Prof. Armando Torres Nephrology Section Hospital Universitario de Canarias University of La Laguna Tenerife, Canary Islands, Spain.

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April Wilson
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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.

1 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 Torres Nephrology Section Hospital Universitario de Canarias University of La Laguna Tenerife, Canary Islands, Spain slide 1 Thank you Mr Chairman. First, I want to thank the ERA-EDTA organisation for inviting me to participate in this course. slide 2

This is my job and my task in these 20-25 minutes just to answer the question if RAS blockade, renin-angiotensin system blockade improves outcomes after kidney transplantation.

2 This is my job and my task in these minutes just to answer the question if RAS blockade, renin-angiotensin system blockade improves outcomes after kidney transplantation. If the answer is yes, we should use systematically these drugs in every kidney transplant patient. slide 3 This is a summary of the contents of what I want to talk to you about. The first one is a brief appraisal of the renin-angiotensin system. My second point will be to review the published systematic reviews of randomised clinical trials using surrogate variables like proteinuria, GFR and safety of ACE inhibition in the renal transplant arena. The third point is the relationship or the role of the RAS blockade in patients with persistent left ventricular hypertrophy. Finally, I will deal with the RAS blockade and hard outcomes like graft survival and patient survival and decrease in graft function. slide 4

3 Angiotensin 2 is the central product of the RAS system. Angiotensin binds in the cell surface to each receptor: angiotensin receptor 1 and angiotensin receptor 2. The binding to angiotensin receptor 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 the RAS system. slide 5

4 Angiotensin 2 plays a central role in the controlling of blood pressure but the RAS is widely spread in the organism in many cell types: in the endotheliocytes, in the smooth muscle cells, in the kidney, in the heart. slide 6 Thus, many of the alterations observed by an activation of RAS may produce vascular damage and LVH, and slide 7 also organ fibrosis specifically chronic kidney damage in the kidney transplant patients. Thus in theory, the blockade of all these pleiotropic actions of the RAS system could be beneficial for the renal transplant recipient. slide 8

5 The next point will be to review with you the two systematic reviews about surrogate variables and safety of RAS blockade by these drugs specifically in the kidney transplant recipient. slide 9 This is a systematic review of randomised controlled trials comparing RAS blockade with a control 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 as compared 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 hemodynamic response of the kidney or whether it is associated to organ damage. On the other hand, in all these randomised controlled trials ACE inhibitors or ARBs were associated with a significant and consistent decrease in proteinuria. The magnitude was almost 0.5 g/day as compared to controls.

slide 10 Other points are a significant decrease in haematocrit and haemoglobin, the size of the effect was a decrease in the RAS blockade group of 3.5 units, 3.5%.

6 slide 10 Other points are a significant decrease in haematocrit and haemoglobin, the size of the effect was a decrease in the RAS blockade group of 3.5 units, 3.5%. Finally, a marginal increase in serum potassium was documented. slide 11 In this second systematic review, the effect of different anti-hypertensive drugs in kidney transplantation was compared. In this particular case, ACE inhibitors were compared with calcium channel blockers. Again, there was a significant decrease of egfr in the group treated with ACE inhibitors, as compared with calcium channel blockers. The magnitude in this case was even higher than in the previous systematic review, 11.5 ml/min because calcium channel

7 blockers increase the GFR and ACE inhibitors just decreased it, then maximizing the differences 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 use of ACE inhibitors. slide 12 Let me move to the possible role of RAS blockade and LVH. slide 13

In this Italian randomised controlled trial, 70 transplant non-diabetic recipients with persistent LVH after transplantation were randomised to receive placebo or to receive an ACE inhibitor and in

8 In this Italian randomised controlled trial, 70 transplant non-diabetic recipients with persistent LVH after transplantation were randomised to receive placebo or to receive an ACE inhibitor and in particular, Lisinopril. After 18 months of follow-up, the group receiving the ACE inhibitor significantly reduced around 8-9% the left ventricular mass index and no change was observed in the placebo group. slide 14 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 the left ventricular mass index in the group treated with Lisinopril and a 3% increase in the group treated with placebo. Thus, the RAS blockade in patients with persistent LVH after kidney transplantation may be an indication for this particular drug class. slide 15

Finally, I will talk about the RAS blockade and hard outcomes. slide 16 In this study, also from my institution, a historical cohort including almost 1.

