Results from the COSMOS study were reported today. This is an observational, non interventional study comparing the outcomes of patients treated with phosphate binders compared to those not received any binders. It is a nulti-centre study that compared the outcomes of some 4500 patients from 220 centres who received binders to 2000 patients who didn't. Those treated with binders had a better survival.
Clearly a lot of money has been invested to show that if you have low phosphate not needing binders you are probably elderly, frail and malnourished with likely poor outcome. In fact the authors admit that the non-binder group were older.
I am sure we will have many drug reps knocking on our doors telling us how phosphate binders save lives!
Dr Alaas Sabry blogged:
ERA/EDTA precongress CME course - Renal Pathology- an interesting course, the following topics were presented:
1-New insight in C3 glomerulopathy ( Terry cook- Imerial college London) THE PATHOPHYSIOLOGY AND CLASSIFICATION OF THIS TYPE OF NEPHROPATHY , RENAL PATHOLOGY AND FUTURE TREATMENT OPTIONS- CASE REPORTS FOR THE VALUE OF ECULIZUMAB IN TREATMENT OF C3 NEPHROPATHY
2-Critical review of the ISN/RPS LN Classification (IAN ROBERTS , OXFORD ,UK) :
Excellent comparative presentation with WHO classification and the reperoducability of ISN/RPS classification
3- Update in renal Tx biobsy ; stress on C4d negative , microvascular injury ( capilaritis) positive AMR and the future value of Endothelial Cell Associated Transcripts (ENDATA ) was elaborated.
So last week I saw 2 patients within a few hours each of whom tells their own story. The first was in transplant clinic. She was transplanted 10 years ago and has perfect kidney function. Her BMI was 40 at the time of transplant and is now 50. She sailed through the transplant without any technical or imunnological problems. Transplantation was undoubtedly a life-saver – she had factor V Leiden mutation and was running out of access due to recurrent clotting of access.
In the afternoon I saw a 50 year old patient on haemodialysis. She had a BMI of 35 and had previously been active on the transplant list. She was otherwise well with no other significant comorbidity. She was reviewed by a surgeon who felt that as she had significant central obesity, transplantation would be technically challenging and so she was suspended from the list until her BMI was 30. She asked to see me as she was in a terrible state. She was literally starving herself and had lost 8Kg but needed to lose a further 8 kg before her BMI hit the magic 30. She pleaded for me to be reactivated on the transplant list though I explained this was ultimately a surgical decision. What was clear was that i) I had never seen her look so ill as she did now she was trying to lose weight and ii) for her to maintain herself at a BMI of 30 she would need to continue to starve herself.
So these two cases prompted me to look a bit at the literature around obesity and transplantation and the following themes emerged:
- While it has long been recognised that higher BMI associates with survival on dialysis there is also some data to suggest that weight loss is harmful. Molnar and colleagues looked at over 14000 wait listed dialysis patients and found that those who had loss greater than 5Kg had a death hazard ratio of 1.51. Of course this doesn’t mean necessarily that intentional weight loss is harmful but it is food for thought when telling dialysis patients to lose weight.
- Whilst surgical complications post transplantation ( e.g. wound infections) do increase with BMI, the data on the effect of obesity on graft survival is conflicting. Streja and colleagues analysed10,090 kidney transplant recipients were followed for up to 6 years posttransplantation. Low pretransplant BMI (<22 kg/m2) showed a trend toward higher posttransplant mortality, whereas obesity (BMI ≥ 30 kg/m2) was not associated with mortality, albeit it showed a trend toward higher graft loss. A smaller analysis of over 1000 patients showed recipient BMI to correlate with delayed graft function which of course in itself is a risk factor for poorer graft survival. In a 20 year follow up of around 1800 patients from Holland, BMI increment post transplantation and BMI at one year were both much more powerful predictors of adverse graft and patient survival than pre-transplant BMI. Indeed pretransplant BMI didn’t have a statistically significant association with adverse outcomes
- The key question perhaps isn’t whether the obese are more likely to run into complications but whether they still have a survival advantage from transplantation. In an analysis of around 7000 patients who had a BMI of >30 who were wait listed for transplantation, the incidence of mortality in those who underwent transplantation was still less than half of those who stayed on dialysis waiting for a kidney. The beneficial effect of transplantation was lost when BMI>41
So what to do? Well given the fact that the safety of weight loss isn’t established in dialysis patients (and may be harmful in some patients) we need to be honest with patients and tell them that we don’t know whether this is safe - it may well be safe to lose weight but it may not be and so we need to tell patients that. There is no evidence to show that weight loss pre-transplant improves outcomes post-transplant and the observational data seems to suggest that patients with a pre-transplant BMI of upto 40 still gain a survival benefit from transplantation. Therefore as ever we need to make individual decisions on a holistic evaluation of the patient taking into account all other comorbidities rather than plucking arbitrary numbers and targets out of the air. This is of course only opinion but I'm not convinced that the patient with a BMI of 35 who is currently starving herself to get to a BMI of 30, will get any health benefit from such starvation.
