diastolic blood pressure; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HLA, human leukocyte antigen; IF/TA, interstitial fibrosis/tubular atrophy; MMF, mycophenolate mofetil; OR, odds ratio; Pred., prednisone; SBP, systolic blood pressure; VvInt/C, cortical interstitial volume fraction. Open table in a new tab Figure 2Majority of patients had normal plasma renin activity (PRA) and plasma aldosterone levels values at baseline and at visit number 5. PRA versus plasma aldosterone at (a) baseline and (b) visit number 5 (4 years after transplant). Shaded area indicates patients with normal values for both parameters.View Large Image Figure ViewerDownload (PPT) Abbreviations: CI, confidence interval; CSA, cyclosporine; DBP, diastolic blood pressure; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HLA, human leukocyte antigen; IF/TA, interstitial fibrosis/tubular atrophy; MMF, mycophenolate mofetil; OR, odds ratio; Pred., prednisone; SBP, systolic blood pressure; VvInt/C, cortical interstitial volume fraction. Over time, a decrease in urine sodium and an increase in urine potassium excretion rates, diastolic blood pressure, and body mass index were associated with an increase in Paldo. The subjects with living donors had Paldo 33.3pg/ml (P=0.04) lower than those with deceased donors. On examining PRA over time, it was found that subjects taking losartan had a PRA 1.61ng/ml/h (P<0.01) higher than those taking placebo. Subjects with a kidney from a female donor had PRA 1.11ng/ml/h (P=0.01) higher than those with a kidney from a male donor, and those with a kidney from a living donor had PRA 0.93ng/ml/h lower than those with a kidney from a deceased donor (Table 3 and Appendix 2). An increase in urine sodium and potassium excretion rates and diastolic blood pressure were also associated with a decrease in serial PRA. Subjects whose kidney disease was caused by hypertension had PRA 1.54ng/ml/h (P=0.049) higher than those who did not. There were no differences in PRA or Paldo for the different immunosuppressants' combinations (cyclosporine (CSA)+mycophenolate mofetil (MMF), tacrolimus+MMF, or tacrolimus+rapamycin) regardless of steroid use (data not shown). Filtration fraction was consistently lower in the losartan group, except for the last visit when the drug was stopped 1 month earlier. Filtration fraction averaged approximately 20% in the losartan group and 22% in the placebo group.Table 3Predictors of last VvInt/C, last GFR, last ACR, and VvInt/C changeVariableEstimate (95% CI)P-valueLast VvInt/C Plasma aldosterone0 (0, 0)0.47 Plasma renin activity−0.001 (−0.018, 0.017)0.94 Caucasian donor0.044 (−0.004, 0.092)0.07 Tacrolimus + rapamycin0.067 (−0.014, 0.148)0.10Last GFR Plasma aldosterone0.01 (−0.03, 0.06)0.62 Plasma renin activity0.84 (−3.32, 4.99)0.69 Caucasian recipient−11.86 (−23.09, −0.64)0.04 <3 HLA matches−7.74 (−15.68, 0.19)0.06 Losartan−6.78 (−14.95, 1.39)0.10 Tacrolimus + rapamycin−16.2 (−34.78, 2.37)0.09Last ACR Plasma aldosterone−0.36 (−1.02, 0.3)0.28 Plasma renin activity18.16 (−47.8, 84.12)0.58 Recipient BMI17.72 (3.09, 32.36)0.02 Tacrolimus + MMF−322.12 (−612.94, −31.31)0.03 Tacrolimus + MMF + Pred.−362.28 (−750.67, 26.1)0.07 CSA + MMF−334.44 (−635.84, −33.04)0.03 CSA + MMF + Pred.