Does RAS blockade improve outcomes after kidney transplantation?Armando Torres, La Laguna, Spain

Chairs: Hans De Fijter, Leiden, The Netherlands Armando Torres, La Laguna, Spain

Prof. Armando TorresNephrology Section

Hospital Universitario de CanariasUniversity of La Laguna

Tenerife, Canary Islands, Spain

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Thank you Mr Chairman. First, I want to thank the ERA-EDTA organisation for inviting me toparticipate in this course.

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This is my job and my task in these 20-25 minutes just to answer the question if RASblockade, renin-angiotensin system blockade improves outcomes after kidney transplantation.If the answer is yes, we should use systematically these drugs in every kidney transplantpatient.

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This is a summary of the contents of what I want to talk to you about. The first one is a briefappraisal of the renin-angiotensin system. My second point will be to review the publishedsystematic reviews of randomised clinical trials using surrogate variables like proteinuria, GFRand safety of ACE inhibition in the renal transplant arena. The third point is the relationship orthe role of the RAS blockade in patients with persistent left ventricular hypertrophy. Finally, Iwill deal with the RAS blockade and hard outcomes like graft survival and patient survival anddecrease in graft function.

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Angiotensin 2 is the central product of the RAS system. Angiotensin binds in the cell surface toeach receptor: angiotensin receptor 1 and angiotensin receptor 2. The binding to angiotensinreceptor 1 produces most of the actions we know about angiotensin 2. On the other hand,the binding to angiotensin receptor 2 is a binding to negatively regulate the stimulation of theRAS system.

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Angiotensin 2 plays a central role in the controlling of blood pressure but the RAS is widelyspread in the organism in many cell types: in the endotheliocytes, in the smooth muscle cells,in the kidney, in the heart.

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Thus, many of the alterations observed by an activation of RAS may produce vascular damageand LVH, and

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also organ fibrosis specifically chronic kidney damage in the kidney transplant patients. Thusin theory, the blockade of all these pleiotropic actions of the RAS system could be beneficialfor the renal transplant recipient.

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The next point will be to review with you the two systematic reviews about surrogatevariables and safety of RAS blockade by these drugs specifically in the kidney transplantrecipient.

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This is a systematic review of randomised controlled trials comparing RAS blockade with acontrol group. In this systematic review, the point is that the use of ACE inhibitors or ARBs(angiotensin receptor blockers) was associated with a significant decrease in GFR ascompared to controls. The magnitude of the effect, this is the mean difference, was 5.8ml/min,which is a clinically relevant decrease in GFR. The question is whether this is a hemodynamicresponse of the kidney or whether it is associated to organ damage. On the other hand, in allthese randomised controlled trials ACE inhibitors or ARBs were associated with a significantand consistent decrease in proteinuria. The magnitude was almost 0.5 g/day as compared tocontrols.

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Other points are a significant decrease in haematocrit and haemoglobin, the size of the effectwas a decrease in the RAS blockade group of 3.5 units, 3.5%. Finally, a marginal increase inserum potassium was documented.

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In this second systematic review, the effect of different anti-hypertensive drugs in kidneytransplantation was compared. In this particular case, ACE inhibitors were compared withcalcium channel blockers. Again, there was a significant decrease of eGFR in the group treatedwith ACE inhibitors, as compared with calcium channel blockers. The magnitude in this casewas even higher than in the previous systematic review, 11.5 ml/min because calcium channel

blockers increase the GFR and ACE inhibitors just decreased it, then maximizing thedifferences between the two groups. But again, proteinuria favours the use of ACE inhibitors.The mean difference in this case was a decrease of 208 mg/day, 0.28 g/day favouring the useof ACE inhibitors.

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Let me move to the possible role of RAS blockade and LVH.

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In this Italian randomised controlled trial, 70 transplant non-diabetic recipients withpersistent LVH after transplantation were randomised to receive placebo or to receive an ACEinhibitor and in particular, Lisinopril. After 18 months of follow-up, the group receiving the ACEinhibitor significantly reduced around 8-9% the left ventricular mass index and no change wasobserved in the placebo group.