9 Finally, I will talk about the RAS blockade and hard outcomes. slide 16 In this study, also from my institution, a historical cohort including almost first kidney transplant recipients performed in the period , our primary outcomes were patient survival and death censored graft survival. This is a retrospective study. 42% of our patients were treated with an ACE inhibitor or an angiotensin receptor blocker. First, by logistic regression analysis, we investigated the predictors for a prescription of an ACE inhibitor or an angiotensin receptor blocker. In this table, you can see that patients with diabetes with a lower serum creatinine at 1 year, patients with post-transplant LVH, with proteinuria at 1 year, with post-transplantation statin use or using erythropoietin ESA drugs were more probably treated with a RAS blockade. Importantly, this different probability to use the drug was introduced in the multivariate model just to adjust for this confounding. slide 17

In this table, we showed that in the crude model, in the adjusted model, the Cox regression model and in the weighted estimated model, ACE inhibitors or angiotensin receptor blockers were associated

10 In this table, we showed that in the crude model, in the adjusted model, the Cox regression model and in the weighted estimated model, ACE inhibitors or angiotensin receptor blockers were associated with a significantly reduction of 30-35% in patient mortality. However, death censored graft survival was not significantly modified by the use of these drugs. We have to take with caution the causal relationship from these particular observational studies and this has to be confirmed in appropriately designed prospective trials. slide 18

11 In this randomised controlled trial from Italy, 74 patients were randomised to receive an ACE inhibitor or a placebo. All the patients were non-diabetics; all of them showed persistent LVH and the strength of this study is the long follow-up, 10 years of follow-up. slide 19 As shown in this slide, time to a composite endpoint, defined as death, time to non-fatal cardiovascular 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 significantly superior in the group receiving an ACE inhibitor. slide 20 In the multivariate analysis, in the Cox regression analysis, the ACE inhibitors were protectors in mortality in the composite and cardiovascular endpoints with a protection shown in the multivariate hazard ratios. For the cardiovascular endpoint, the ACE inhibitor in the multivariate analysis were also protective. However, the ACE inhibitors did not influence the renal endpoints defined as ESRD or doubling of serum creatinine.

12 slide 21 This is the last study I want to show you. This is a recently published randomised controlled trial comparing two groups of patients: one receiving losartan, 77 patients, 100 mg/day and another receiving placebo. All the treatments were started in the first 3 months after transplantation. The number of patients with a baseline and an exit biopsy after 5 years of transplantation was 47 cases in the losartan group and 44 patients in the placebo group. In the biopsies, the authors measured the proportion of cortical tissue occupied by interstitium. This is a surrogate marker of the degree of interstitial fibrosis. slide 22 The primary endpoint of the study was doubling of interstitium or ESRD from interstitial fibrosis or tubular atrophy. Numerically, the percent of patients reaching this endpoint at 5 years was lower in the losartan group than in the placebo group but the differences did not reach statistical significance. Similarly, for the secondary endpoint of doubling of interstitium or ESRD of any cause, the differences were numerically different but didn't reach a statistical significance. Importantly, the renal outcomes, doubling of serum creatinine, the composite of doubling serum creatinine, ESRD or death were no different between the placebo and the losartan group. Finally, the GFR measured with a radioisotope method was no different

13 between groups along the study. Proteinuria did not reach a statistically significant difference between groups. slide 23 In conclusion, I will be very brief, there is not sufficient evidence based on large randomised controlled studies to support the widespread use of RAS blockade as a prevention for hard outcomes such as mortality, graft survival and graft function. The RAS blockade has a consistent benefit in reducing albuminuria and proteinuria in transplant recipients. Third, the RAS blockade may have a role in patients with persistent LVH when the blood pressure is controlled. slide 24 Third, the losartan trial proves that RAS blockade is not associated with graft damage and does not decrease significantly the graft function in the long term at 5 years. Finally, the preliminary results of this study provide an invaluable basis for planning future studies, for future powered studies for the prevention of interstitial fibrosis and tubular atrophy in the kidney transplantation arena. Thank you very much.

slide 25 Chairman: Thank you Armando. I think especially the last study indicates that the renal function may no longer be a valid tool for trials to compare these drugs. What would you suggest?

