WHEN TO START, WHEN TO STOP RRTClaudio Ronco, Vicenza, Italy

Chair: Jonathan G. Fox, Glasgow, UKRavindra L. Mehta, San Diego, USA

Prof. Claudio RoncoDepartment of Nephrology

International Renal Research Institute (IRRIV)San Bortolo Hospital

Vicenza, Italy

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Thank you Mr Chairman. When to start and when to stop,

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is the most frequently asked question and I think we should see andtry to understand what is the current practice, what can be thebenefits and limitations of an earlier start, if we can provide evidenceor at least an objective algorithm to start RRT and what- do theguidelines say about this?

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Definitely, this is an area of controversy.

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We have many facts in which we are not sure about RRT in the acutepatient.

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For example, conservative therapy, I think that besides criticismdialysis is the cornerstone for AKI in the ICU when prevention orconservative therapy do not work. We have seen the presentation ofthe previous speaker.

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But if you look at the prospective multinational epidemiologicalsurveys, you see that considering the incidence, overall hospitalmortality in the AKI population was 60% more or less. The mostcommon contributing factor was sepsis but only 62% of the AKIpopulation was treated.

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So are we sure we treated all the patients who required RRT?

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That depends on the clinical indications and this slide was taken fromRavi Mehta where he described the difference between RRT andrenal support therapy.So indication to start actually can be different whether you have life-threatening situations or you may have conditions that may require thetreatment to help the kidney.

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The other question is whether mortality or not has changed over theyears

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and the problem is that we have two different patients compared tothe past. The mortality is more or less the same but the patients aredefinitely different.

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If you look at the database of our own institution at the beginning from1974 to 1979, 48 patients treated only 15% in the ICU, while from 1995to 2000, 525 patients treated, only 8% in the ward, all the rest in theICU. Mortality is the same but the case mix is changed tremendously.

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A question also is whether or not patients who do RRT are exposed toa specific risk. Apparently, in this study by Metnitz there is a high riskwhen you have the need for RRT.

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In patients doing RRT mortality is higher, length of stay is longer,hospital length of stay is longer.

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Nevertheless, over the years mortality has progressively decreasedand in the last large trials done specifically on dose, mortality rate hassomehow decreased over time.

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Is this due to dose? Well, we don’t know but certainly still in 2004 andthen in 2007 if you asked people how do you prescribe your dialysis,still you had a large quantity of people saying ‘I don’t know how I amprescribing my therapy’.

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So we are probably missing something in the equation, we’re mixingdifferent clinical settings and we don’t know whether RRT itself is arisk factor.

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So this makes adequacy of treatment a nice iceberg where all theunknown aspects are under the water compared to what we normallybase adequacy on.

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Therefore, the question when to start and when to stop have to take

care of all these aspects that I just mentioned.

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The key questions today are therefore indication, timing, modality anddose prescription.

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We have seen that it depends very much on whether you want to bebecause you have a life-threatening situation or whether you requiresupport.

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So, there is a biological rationale to start early because actually thereare some studies that seem to show that you may improve survival,renal recovery and have a shorter duration if you start early.

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But the determinants of initiation depend on several issues includinghow the conservative therapy was working, what are the goals forclinical management and different situations concerning other organswe are dealing with.

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How do we define timing? Based on symptoms, on biochemicalmarkers or relative to onset of AKI, ICU admission, RIFLE class. Sothere is no pro-consensus to guide this.

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Before judging this, we must know that current practice is enormouslyvariable and surveys of practise have shown this and there are limitedquality of data. The fact that there is a current variability and here Imight disagree with my friend Norbert Lameire, I think it’s very goodsense that people are still watching the patients rather than watchingthe guidelines that in this case are not telling us anything useful.

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But definitely we have additional factors in RRT initiation. If you are ina different country, type of institution, type of ICU, depending onwhether or not you have resources and there are people that say‘Well,

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I’m in favour of an early start. I have theoretical advantages. I don’twant to have a lot of derangements to develop. I want to treat thepatient before it comes into a severe state’.

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This is a typical example that if you start early, you will never reach thelevel of uremic intoxication that you would achieve if you started late.

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But there are people that are somehow posing some scepticism.You may need a catheter; you potentially expose the patient to acatheter infection, to an extracorporeal circuit, and to RRT itself.

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There are few data and they are based on biochemistry. They seemto show a signal towards reduced mortality in patients who start withthe lower level of serum urea.

