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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:

  1. 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.
  2. 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
  3. 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.

 References

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.

Impact of renal transplantation on survival in end-stage renal disease patients with elevated body mass index. Glanton CW, Kao TC, Cruess D, Agodoa LY, Abbott KC. Kidney Int. 2003 Feb;63(2):647-53.

 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.

 

 

 

 

 

 

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by Arif Khwaja - Friday, 18 May 2012, 7:18 AM
Anyone in the world

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.

References

 

  1. Medline
  2.  
    Medline
  3.  
    Abstract/FREE Full Text
  4. Renal Denervation in moderate to severe CKD. Hering D et al. http://jasn.asnjournals.org/content/early/2012/05/16/ASN.2011111062.abstract

 

 

 

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Picture of Arif Khwaja
by Arif Khwaja - Wednesday, 16 May 2012, 3:34 PM
Anyone in the world

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:

  1. 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
     
  2. 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…
     
  3. 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.
     
  4. 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.
     
  5. 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........

References

  1. 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.
  2. Clinical practice Guidelines for Acute Kidney Injury 2012. http://www.kdigo.org/clinical_practice_guidelines/AKI.php
  3. 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.
  4. 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.
  5. 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.
  6. 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.
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Anyone in the world
Published this month in JAMA by Matsushita and al on behalf of the CKD prognosis consortium a reevaluation of CKD prevalence in communities as well as the implications in term of all cause and cardiovascular mortality.
 
"Main Outcome Measures All-cause mortality (84 482 deaths from 40 cohorts), cardiovascular mortality (22 176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years).
Results Estimated GFR was classified into 6categories(>90,60-89,45-59,30-44,15- 29, and <15 mL/min/1.73 m2) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

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.

 

 

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Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 9 May 2012, 8:58 AM
Anyone in the world

DAY2 MASTER CLASS IN KHARTOUM:

CRITICAL APPRAISAL SESSION 

MAJOR HIGHLIGHT:

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....!!!!!

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Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 9 May 2012, 4:12 AM
Anyone in the world

 

Proposed KDIGO staging of AKI

 

Stage

Serum Creatinine

Urine Output

1

1.5-1.9 times baseline

OR

³0.3mg/dl (³26.5mmol/l) increase

<0.5ml/kg/hour for 6-12 hours

2

2.0-2.9 times baseline

<0.5ml/kg/hour for ³12 hours

3

3 times baseline

OR

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

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 9 May 2012, 3:47 AM
Anyone in the world

 

The American College of Rheumatology (ACR) has issued the first-ever guidelines for the screening, treatment, and management of lupus nephritis (LN). 
The guidelines are published in the June issue of Arthritis Care & Research
They were initially presented at ACR 2011.

Clinical conclusions
1- the 2012 guidelines are a significant advance because they address total therapy of LN, not just short-term treatment.

2- At this time, more than half of patients with systemic lupus erythematosus develop LN within 10 years and up to 30% of those cases progress to end-stage renal disease within 15 years of diagnosis.

3- The ACR panel, which developed the guidelines, recommends renal biopsy for all patients with clinical evidence of active, previously untreated LN. 

4- They do not recommend immunosuppressive treatment for patients with class 1 (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) or class 2 (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium) renal damage. However, they do recommend aggressive treatment for patients with class 3 or higher renal pathology.

5- Mycophenolate and cyclophosphamide plus glucocorticoids are the mainstay of treatments for induction of improvement in [LN] of serious histologic classes (except if patient is pregnant), and azathioprine [AZA] and mycophenolate are both acceptable for maintenance of improvement (except in pregnancy). Recommending pulse steroids in treatment of class 3 and 4 active proliferative disease. Rituximab or calcineurin inhibitors should be considered if standard treatments fail."

6- An algorithm for management of pregnant woman with active [LN] is included in the guidelines.The guidelines note that women should be off MMF or CYC for at least 6 weeks prior to conception.

7- Renal failure may not come quite as quickly in pure membraneous nephritis, but the long-term prognosis is not great."

8- Studies have shown that MMF is more effective than CYC in African-American woman, and this is highlighted in these guidelines."

9- Consensus on the use of calcineurin inhibitors: The agents have potential renal toxicity, but have been shown to be effective in membranous lupus during the short term.

10- The role of rituximab in LN also remains somewhat uncertain. Rituximab is listed as a relatively late intervention.