Associations of body mass index and weight loss with mortality in transplant-waitlisted maintenance hemodialysis patients. Molnar MZ, Streja E, Kovesdy CP, Bunnapradist S, Sampaio MS, Jing J, Krishnan M, Nissenson AR, Danovitch GM, Kalantar-Zadeh K. Am J Transplant. 2011 Apr;11(4):725-36
Associations of pretransplant weight and muscle mass with mortality in renal transplant recipients. Streja E, Molnar MZ, Kovesdy CP, Bunnapradist S, Jing J, Nissenson AR, Mucsi I, Danovitch GM, Kalantar-Zadeh K. Clin J Am Soc Nephrol. 2011 Jun;6(6):1463-73.
Recipient and donor body mass index as important risk factors for delayed kidney graft function. Transplantation. 2012 Mar 15;93(5):524-9.Weissenbacher A, Jara M, Ulmer H, Biebl M, Bösmüller C, Schneeberger S, Mayer G, Pratschke J, Öllinger R.
Effect of obesity on the outcome of kidney transplantation: a 20-year follow-up.Hoogeveen EK, Aalten J, Rothman KJ, Roodnat JI, Mallat MJ, Borm G, Weimar W, Hoitsma AJ, de Fijter JW. Transplantation. 2011 Apr 27;91(8):869-74.
An interesting pilot, proof of concept study is published in JASN online today looking at the role of renal dennervation in patients with resistatnt hypertension and CKD. In the last couple of years a number of studies have suggested that renal dennervation maybe useful in the management of resistant hypertension and larger scale clinical trials are currently underway to test this hypothesis. As yet however there have been no studies in the CKD population. The rationale is that there is increased renal sympathetic activation in CKD and further that activation of the renal afferent sympathetic system in response to CKD also increases central sympathetic activation. Renal denervation involves placing a radiofrequency catheter in the renal artery ( accessed by femoral artery) to allow ablation of renal sympathetic chain.
In this study by Hering and colleagues from Melbourne, 15 patients with CKD 3/4, a mean office BP of around 174/9, taking an average of 5.6 drugs underwent the procedure. At follow up that is between 3-12 months there was no difference in creatine-based eGFR or cystatin C suggesting that the procedure has no adverse effects on kidney function. Mean changes in office systolic and diastolic BP at 1, 3, 6, and 12 months were −34/−14, −25/−11, −32/−15, and −33/−19 mmHg, respectively. Interestingly and perhaps disappointingly the mean 24 hour BP and daytime BP didnt change. However there was a significant reduction in nightime systolic BP on 24 hour monitoring falling from a mean of 154 to 144mmHg at 6 months. i.e. there was a restoration of nightime dipping of BP - lack of nightime dipping is a stronger predictor of CV events than daytime BP. Interestingly there was no significant change in the number of medications being taken at the end of the study. The lack of effect on daytime BP is not easily explainable but the numbers are of course small and there is substantial intrpatient variability. Peripheral arterial stiffness as assessed by augmentation index was significantly reduced at 3 months suggesting that the effect on blood pressure was real. There were reductions in proteinuria, BNP and increases in hamegloblin at 3 months but these did not reach statistical significance.
Theres clearly a long way to go before we know whether this technique will impact on meaningful outcomes but in CKD but as the authors say this preliminary study provides guidance for the design of further cinical trials to evaluate the short and long term effects of the technique in CKD.
The recently published KDIGO guidelines provide a welcome and timely synthesis of the evidence base to support the management of AKI.The guidelines focused on 4 key domains: i) AKI Definition, ii) Prevention and Treatment of AKI, iii) Contrast-induced AKI and iv) Dialysis Interventions for the treatment of AKI.
The full summary of clinical practice statements is available at www.kdigo.org but a key recommendation is that clinicians effectively adopt the previously published AKI Network definition and staging. The rationale for the staging system comes from a plethora of studies showing that the risk of death and renal replacement therapy (RRT) increases with each stage. Furthermore evidence suggesting patients in whom AKI resolves are at increased risk of death, CKD and cardiovascular disease has prompted KDIGO to make an ungraded suggestion that all those with resolved AKI should be considered to be at increased risk of CKD and be managed as per the KDOQI guidelines for individuals at risk of CKD. However whilst there is no doubt that standardising the definition and staging of AKI provides a clear framework for studying outcomes in both epidemiological and clinical research the bedside utility of the proposed classification and staging maybe be questioned by many 'real-world' practicing clinicians. In particular it is not clear how staging will alter immediate management and outcomes. As with the CKD classification sustem the danger is that an epidemiological tool gets imposed onto clinical practice without any evidence that the classification system per se can improve outcomes or can lead to specific interventions. Furthermore the evidence that monitoring people with resolved AKI as being at risk of CKD can i) prevent the onset of CKD or ii) is cost-effective is not presented.
