CME Slides Forum - J.F.M. Wetzels

A joint Congress by ERA-EDTA and ISN

RENIN-ANGIOTENSIN SYSTEM BLOCKADE IN KIDNEY TRANSPLANTATION

Jack F.M. Wetzels, Nijmegen, Netherlands

Chair: Michael J. Mihatsch, Basel, Switzerland

Mai Ots, Tartu, Estonia

wetzels

Prof Jack F.M. Wetzels
Department of Nephrology
Radboud University Nijmegen
Nijmegen, The Netherlands

Doctor Mihatsch, Doctor Ots, Ladies and Gentlemen I would like to thank the organisers for this invitation. I would like to show you some data on the effects of the renin-angiotensin system blockade in kidney transplantation.

As you have heard in the previous talk, although half life is increasing there is still need for improvement since many patients who have a functioning kidney at one year after transplantation will show a continuous decrease of graft function.

The major causes of this late graft failure are chronic allograft nephropathy and death. If you look at the factors which are important, then we know that a relentless decrease of graft function is related to proteinuria and increased blood pressure and we know that the majority of the causes of death are cardiovascular mortality.
We know from evidence in patients with CKD that ACE inhibitors and angiotensin-1 blockers reduce cardiovascular morbidity and also attenuate progressive kidney failure and this is especially proven in patients with proteinuria.

There are many studies and I have no time to go into details but the references are mentioned there.

From this evidence there’s a rationale for RAAS blockade in patients who are transplanted, they lower blood pressure, they lower proteinuria and they decrease the risk of cardiovascular events in patients with CKD.
Moreover, it has been shown also in renal transplant patients that RAAS inhibitors decrease TGF-β and also decrease PAI-1, both factors involved in the development of fibrosis which is an important part of chronic allograft failure.

So, with this evidence do we need the evidence in patients with kidney transplantation too? Well, the answer probably is yes, why? Because in animal models it has been shown that ACE inhibitors can worsen the vascular lesions in a rat model of chronic allograft nephropathy.
This is a study showing that when you look at the vascular intima that the use of ACE inhibitors which lowered proteinuria in this model and also the use of angiotensin 1 receptor antagonist increased the thickness of the intima which obviously is a problem.
Similar findings have been done, although not repeatedly I must say, in human studies looking at the increased rate of restenosis in patients after coronary stenting. But we also know that if you look at angiotensinogen knockout mice, you can see similar changes in the vessel.

Second we know that when you use ACE inhibitors, especially in patients who are being treated with calcineurin inhibitors, you can see in the short term a decrease in GFR of approximately 5-10% This is a short term study looking at decrease of GFR within one week after starting an ACE inhibitor. Also we are aware that ACE inhibitors can increase the risk of hyperkalemia in patients which may be especially important in patients with a decreased kidney function using calcineurin inhibitors.

So what do we know about the use of these drugs in patients who have been transplanted?
First of all, I think without looking at the evidence in clinical practice it’s clear that the prevalence of the use of these agents has increased in transplantation.
This is a study looking at the prevalence of the use of ACE inhibitors in patients and showing that from 1990-2003 there has been a dramatic increase in the use of these drugs. So we are using them in almost 50% of our patients.
It’s also clear that most patients get ACE inhibitors very soon after transplantation. In the first month the use is I would say 10% and then it increases to 30% in this particular study at 12 months after transplantation.

Looking at the patient characteristics of the patients who received this ACE inhibitor it was especially given to patients with pre-transplant hypertension, patients who used ACE inhibitors pre-transplant, patients who got post-transplant proteinuria, they were more often male patients, and they were younger. So we select patients when we use these agents.

Is it safe? I have two summarising studies, one review of 5 studies looking at the use of ACE inhibitors within the first 3 months after transplantation and in this summary study it was shown that there was no dramatic change in creatinine and also no major change in the potassium values. So in the short term it appeared relatively safe.