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Basically, the studies seem to show that actually, if you start early,you reach a steady state condition but you may avoid a very earlyphase of acute serious derangement.

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Then of course, there are other studies that have shown like in thiscase post-cardiac surgery but as Norbert has said, many of thesestudies are underpowered, they are very small but they seem to showthat with shorter stay in the ICU, some survival benefit.

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The PICARD study, and Ravi may comment even better, seems tohave a signal for a better survival probability when you start early.

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The BEST kidney study that was a large retrospective analysis onprospective data collected in 54 centres seems to show that basedon,

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for example, relative to ICU admission and creatinine level mortalityseems to increase when you wait 5 or more days from the ICUadmission to start RRT.

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This is important because also in the meantime the practise haschanged and in fact in some centres it has been shown that whenthey change the so-called ‘door-to-dialysis time’ due to differentpractice they might have seen improved survival and shorter durationof RRT.

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So based

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on some studies,

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which have a quality that is the questionable however, both inrandomised controlled trials and in cohort trials you have a relativereduction of the risk for dying when you start early therapy.

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There is also the point relevant to the fact that the fluid overload isconsidered a biomarker. In most cases when you analyse fluidoverload, patients who survive tend to be less fluid overloaded

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compared to patients who do not survive, especially, if you express interms of percent of overhydration compared to baseline body weight.

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We have applied what today is called an IT sniffer. Basically it isbased on a database

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that prospectively collects data. You keep going, you have data

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on general

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details

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of the patient, so

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the system automatically

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looks at

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the different aspects

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and the important thing is that we used both RIFLE criteria

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or AKIN criteria to define AKI and

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at certain point you have alerts. So it tells you, look I don’t know whatyou want to do but just to let you know that you have achieved thatlevel of AKI in the diagnosis and so on.

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So based on this we have initiated the possibility to develop algorithmsthat somehow should be tested in clinical trials.

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What can we say about timing so far? There is little consensus onwhen to initiate. Early initiation probably improves outcome, I must saybecause you don’t want to hear form me just PubMed, you want toknow what I think. What I think, I prefer to start quite early but I want tosee the patient before I say let’s go and let’s start.RIFLE and AKIN stratification stages may represent an interestingsurrogate of timing so we will not say early and late but we can saywe start at RIFLE-I and so on. There is a rational for early initiation,there are drawbacks for early initiation, objective arguments havebeen proposed. We definitely need some additional studies.

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Let’s see what the guidelines say. Well more or less, we can say thatabout this the guideline agreed on the fact that the sky is blue, that’s it.

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Because there was very, very little exposure probably because therewas not enough evidence to say that.So ‘when do we stop this continual RRT? When it is no longerrequired’. Thank you very much.‘We suggest not using antidiuretics to enhance kidney recovery’.

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That is interesting because in fact, it has been analysed that if you usea lot of diuretics in the patient, you may decrease your sensitivity andspecificity in analysing when you are capable

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of stopping

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the therapy.

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Now, what about timing? Initiate RRT emergently when life-threateningchanges in fluid electrolyte and acid-base exist. This is not graded butthis is life. I’m fed up about guidelines that say this is not graded. Whatdo you do? This is what you do, so we have to interpret guidelineswith good sense; we have to teach our fellows to look at the patientsand not just at numbers. Consider the broader clinical context. This isgood advice, this is very important because when you make adecision to start RRT, every patient is a single entity.

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So criteria

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for starting, again life-threatening situations

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or non-life threatening but you may need support is one condition.

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Typical condition of life-threatening situations are those that you find inany type of book of intensive care in nephrology. But every time youreach a potassium of 7 mmol/L there must be a moment 3 hoursbefore in which potassium was 6 mmol/L. So if you don’t watch yourpatients, you may reach a potassium of 9 mmol/L and then you havean emergency. That’s where the nephrologist and the intensivistshave to work together. You have to watch the patient, you have tofollow him that’s why I prefer to start when potassium is 5.5 mmol/Lrather than when potassium is 7 mmol/L.

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So renal support again is a condition that may require the treatment toenable nutrition, drug delivery, volume control, regulation ofelectrolytes, salt modulation and so on.

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There was no position about early or late in the guidelines.

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There is an interesting series of new studies. This is one, which hasbeen presented recently in Canada, showing what the characteristicsof the patients in Canada were when they started RRT. Theydescribed different conditions in terms of SOFA score, urine output,potassium and so on, so you can somehow confront yourself with thatsituation.