Many other recommendations are made most of which are eminently sensible/obvious (e.g. use vasopressors for those with shock) but a few caught my eye:
recommended use of oral NAC in contrast nephropathy – despite v weak evidence, plus the fact that NAC has poor oral bioavailability and increases tubular secretion of creatinine
that regional citrate be the anticoagulant of choice in CRRT unless the patient is shocked/has liver disease – of course these are the very patients that are most likely to be on CRRT and given the complexities of citrate use it’s a shame no practical protocol was provided…
that dialysis dose be measured in AKI either by using Kt/V ( almost certainly meaningless in a catabolic patient with AKI) or the effluent flow rate in CRRT – again no evidence from the Veterans and Australasian studies that dose of RRT in AKI has any impact on survival.
support the use of CRRT in haemodynamically unstable patients whilst this is routine practice in many places the meta-analyses indicate this again has no impact on patient outcomes… and as well all know CRRT is rarely continuous.
- The use of insulin to maintain glycaemic control despite the risks of hypoglycaemia.
As with previous KDIGO reviews, the clear message is that there is a lack of evidence (particularly, well-designed interventional outcome studies) to underpin much of our everyday clinical practice. Indeed only 14.8% of the recommendations were graded '1A' whilst 63.9% of the recommendations were level 2. Thus these are not prescriptive guidelines but provided nuanced guidance for the clinician. The KDIGO co-chairs bullishly argue that recommendations should be made even when the evidence is weak as clinicians often ask "what do the experts do?" – this may be true but as history tells us the track record of expert opinion in the absence of evidence can often be deeply flawed.
The recommendation that an empirical definition and staging system be used in the management of AKI will arouse controversy and debate. As yet no data has been presented to show that these tools in themselves can improve outcomes in AKI and many clinicians will be wary about implementing what is essentially a research-based diagnostic and staging system into the clinical arena in the absence of such data – as was the case in CKD........
- Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-3370.
- Clinical practice Guidelines for Acute Kidney Injury 2012. http://www.kdigo.org/clinical_practice_guidelines/AKI.php
- Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A: Acute kidney injury network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
- Rabindranath K, Adams J, Macleod AM, Muirhead N: Intermittent versus continuous renal replacement therapy for acute renal failure in adults. Cochrane Database Syst Rev 2007:CD003773.
- Palevsky PM, Zhang JH, O'Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan A, Watnick S, Star RA, Peduzzi P: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008;359:7-20.
- lomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S, Myburgh J, Norton R, Scheinkestel C, Su S: Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 2009;361:1627-1638.
35% of transplanted adolescent transferred to adult nephrology unit reject their kidneys within 36 months....non compliance, non-adherence, non-concordance....Transition from pediatric to adult units is a major issue with regard to transplanted adolescent...transition multi-disciplinary approach and transition clinics are key components of a smooth transition.
DAY2 MASTER CLASS IN KHARTOUM:
CRITICAL APPRAISAL SESSION
DO NOT EQUATE eGFR with mGFR!!!!!!
eGFR is subject to all the confounders of changes in serum creatinine:
Diet, metabolism, GFR and Tubular secretion
MEASURED GFR IS THE ONLY MARKER OF CHANGES IN GFR AND SHOULD BE USED IN CLINICAL TRIALS TO ASSESS CKD PROGRESSION!!!!
The question is:
WHY ARE NEPHROLOGISTS RELUCTANT TO MEASURE TRUE GFR IN CLINICAL TRIALS OF CKD PROGRESSION????
Is it convenience?
Is it pressure from Sponsors to fudge the real result?
Is it just ignorance that eGFR is an inadequate marker of true GFR?
I am bewildered....!!!!!
Proposed KDIGO staging of AKI
1.5-1.9 times baseline
³0.3mg/dl (³26.5mmol/l) increase
<0.5ml/kg/hour for 6-12 hours
2.0-2.9 times baseline
<0.5ml/kg/hour for ³12 hours
3 times baseline
4.0 mg/dl (353.6mmol/l) increase
OR initiation of renal replacement therapy
OR in patients less than 18 years a decrease in eGFR <35mls/minute/1.73m2
<0.3ml/kg/hour for ³24 hours OR
Anuria 12 hours