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In this study from my institution, we randomised 52 patients to receive placebo or Lisinopril,the same drug as in the previous study. Again after 1 year we observed a 9% decrease in theleft ventricular mass index in the group treated with Lisinopril and a 3% increase in the grouptreated with placebo. Thus, the RAS blockade in patients with persistent LVH after kidneytransplantation may be an indication for this particular drug class.

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Finally, I will talk about the RAS blockade and hard outcomes.

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In this study, also from my institution, a historical cohort including almost 1.000 first kidneytransplant recipients performed in the period 1996-2005, our primary outcomes were patientsurvival and death censored graft survival. This is a retrospective study. 42% of our patientswere treated with an ACE inhibitor or an angiotensin receptor blocker. First, by logisticregression analysis, we investigated the predictors for a prescription of an ACE inhibitor or anangiotensin receptor blocker. In this table, you can see that patients with diabetes with alower serum creatinine at 1 year, patients with post-transplant LVH, with proteinuria at 1year, with post-transplantation statin use or using erythropoietin ESA drugs were moreprobably treated with a RAS blockade. Importantly, this different probability to use the drugwas introduced in the multivariate model just to adjust for this confounding.

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In this table, we showed that in the crude model, in the adjusted model, the Cox regressionmodel and in the weighted estimated model, ACE inhibitors or angiotensin receptor blockerswere associated with a significantly reduction of 30-35% in patient mortality. However, deathcensored graft survival was not significantly modified by the use of these drugs. We have totake with caution the causal relationship from these particular observational studies and thishas to be confirmed in appropriately designed prospective trials.

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In this randomised controlled trial from Italy, 74 patients were randomised to receive an ACEinhibitor or a placebo. All the patients were non-diabetics; all of them showed persistent LVHand the strength of this study is the long follow-up, 10 years of follow-up.

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As shown in this slide, time to a composite endpoint, defined as death, time to non-fatalcardiovascular events and time to first renal events, ESRD or doubling of serum creatinine,was less common over time in the group treated with Lisinopril, the ACE inhibitor Lisinopril.This difference was significant. Also, cardiovascular event free survival was significantlysuperior in the group receiving an ACE inhibitor.

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In the multivariate analysis, in the Cox regression analysis, the ACE inhibitors were protectorsin mortality in the composite and cardiovascular endpoints with a protection shown in themultivariate hazard ratios. For the cardiovascular endpoint, the ACE inhibitor in themultivariate analysis were also protective. However, the ACE inhibitors did not influence therenal endpoints defined as ESRD or doubling of serum creatinine.

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This is the last study I want to show you. This is a recently published randomised controlledtrial comparing two groups of patients: one receiving losartan, 77 patients, 100 mg/day andanother receiving placebo. All the treatments were started in the first 3 months aftertransplantation. The number of patients with a baseline and an exit biopsy after 5 years oftransplantation was 47 cases in the losartan group and 44 patients in the placebo group. Inthe biopsies, the authors measured the proportion of cortical tissue occupied by interstitium.This is a surrogate marker of the degree of interstitial fibrosis.

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The primary endpoint of the study was doubling of interstitium or ESRD from interstitialfibrosis or tubular atrophy. Numerically, the percent of patients reaching this endpoint at 5years was lower in the losartan group than in the placebo group but the differences did notreach statistical significance. Similarly, for the secondary endpoint of doubling of interstitiumor ESRD of any cause, the differences were numerically different but didn't reach a statisticalsignificance. Importantly, the renal outcomes, doubling of serum creatinine, the composite ofdoubling serum creatinine, ESRD or death were no different between the placebo and thelosartan group. Finally, the GFR measured with a radioisotope method was no different

between groups along the study. Proteinuria did not reach a statistically significant differencebetween groups.

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In conclusion, I will be very brief, there is not sufficient evidence based on large randomisedcontrolled studies to support the widespread use of RAS blockade as a prevention for hardoutcomes such as mortality, graft survival and graft function. The RAS blockade has aconsistent benefit in reducing albuminuria and proteinuria in transplant recipients. Third, theRAS blockade may have a role in patients with persistent LVH when the blood pressure iscontrolled.