11- Recommendation to perform renal biopsies whenever the therapeutic decisions would be altered by knowing 1) histologic classification and 2) level of activity and of chronicity on the biopsy.

12- There needs to be more use of remission-inducing agents at proper doses for proper duration, transition from induction to maintenance therapies without a gap if possible, prevention of adverse effects when possible.

13- The guidelines do not address the questions of how long to treat during maintenance therapy and when begin to taper MMF because there are few data on the topic.

14- With regard to the increasing incidence of end-stage renal disease associated with LN, there are fibrotic processes plus other reasons such as hypertension that contribute to atherosclerosis. Many patients progress to renal failure not due to active nephritis, but due to the combined effects of irreversible damage accrued over many years.

Arthritis Care Res. 2012;64:797-808.
 
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by Meguid El Nahas - Thursday, 3 May 2012, 9:09 AM
Anyone in the world

 

Annals of Internal Medicine

Screening for, Monitoring, and Treatment of Chronic Kidney Disease Stages 1 to 3: A Systematic Review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline

Howard A. Fink, MD, MPH; Areef Ishani, MD, MS; Brent C. Taylor, PhD, MPH; Nancy L. Greer, PhD; Roderick MacDonald, MS; Dominic Rossini, MD; Sameea Sadiq, MD; Srilakshmi Lankireddy, MD; Robert L. Kane, MD; and Timothy J. Wilt, MD, MPH 

This is a balanced systematic review of the literature relating to the impact of treatment including ACE inhibitors and ARBs on outcomes in CKD; ESRD and Mortality. The authors conclude that the evidence is in general fair but seldom strong and therefore current recommendations for screening and early treatment to prevent hard endpoints such as death or ESRD are weak.

They also reported that the evidence for strict BP control is weak.

They conclude that the role of screening or monitoring in improving outcomes is uncertain as hardly any study reviewed addressed that point. And that the evidence for benefit is strongest for ACE inhibitors and ARBs, and more specifically in patients with albuminuria combined with diabetes and cardiovascular disease. 

This manuscript should be read by all those interested in the management of CKD as it shows the limitations of available data and highlights the value of careful and systematic analysis.

Read the full article on OLA:

https://www.gkaonlineacademy.com/resources/library/cat_view/6-ckd

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

For a number of years some nephrologists have advocated online hemodiafiltration (HDF) as the therapy of choice in chronic dialysis patients. The theory being that enhanced convective removal of middle molecules allows the removal of uraemic toxins that contribute to the inflammatory state in haemodialysis and promote cardiovascular disease.  A number of observational studies have shown a survival benefit of HDF.

This months JASN publishes the results of the Dutch CONTRAST RCT that compared HDF to low flux dialysis in 714 RRT patients. Ultra pure water was used in both arms of the study. There was good separation of beta two micro globulin between the two groups indicating good convective removal with HDF. It appears to be a very  well conducted study.
The results are disappointing. There was no difference in the primary endpoint of death after three years of therapy. Nor was there any difference in fatal and non-fatal cardiovascular outcomes between the two groups. In a post-hoc analysis of patients who achieved a delivered convective volume of > 21.95litres there was an associated reduction in mortality. However as the authors clearly state this kind of post-hoc analysis does not support the use of HDF. Indeed it maybe those that achieved the higher convective volumes simply had better vascular access and few patients achieved these volumes.
What may explain the lack of effect of HDF... A number of explanations are possible including i) the beneficial effects of HDF in observational studies is due to the use of ultra pure water.. In this study the control groups also dialysed with ultra pure water.ii) "beneficial" mediators as well as uraemia toxins are removed by HDF iii) the follow up of 3 years is too short to realise any benefit iv) the HDF dose delivered was simply too low... In fact few patients achieved the intended convective volume of 24 litres v) the wrong end-point was chosen - perhaps intradialtic hypotension would be a more appropriate endpoint or a quality of life measure. vi) the treatment is no more effective than modern-day conventional HD!!
The latter may well be true and once the Turkish HDF study and others are published in the next year or so we will have the answer for sure. ... Of course HDF was non-inferior to standard dialysis so if cost is not an issue the it would be perfectly reasonable to use HDF - though the environmental cost may be significantly higher with HDF.
For now as is so often the case expert opinion supported by observational data once again has been found wanting...
 
Reference

http://jasn.asnjournals.org/content/early/2012/04/26/ASN.2011121140.abstract?papetoc

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