14 slide 25 Chairman: Thank you Armando. I think especially the last study indicates that the renal function may no longer be a valid tool for trials to compare these drugs. What would you suggest? Should all trials go to protocol biopsies in the end or pulse wave velocity measurements? Prof. Torres: Yes in the majority of the trials, the GFR was estimated by MDRD or evaluating serum creatinine. If you compare and Doctor Porrini has some data about that, the estimation of 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 they use 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 protecting against fibrosis. Do you know any studies about spironolactone used in transplanted patients? Spironolactone, aldosterone? Prof. Torres: Ok, I understand now. No, I don't know a study comparing aldosterone blocking agents, Eplerenone or spironolactone in transplantation compared with ACE inhibitors. I think they are more potent in decreasing proteinuria than ACE inhibitors as occurs in other nephropathies. In my experience, I have used spironolactone with a consistent decrease in proteinuria, 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 because this predisposes these patients a lot to acute injury in situations of dehydration, hypovolemia and so on or infections. So, my advice is to use an ACE inhibitor, an ARB or even an antialdosterone 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, you stated this state of evidence as 1a but at least in the last study and I think there are many other studies that didn't actually demonstrate a significant reduction of proteinuria in using this class of drugs. Prof. Torres: Yes. Question: And you also showed that the last set of JASN trials actually could not demonstrate any reduction of proteinuria. Prof. Torres: This is an important question. Certainly there is no explanation for the finding of this study where angiotensin receptor blockade was started very early after transplantation. Just in the first few weeks after transplantation and probably, not allowing proteinuria to develop. On the other hand, there are 45 patients in each arm and in the two systematic reviews, 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

15 blood pressure because we're not sure whether they will have any negative effect on the renal function of these patients. Prof. Torres: Most guidelines recommend to start this type of drugs 3 months after transplantation. Because during the first 3 months you may have artery stenosis, you may have acute rejection and then you add a confounding factor with small increases in serum creatinine or decreases in egfr. So the recommendation is to start the blockade not before the second month after transplantation. Question: Maybe, if I may ask you a final more general comment. If you look at all these studies on blood pressure after transplantation, at best we achieve our targets in 50% of patients that we study. So in 50% we're quite unsuccessful. What would you advise us to change? 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 high levels or medium levels, then you have to adapt the immunosuppression just to try to stop corticosteroids if possible, to decrease the calcineurin inhibitor exposure and then add on different anti-hypertensive drugs. You can start with calcium antagonists or RAS blockade and then, you have to add a second drug beta-blockers or a third drug, beta-blockers or alphablockers. But the most important point is to reach the target of less than mms of SBP and don't forget also the use of diuretics. If you look to the 24 hour urinary excretion of sodium, a surrogate of sodium intake, many of them have more than meq/day and this is a very important point. Thus, to manage hypertension in the transplant recipient you can use different classes of drugs but adding a diuretic is usually needed because these patients exhibit a median GFR of ml/min a point that we would not forget. Chairman: Ok thank you Armando. Thank you for participating.

Prof. Rosanna Coppo Director of the Nephrology, Dialysis and Transplantation Department Regina Margherita Hospital Turin, Italy. Slide 1.

Prof. Rosanna Coppo Director of the Nephrology, Dialysis and Transplantation Department Regina Margherita Hospital Turin, Italy. Slide 1. ROLE OF PATHOLOGY AND CLINICAL FEATURES IN PREDICTING PROGRESSION OF IGA NEPHROPATHY: RESULTS FROM THE ERA-EDTA RESEARCH VALIGA Rosanna Coppo, Turin, Italy Chairs: François Berthoux, Saint-Etienne, France