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What was the trigger? Well, hyperkalaemia most of the time, nouniformity about the rational, no clinical factors play an important role. Imust say that in our reality probably volume is definitely one of themost frequent triggers for starting RRT.

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The reality around RRT initiation is that there is no true standard ofcare, which may be a good thing again because you may want tojudge patient by patient. The problem is that if you see a patient that

requires RRT, from that moment treatment should be instituted andbe there in one hour. There is no reason to wait for 7 hours, 12 hoursand so on. To tell you the truth there are some discrepancies,

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for example, comparing the RENAL trial and the ATN trial when yousee the door-to-dialysis from ICU admission were so different, youreally don’t know exactly what were the factors affecting the start andthe decision to decide.There are plausible reasons to support earlier initiation, again if youwant to improve volume control or reach early correction or avoidmorbidity associated with complications guided.

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Again we have presented the results of the PICARD cohort thatcommenced RRT after adjustment for the propensity to receive lateRRT where it was associated with a two-fold risk of death.

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Again, in this study of Karvellas there seems to be a reduction in therelative risk when you start early.

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I mentioned the ATN and RENAL trial, you see the door-to-dialysisfrom ICU admission, 171 hours compared to 51 hours. So there is

something that is also important because there were differences inmortality, 52% at 60 days, 45% at 90 days and dependence on RRTat 60 days and 90 days. But we have reason to be cautious.

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Definitely most definitions are problematic because BUN andcreatinine thresholds, duration of ICU stay, RIFLE, they don’t reallyaddress the actual duration of kidney injury, the severity of kidneyinjury. They don’t tell us too much.

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Only 10% of critically ill patients normally receive RRT and we don’treally know if we are treating all the right patients. Our ability to predictprogression is rudimentary and the exposure of patients to riskvascular access may not be justified sometimes.

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There are measures confounding observations. It can’t be certain thatindividuals with high BUNs were not inherently different from thosewith low BUNs in the studies that were performed.

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The largest trial done,

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which is the Bouman trial, basically compared

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early hemofiltration with late hemofiltration, 7 hours versus42 hours, different urea levels.

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The trial results showed that late patients seemed to have lessmortality, also surviving patients recovered renal function, which wasquite curious.

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The study was definitely underpowered. Its generalizability wasquestionable, in the end it was quite inconclusive. So anothermessage. Do not quote the studies but do not misquote the studies.Quote the study but do not quote the abstract. Read the paper not justthe abstract because sometimes reading the paper you find a lot ofinteresting things.

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Why is a definitive trial needed? Because we would like to know sincethis is the most frequently asked question, when to start. An earlyRRT approach may harm patients or may be beneficial. Is adoption ofthis approach occurring anyway in spite of lack of evidence?

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In Canada they have started this so-called STARRT-AKI trial.

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It’s a randomised open-label pilot trial of accelerated versus standardinitiation of RRT in 12 academic centres.

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There are classic inclusion criteria with evidence of severe AKI basedon two of the following criteria: doubling of serum creatinine, very lowurine output or whole blood neutrophil gelatinase-associated lipocalin.This is an interesting thing. For the first time they are introducing theconcept of a biomarker,

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which still problematic, but may add some information to our study.

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So I think this is very important.Again there are other inclusion criteria including serum potassium,high central venous pressure.

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Randomisation is in blocks stratified by centre. Accelerated startwithin 12 hours, standard initiation, they discourage the starting unlesssevere conditions will develop.

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There are other co-interventions according to standard of care,modality, mode, and dose. These are what the physician normallyprescribes and clear criteria for renal recovery permitting withdrawalof RRT.

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The primary outcome is to have 90% in each arm of the peopleadhering to the protocol and the fact that more than 50% are eligible.The follow-up is at 90 days and they want to look for safety related toRRT and vascular access specifically.

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They have been actively recruiting. 81 patients enrolled last week,plans for definitive principle trials are underway and so far, there have

been no significant safety concerns.

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So current practice is variable. Initiation before life-threateningindications are evident in some studies and they have become to beincreasingly accepted. This approach has plausible benefits but alsosignificant potential harm. Is a definite trial needed or not? I don’t knowbecause again, unless we are going to be able to design a very, verygood trial we have to stop spending money in useless trials that areonly applicable to the population to which the trial has beenaddressed.