−401.41 (−715.09, −87.73)0.01VvInt/C change Plasma aldosterone0 (0, 0)0.61 Plasma renin activity−0.001 (−0.034, 0.033)0.96 Acute rejection0.085 (−0.006, 0.175)0.06Abbreviations: ACR, albumin–creatinine ratio; BMI, body mass index; CI, confidence interval; CSA, cyclosporine; GFR, glomerular filtration rate; HLA, human leukocyte antigen; MMF, mycophenolate mofetil; Pred., prednisone; VvInt/C, cortical interstitial volume fraction. Open table in a new tab Abbreviations: ACR, albumin–creatinine ratio; BMI, body mass index; CI, confidence interval; CSA, cyclosporine; GFR, glomerular filtration rate; HLA, human leukocyte antigen; MMF, mycophenolate mofetil; Pred., prednisone; VvInt/C, cortical interstitial volume fraction. In all, 30% of recipients harbored the deletion/deletion (D/D) allele, 52% the deletion/insertion (D/I) allele, and 18% the insertion/insertion (I/I) allele. These proportions were 30%, 46%, and 23% in the donors, respectively. There were no differences among the three allele carriers in PRA or Paldo (Appendix 3). Importantly, there were no differences in these levels for the nine different possible donor–recipient permutations, and there were no statistically significant associations with any of the outcomes studied (Appendix 3). Paldo and PRA, along with other baseline values, were used as predictors of the continuous outcomes of the cortical interstitial volume fraction (Vvlnt/C), VvInt/C change, GFR, and ACR. We found no significant predictors of last VvInt/C or VvInt/C change (Table 3 and Appendix 2). Greater iothalamate GFR and ACR at baseline were associated with a higher final GFR (P<0.01 and P=0.02, respectively). White recipients had a lower final GFR than non-Whites (P=0.04). An increase in body mass index was associated with an increase in final ACR (P=0.02), whereas MMF-based immunosuppression regimens resulted in a significant decrease. The effects of Paldo, PRA, and other covariates over time on serial GFR and serial ACR are shown in Table 4 and Appendix 4. Again, neither serial PRA nor serial Paldo were associated with serial GFR or ACR over time. Recipients who were White (estimate=-6.78, P=0.049), had older donors (P=0.01), or a higher serial ACR (estimate=-0.01, P=0.01) had a significantly lower final GFR. Those with a higher serial GFR (P=0.02) or cause of kidney disease listed as other (P=0.03) had a significantly lower final ACR. Subjects who had acute rejection (P=0.01) or a higher systolic blood pressure (P<0.01) had a significantly higher final ACR. Whether recipients with low GFR may have elevated PRA and/or Paldo levels by virtue of possible increased production from scarred areas in the setting of chronic allograft dysfunction was then examined. There was no relationship between the iothalamate GFR values and PRA and/or Paldo at baseline (Figure 3a and b) or visit 5 (Figure 3c and d). Furthermore, when we divided PRA and Paldo into quartiles and related them to GFR, there was no evident pattern or a statistical correlation (data not shown).Table 4Predictors of serial GFR and urinary albumin–creatinine ratio (ACR)VariableEstimate (95% CI)P-valueGFR Plasma aldosterone0 (−0.02, 0.01)0.45 Plasma renin activity−0.13 (−0.61, 0.34)0.58 Caucasian recipient−6.78 (−13.55, −0.01)0.05 Donor age (years)−0.28 (−0.49, −0.07)0.01 Female donor−4.02 (−8.86, 0.81)0.10 CSA + MMF−9.35 (−18.71, 0)0.05ACR Plasma aldosterone0.07 (−0.06, 0.2)0.30 Plasma renin activity−2.23 (−7.19, 2.74)0.38 SBP (mmHg)2.07 (0.72, 3.42)<0.01 Acute rejection66.42 (16.03, 116.81)0.01Cause of kidney disease Other (vs. DM)−57.85 (−108.47, −7.23)0.03Abbreviations: CI, confidence interval; CSA, cyclosporine; DM, diabetes mellitus; GFR, glomerular filtration rate; MMF, mycophenolate mofetil; SBP, systolic blood pressure. Open table in a new tab Abbreviations: CI, confidence interval; CSA, cyclosporine; DM, diabetes mellitus; GFR, glomerular filtration rate; MMF, mycophenolate mofetil; SBP, systolic blood pressure. The following dichotomous outcomes were considered: doubling of VvInt/C or ESRD from IF/TA, doubling of VvInt/C and all-cause ESRD, and the more conventional end point of doubling of serum creatinine, ESRD, or death (Table 5 and Appendix 5). PRA and Paldo were not statistically significantly associated with these outcomes. Subjects