Considering the use of ACE inhibitors in the long term after transplantation this is one retrospective study looking at 177 patients where the ACE inhibitor or the ARB was started median at 9 months after transplantation and used for an average of 2 and a half years. Then it was clear that less than 10% of the patients had to discontinue this therapy, 4% because of hyperkalemia, 2% because of anaemia and 2% because of a certain increase in creatinine. So also in the long run it is relatively safe. Obviously these studies are biased because patients got the ACE inhibitor because of an indication and although they didn’t have it all it’s likely that these drugs were not started in patients who already had elevated potassium levels.

What about the efficiency of the use of these drugs? First of all let’s see whether it’s beneficial or detrimental when using it early on after transplantation. One of the risks considered was that because of lowering blood pressure and lowering of renal perfusion pressure there could be an increased risk of delayed graft function or longer duration before recovery of delayed graft function. In one retrospective study looking at patients transplanted in the period between 2001 and 2002 it was shown that there was no significant difference in percentage of patients who developed delayed graft function.

This was 20% in patients using ACE inhibitors and 25% in the patients who didn’t receive ACE inhibitors. So in this study there was no increased risk of delayed graft function. More provocative were the findings that the patients who had delayed graft function and used the ACE inhibitor had a faster recovery to normal or nearly normal serum creatinine levels. This curve shows you the recovery rate where in patients who had RAAS inhibitor all of them improved within this time period where still many patients who did not receive this treatment had a creatinine higher than 2 mg/dL after this period.
So this retrospective study showed that ACE inhibition is not likely to increase the rate of delayed graft function and maybe could improve the outcome of these patients.

These authors then studied their whole database looking at more than 2000 patients, again a retrospective study in the transplanted patients in the period between 1990 and 2003 where the majority of patients were treated with RAAS inhibitor after transplantation. Again this larger retrospective database showed that there was no difference in delayed graft function. Even if you look at the clinical data it suggests that the patients who were treated with an ACE inhibitor or an ARB had a slightly I would say worse patient profile, greater percentage of patients having diabetes, more known with hypertension. So if you look at this data you would expect that if anything probably they could do a little bit worse.

What they found was that in the patients with delayed graft function again there was better survival in the cohort that used the ACE inhibitor from the start of transplantation confirming the small retrospective study. It was a benefit both in terms of patient survival and also in functional graft survival.

When they then looked at the whole database so including also the patients without delayed graft function, again there was a difference with a better survival in patients using ACE inhibitors or ARBs and in the survival curve no significant difference in the functional graft survival and so patient survival was better. No major difference in graft survival but then when they did a multivariable analysis correcting for all the risk factors such as hypertension, diabetes and so on it was clear that the use of the ACE inhibitors was paralleled by lower hazard ratios for actual graft survival but also functional graft survival which is the graft survival after censoring for death. So again this retrospective study suggested that early treatment with these drugs could improve patient survival and graft survival.

What about the use of these drugs in chronic allograft nephropathy? I have used this term because in the literature published before 2005 these were the patients who had this slow decrease of kidney function. There are some retrospective studies suggesting that the use of ACE inhibitors could improve graft survival. This is one study with 63 patients with a mean follow up of 27 months. Looking at the 50% increase of serum creatinine there were differences but they were not significant. If they then looked at the endpoints allograft failure or death then there were significant differences in the survival curve. This upper curve is the line of patients who were treated with the ACE inhibitors. So in this study there is again a benefit of ACE inhibition.

The next study is from our group. This was also a retrospective study, with 72 patients where 23 were treated with an ACE inhibitor or an ARB and 49 patients didn’t receive these drugs. They were followed for 22 months and again, in these patients who were diagnosed with chronic allograft nephropathy and all of them had proteinuria there was a better survival in the patients who received the ACE inhibitor treatment and we observed a small but significant increase in serum potassium from 4.1-4.6 mmol/L.
When we did a multivariable analysis, again the use of these agents was paralleled by an improved survival. So also correcting for several baseline characteristics at the time of the biopsy. But these retrospective data cannot be enough to provide evidence.

and this study looked at 21 trials including over 1500 patients. Unfortunately, of all these trials there was only one randomised controlled trial and that was a trial which was only published as an abstract, which was prematurely ended because the total number of events was too low to expect a difference at the end. So this study will not provide any data. Of all these remaining 20 trials only 4 studies had a follow up of more than 12 months which means that it will be very unlikely to see a difference in graft or patient survival because that’s something which happens 24 or 60 months after the diagnosis of chronic allograft nephropathy.