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Third, the losartan trial proves that RAS blockade is not associated with graft damage anddoes not decrease significantly the graft function in the long term at 5 years. Finally, thepreliminary results of this study provide an invaluable basis for planning future studies, forfuture powered studies for the prevention of interstitial fibrosis and tubular atrophy in thekidney transplantation arena. Thank you very much.

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Chairman: Thank you Armando. I think especially the last study indicates that the renalfunction may no longer be a valid tool for trials to compare these drugs. What would yousuggest? Should all trials go to protocol biopsies in the end or pulse wave velocitymeasurements?

Prof. Torres: Yes in the majority of the trials, the GFR was estimated by MDRD or evaluatingserum creatinine. If you compare and Doctor Porrini has some data about that, the estimationof the GFR with creatinine, whith the use of a gold standard like Iohexol or another method,differences are very important. The strength of this randomized study by Ibrahim is that theyuse a radioisotope method to measure exactly the changes in GFR.

Chairman: Are there questions for this presentation? On the left.

Question: Just a quick one. You didn't mention anything about spironolactone in protectingagainst fibrosis. Do you know any studies about spironolactone used in transplantedpatients? Spironolactone, aldosterone?

Prof. Torres: Ok, I understand now. No, I don't know a study comparing aldosterone blockingagents, Eplerenone or spironolactone in transplantation compared with ACE inhibitors. I thinkthey are more potent in decreasing proteinuria than ACE inhibitors as occurs in othernephropathies. In my experience, I have used spironolactone with a consistent decrease inproteinuria, even higher, even more profound than produced by the others (ACE or ARB).What I do not recommend is the combination of these drugs with an ACE inhibitor becausethis predisposes these patients a lot to acute injury in situations of dehydration, hypovolemiaand so on or infections. So, my advice is to use an ACE inhibitor, an ARB or even an anti-aldosterone drug, which are more potent. But the literature is very scarce about that.

Question: I would like to ask. Sorry can you hear me? About your second conclusion, youstated this state of evidence as 1a but at least in the last study and I think there are manyother studies that didn't actually demonstrate a significant reduction of proteinuria in usingthis class of drugs.

Prof. Torres: Yes.

Question: And you also showed that the last set of JASN trials actually could not demonstrateany reduction of proteinuria.

Prof. Torres: This is an important question. Certainly there is no explanation for the finding ofthis study where angiotensin receptor blockade was started very early after transplantation.Just in the first few weeks after transplantation and probably, not allowing proteinuria todevelop. On the other hand, there are 45 patients in each arm and in the two systematicreviews, you have hundreds of patients, and then the statistical power is higher in this case.

Question: -- ARB in the immediate post-transplant period when the patient has quite high

blood pressure because we're not sure whether they will have any negative effect on therenal function of these patients.

Prof. Torres: Most guidelines recommend to start this type of drugs 3 months aftertransplantation. Because during the first 3 months you may have artery stenosis, you mayhave acute rejection and then you add a confounding factor with small increases in serumcreatinine or decreases in eGFR. So the recommendation is to start the blockade not beforethe second month after transplantation.

Question: Maybe, if I may ask you a final more general comment. If you look at all thesestudies on blood pressure after transplantation, at best we achieve our targets in 50% ofpatients that we study. So in 50% we're quite unsuccessful. What would you advise us tochange?

Prof. Torres: Ok what I suggest is to be more aggressive in the treatment of hypertension.The first choice depends on the patient. If the patient is receiving calcineurin inhibitors highlevels or medium levels, then you have to adapt the immunosuppression just to try to stopcorticosteroids if possible, to decrease the calcineurin inhibitor exposure and then add ondifferent anti-hypertensive drugs. You can start with calcium antagonists or RAS blockade andthen, you have to add a second drug beta-blockers or a third drug, beta-blockers or alpha-blockers. But the most important point is to reach the target of less than 130-140 mms of SBPand don't forget also the use of diuretics. If you look to the 24 hour urinary excretion ofsodium, a surrogate of sodium intake, many of them have more than 150-200 mEq/day andthis is a very important point. Thus, to manage hypertension in the transplant recipient youcan use different classes of drugs but adding a diuretic is usually needed because thesepatients exhibit a median GFR of 40-50 ml/min a point that we would not forget.

Chairman: Ok thank you Armando. Thank you for participating.