who experienced acute rejection (odds ratio (OR)=4.62 (95% confidence interval (CI) 1.8–11.83), P<0.01)) or had <3 human leukocyte antigen (HLA) matches (OR=3.13 (95% CI 1.08–9.11) P=0.04)) had higher risks of doubling of VvInt/C or ESRD from IF/TA. Subjects taking losartan (OR=0.24 (95% CI 0.08–0.76), P=0.02), having lower diastolic blood pressure (OR=0.85 (95% CI 0.73–0.99), P=0.049), or on CSA+MMF without prednisone (OR=0.06 (95% CI 0.01–0.59), P=0.02) had lower risks of doubling of VvInt/C. Subjects with <3 HLA matches (OR=6.17 (95% CI 1.37–27.74), P=0.02), hypertension (OR=11.99 (95% CI 1.9–75.5), P=0.01), or who had an acute rejection (OR=8.14 (95% CI 2.04–32.38), P<0.01) were also at higher risk for these outcomes. Subjects on losartan (OR=0.50 (95% CI 0.27–0.91), P=0.02) or who had a White donor (OR=0.37 (95% CI 0.19–0.77) P<0.01) were at a lower risk of doubling of serum creatinine, all-cause ESRD, or death. In contrast, having a higher iothalamate GFR (OR=1.04 (95% CI 1.01–1.08), P=0.02), hypertension (OR=2.07 (95% CI 1.03–4.18), P=0.04), or acute rejection (OR=2.66 (95% CI 1.36–5.18), P<0.01) resulted in a higher risk of doubling, death, or ESRD (Table 5 and Appendix 5).Table 5Predictors of interstitial expansion and ESRDVariableOR (95% CI)P-valueVvInt/C doubling or ESRD from IF/TA Plasma aldosterone1.01 (1, 1.01)0.21 Plasma renin activity0.91 (0.49, 1.7)0.77 Female recipient0.36 (0.12, 1.08)0.07 Acute rejection4.62 (1.8, 11.83)<0.01 <3 HLA matches3.13 (1.08, 9.11)0.04 Tacrolimus + rapamycin3.32 (0.98, 11.27)0.05VvInt/C doubling or any ESRD Plasma aldosterone1.01 (1, 1.02)0.08 Plasma renin activity0.47 (0.17, 1.27)0.14 Female recipient0.37 (0.12, 1.08)0.07 DBP (mmHg)0.85 (0.73, 1)0.05 Hypertension11.99 (1.9, 75.59)0.01 Acute rejection8.14 (2.04, 32.38)<0.01 <3 HLA matches6.17 (1.37, 27.74)0.02 Losartan0.24 (0.08, 0.76)0.02 Loop diuretics3.64 (0.96, 13.77)0.06 CSA + MMF0.06 (0.01, 0.59)0.02 CSA + MMF + Pred.0.13 (0.02, 1.06)0.06CR doubling, ESRD, or death Plasma aldosterone1 (0.99, 1)0.39 Plasma renin activity0.92 (0.57, 1.47)0.73 SBP (mmHg)1.04 (1, 1.09)0.05 Hypertensive2.07 (1.03, 4.18)0.04 Acute rejection2.66 (1.36, 5.18)<0.01 <3 HLA matches1.66 (0.9, 3.04)0.10 Caucasian donor0.37 (0.19, 0.73)<0.01 Losartan0.5 (0.27, 0.91)0.02 Iothalamate GFR1.04 (1.01, 1.08)0.02Abbreviations: CI, confidence interval; CR, creatinine; CSA, cyclosporine; DBP, diastolic blood pressure; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HLA, human leukocyte antigen; IF/TA, interstitial fibrosis/tubular atrophy; MMF, mycophenolate mofetil; OR, odds ratio; Pred., prednisone; SBP, systolic blood pressure; VvInt/C, cortical interstitial volume fraction. Open table in a new tab Abbreviations: CI, confidence interval; CR, creatinine; CSA, cyclosporine; DBP, diastolic blood pressure; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HLA, human leukocyte antigen; IF/TA, interstitial fibrosis/tubular atrophy; MMF, mycophenolate mofetil; OR, odds ratio; Pred., prednisone; SBP, systolic blood pressure; VvInt/C, cortical interstitial volume fraction. Finally, Table 6 shows the results of Cox proportional hazards regression using time-dependent variables for two outcomes: (1) all-cause ESRD and (2) doubling of serum creatinine, all-cause ESRD, or death. An increase in Paldo (hazard ratio (HR)=1.01 (95% CI 1.00–1.02), P=0.02) at any time during the study was associated with an increased risk of ESRD, whereas each additional year spent in the study was associated with a lower risk (HR=0.95 (95% CI 0.89–0.99), P=0.04). Use of loop diuretics (HR=4.72 (95% CI 1.56–25.8), P=0.049), <3 HLA matches (HR=6.35 (95% CI 1.56–25.8), P=0.03), non-White donors (HR=3.85 (95% CI 1.25–12.5), P=0.03), and acute rejection (HR=12.91 (95% CI 