When you look at a summary of the data, then it’s clear that the use of the ACE inhibitors or ARBs was paralleled by a change in proteinuria, a significant increase in hematocrit and a change in potassium, all things which can be expected from the use of these agents. Rather strange but for the study maybe nice there was no significant change in mean arterial pressure between the patients treated with ACE inhibition and the patients not treated with ACE inhibition.

These are the short term effects. What about the long term effects? Well then in the long term there was a significant change in GFR with patients being treated with RAAS inhibitors showing a steeper decrease in GFR of on average 5.7 ml/minute. If you use the data just the data from the studies with a follow up of more than 12 months, the change actually is the same which suggests that these changes are acute changes in GFR probably to be expected when using these kinds of drugs. However, when we look at the long term there are no data. Also in this review there are no effects on graft survival which we can use to provide you with any hard evidence.

So what are we left with? Well I think that we can conclude although they’re not randomised controlled trials that the use of these agents is relatively safe. Probably what I have shown you is that that’s what we do in clinical practice because in some studies nearly 50% of patients are being prescribed these agents.

However, should we use them in all patients? Then I must say we cannot make a recommendation such as in guidelines based on level A evidence. There is no level A evidence. What the retrospective data suggests is that these agents may shorten time to recovery in patients with delayed graft function. They may improve graft survival in patients with chronic allograft nephropathy. They may improve overall patient and graft survival.

What is important I think is that if we treat patients who have received a kidney transplant that we should treat blood pressure and proteinuria aggressively and that’s probably more important than the choice of any type of specific drug. If we treat these patients, we should weigh the risks and benefits because it’s obvious that some patients who need treatment for hypertension may benefit for instance form a calcium channel blocker because that may mitigate calcineurin inhibitor toxicity and patients may need a β-blocker when they are having heart failure or have had previous myocardial infarction.
So I suggest that we at least should use and could use ACE inhibitors or ARBs in patients who have proteinuria, in patients who have diabetes and in patients who have heart failure and also we should consider the use in patients with inadequate blood pressure control.
Thank you very much.

Chairman: Doctor Wetzels thank you very much for your presentation. There may be questions. Yes please.

Question: Yes, I have a question would you suggest the same indications for angiotensin receptor blockers?

Prof. Wetzels: Well, in the studies they have mostly combined the data. I think there is no hard evidence to suggest that although in theory and also in some animal studies there are differences I think for the use in patients probably they are alike. I prefer ACE inhibitors but I think there’s no hard evidence to support it.

Question: One more thing it’s also helpful for ---- ischemia after transplantation.

Question: We should always keep in our mind RAAS inhibition is also helpful in --- ischemia you see after transplantation.

Prof. Wetzels: Well you know I think what was shown for the delayed graft function these data are interesting because they suggest that maybe the recovery from delayed graft function which is related to ischemia could be faster with ACE inhibitors. But what I think that the data shows that we there’s still time and we still need to do randomised controlled studies. I know that in transplants most studies, also the early studies are devoted to avoiding rejections. I think the data showed that it could be important to do also randomised controlled studies in transplant patients using non-immunosuppressive therapy.

Question: Thank you for the lecture. I would like to ask a complete RAAS blockage is better than giving only ACE inhibitor or angiotensin receptor blockers?

Question: Complete RAAS blockage by ACE inhibitor and angiotensin receptor blocker does it have any more advantage than giving any of them separately?

Prof. Wetzels: Well you know I think there are no data in transplants, there are recent studies in patients with cardiovascular disease and with hypertension which suggest that the combination has no advantage on cardiovascular mortality or cardiovascular events. I think the main point of that study and that’s also important probably in our population is that if you use the drugs, you should avoid too low blood pressures because it is suggested that if you use the combination and you have a systolic blood pressure below 110 mm/hg or a diastolic blood pressure below 60 you could have an increased risk of stroke or cardiovascular events and that’s probably because these patients have a pre-existing vascular disease and small vessels.