2.6–61.8), P<0.01) was associated with an increased risk of ESRD. Having a White donor (HR=0.18 (95% CI 0.07–0.4), P<0.01) was associated with a decrease in the risk of doubling of serum creatinine, all-cause ESRD, or death. Having <3 HLA matches (HR=3.79 (95% CI 1.56–9.1), P<0.01), being hypertensive (HR=6.97 (95% CI 2.23–21.7), P<0.01), or having an acute rejection (HR=3.98 (95% CI 1.80–8.8), P<0.01) resulted in an increased risk.Table 6Cox proportional hazards regression with time-dependent covariatesAll-cause ESRDCreatinine doubling, all-cause ESRD, or deathVariableHR (95% CI)P-valueVariableHR (95% CI)P-valuePlasma aldosterone1.01 (1.00, 1.0)0.02Plasma aldosterone0.998 (0.99, 1.003)0.43Plasma renin activity0.82 (0.56, 1.1)0.29Plasma renin activity1.02 (0.90, 1.1)0.74Age at visit (years)0.95 (0.89, 0.99)0.04Losartan0.48 (0.21, 1.0)0.07SBP1.03 (0.998, 1.0)0.07Tacrolimus + rapamycin2.37 (0.98, 5.7)0.05Loop diuretics4.72 (1.01, 22.1)0.05Caucasian donor0.18 (0.07, 0.4)<0.01Caucasian donor0.26 (0.08, 0.8)0.03<3 HLA matches3.79 (1.56, 9.1)<0.01<3 HLA matches6.35 (1.56, 25.8)0.01Hypertension6.97 (2.23, 21.7)<0.01Hypertension7.49 (0.85, 66.3)0.07Acute rejection (ever)3.98 (1.80, 8.8)<0.01Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HLA, human leukocyte antigen; HR, hazard ratio; SBP, systolic blood pressure. Open table in a new tab Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HLA, human leukocyte antigen; HR, hazard ratio; SBP, systolic blood pressure. Our results indicate the following (1) PRA and Paldo levels are not elevated during the first 5 years after kidney transplantation; (2) AII blockade is effective in suppressing the RAAS as evident by a lower PRA in the placebo group; (3) the DD allele of the angiotensin-converting enzyme (ACE) gene polymorphism does not convey increased risk for worse allograft function or structure; (4) a higher Paldo at any time during the study was associated with an increased risk of ESRD; and (5) receiving a kidney from a White donor was associated with a decrease in the risk of doubling serum creatinine, all-cause ESRD, and death. On the other hand, having <3 HLA matches, being hypertensive, having had an acute rejection episode, or receiving tacrolimus—rapamycin-based regimen were associated with increased risk. AII has been singled out as a major mediator in the initiation and progression of native kidney disease.6.Rosenberg M.E. Correa-Rotter R. Inagami T. et al.Glomerular renin synthesis and storage in the remnant kidney in the rat.Kidney Int. 1991; 40: 677-683Abstract Full Text PDF PubMed Scopus (59) Google Scholar Multiple studies have demonstrated the superior efficacy of RAAS blockers in retarding the progression of chronic kidney disease, particularly in those with proteinuria.1.Lewis E.J. Hunsicker L.G. Bain R.P. et al.The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (5018) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. 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: 851-860Crossref PubMed Scopus (5040) Google Scholar, 3.Turner J.M. Bauer C. Abramowitz M.K. et al.Treatment of chronic kidney disease.Kidney Int. 2012; 81: 351-362Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar The presence of such strong evidence to the benefit of these agents is lacking in the kidney transplant arena. A systematic review of 21 randomized kidney trials that included 1549 patients with a median follow-up of 27 months demonstrated that the use of these agents is associated with a significant reduction in GFR and reduction in proteinuria of roughly 500mg/day, but there was insufficient evidence to determine the effects on patient or graft survival.4.Hiremath S. Fergusson D. Doucette S. et al.Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence.Am J Transplant. 2007; 7: 2350-2360Crossref PubMed Scopus (147) Google Scholar Not included in this systematic review is our recent demonstration that AII blocker when compared with placebo was associated with a statistically insignificant (P=0.08) benefit in the primary outcome of retarding the development of IF and graft loss from IF/TA. However, losartan was associated with a reduction in the secondary outcome of doubling of interstitium from baseline to 5-year biopsies or all-cause ESRD (OR=0.36 (95% CI 0.13–0.99), P=0.05).5.Ibrahim H.N. Jackson S. Connaire J. et al.Angiotensin II blockade in kidney transplant recipients.J Am Soc Nephrol. 2013; 24: 320-327Crossref PubMed Scopus (76) Google Scholar Hernandez et al.7.Hernandez D. Muriel A. Abraira V. et al.Renin-angiotensin system blockade and kidney transplantation: a longitudinal cohort study.Nephrol Dial Transplant. 2012; 27: 417-422Crossref PubMed Scopus (34) Google Scholar recently published the results of a longitudinal cohort study of 414 patients who received ACE inhibitors or angiotensin-receptor blockers with a follow-up that ranged between 6 and 40 months and demonstrated that the use of these agents was associated with a reduction in the risk of mortality, but they were not associated with a significant improvement of allograft survival. On the other hand, the evidence regarding the impact of the ACE gene polymorphisms on kidney transplant function has been mixed. Siekierka-Harreis et al.8.Siekierka-Harreis M. Kuhr N. Willers R. et al.Impact of genetic polymorphisms of the renin-angiotensin system and of non-genetic factors on kidney transplant function—a single-center experience.Clin Transplant. 2009; 23: 606-615Crossref PubMed Scopus (17) Google Scholar showed that the DD genotype of the ACE gene was associated with a significantly reduced kidney transplant function during the first 18 to 30 months after transplantation. However, in this study, only the ACE gene polymorphism in the recipient was analyzed. To our knowledge, the data we present herein are unique in that they provide ACE gene polymorphism in not only the recipient but also the donor, and their possible permutations. A large-scale genetic polymorphism analysis would be needed to settle this issue. We also recognize that the power to detect important treatment effects and associations is limited by sample size in our study. For the longitudinal data, it is worth noting that there were also some missing samples. Obviously, given the lack of a large randomized trial with hard clinical end points in the setting of kidney transplantation, there is no conclusive evidence that these agents are beneficial beyond their antihypertensive properties. One has to consider, however, whether the RAAS is as amenable to interruption in this patient population as it is in individuals with their native kidneys. Very little has been published on the activity of this system in the transplant population, and we believe this is the first effort that has an a priori secondary outcome, serial RAAS measurement, and testings of the impact RAAS blockade on multiple clinical parameters, including hard end points. Bantle et al.9.Bantle J.P. Nath K.A. Sutherland D.E. et al.Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients.Arch Intern Med. 1985; 145: 505-508Crossref PubMed Scopus (155) Google Scholar studied CSA-treated kidney transplant recipients and compared them with those maintained on azathioprine-based immunosuppression 7 to 20 months after kidney transplantation. After stimulation by a low-sodium diet and furosemide, CSA-treated patients demonstrated lower PRA and Paldo levels than their azathioprine-treated counterparts. In the case of PRA, azathioprine-treated participants had a four times higher and a tw