User blog: Meguid El Nahas
The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.
The original publication by the Frequent Hemodialysis Network (FHN) implied positive impact of Frequent Daily Dialysis on the coprimary outcomes:
Left ventricular mass index (LVMI) + Death and LVMI + Quality of Life
This, in spite of the fact that the study was underpowered with an inadequate sample size to estimate impact on death over such a short observation time (12 months)! The results of the Daily trial were comparable to those in the literature describing improvements by salt restriction and volume control.
Now the same group publishes that if you do frequent HD at night, there is no benefit on any of the Primary endpoint: LVMI, Death or Quality of Life!
In fact, The FHN Daily and the Nocturnal trial differ in some respect: Time of dialysis, location and length of treatment but laso in the degree of residual renal function.
So, is Frequent HF, 6 times/week, only beneficial if it is done in Daytime not Nightime...???
Are all these trials and sub-trials un-interpretable because they are badly designed and underpowered?!
So don't rush to switch all your patients at a huge cost and inconvenience to frequent HD. Make sure they are not fluidoverloaded with careful ultrafiltration/volume control and dietary salt restriction.
Wait until Nephrologists know how to conduct and interpret clinical trials....
Finally, the assumption that one size fits all with targets systolic levels of <130 or 120mmHg is preposterous. Age, race and comorbidities may dictate different target levels. This is becoming apparent in patients on hemodialysis were older and diabetic individuals had higher mortality rates at lower (<140/70mmHg) blood pressure levels. More remarkably was the observation in this cohort analysis that survival did not seem to be harmed by higher systolic and diastolic values: 140-160 and 70-100mmHg (1).
1. Myers OB, Adams C, Rohrscheib MR, Servilla KS, Miskulin D, Bedrick EJ, Zager PG.Age, race, diabetes, blood pressure, and mortality among hemodialysis patients. J Am Soc Nephrol. 2010 Nov;21(11):1970-8.
An article in the August issue of cJASN by Schinstock and colleagues from the Mayo clinic describe the experience with AVF. They report a large primary and secondary failure rate and identify diabetes mellitus and the size of the arteries as major determinants of reduced primary patency. Larger arteries are associated with better AVF outcomes thus advocating doppler testing and sizing of arteries and veins prior to AVF fashioning. They also raise the important issue of morbidity, complications and subsequent hospitalisations associated with AVF failure.
This leads them to questions whether in elderly patients with comorbidities and reduce life expectancy on HD, the Fistual First approach still holds as failure rate with the associated hospitalisations should be taken into consideration.
In my experience, older age and the associated atherosclerotic arteries specially in those with DM has been a major cause of raised primary and secondary AVF failure. This is indeed associated with frequent hospitalisations, imaging and re-interventions. The question should be raised if AVF in those with low life expectancy and small arteries on doppler should follow the Fistula First Stategy or whether a judicious and careful treatment plan with a permanent internal jugular dialysis catheter is a viable alternative. Some (Allon et al. 2010) have advocated a RCT to address some of these issues.
In the meanwhile, we should not forget the high morbidity and mortality associated with dialysis catheters and should make every asttempt at timely insertion of native AVF.
An interesting controversy and debate is taking place in the Lancet relating to the impact of dietary salt diction on cardiovascular disease (CVD) outcomes. A recent Cochrane review by Taylor and colleagues based on a meta-analysis of 7 trials with 6250 individual implied that dietary salt reduction did not reduce CVD or impact on mortality. This publication led to headlines implying that salt reduction is unnecessary and unjustified. A rebuttal of this publication appears this month in the Lancet by He and MacGregor who criticize the first analysis and reanalyses the data by including all the patients and combining normotensive as well as hypertensive individuals in the new analysis. This draw different conclusions; they show that a dietary salt reduction leads to a significant reduction in CVD events by 20% but no significant reduction in all causes mortality. I would side on He and McGregor side and remind readers that there a large body of evidence in favour of salt reduction for the prevention and treatment of hypertension; hypertension is one of the major causes of CVD morbidity and mortality. The WHO recommends salt reduction as one of the top priorities along with smoking cessation and fighting obesity to reduce the rising tide of non-communicable disease. This debate in the Lancet highlights once more that different results and conclusions can be obtained from the analysis of a single dataset; it all depends on the investigators bias as well as the statistical methods applied. Beware, of the manipulation of statistics to prove a point. Investigators arvall too often i cloned to call statistics as an ally to prove their Pints. Truth is often hostage to statistical analyses...!?
Taylor et al. Reduced dietary salt for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;7:CD 009217
He and MacGregor. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials. Lancet 2011:378:380-82.
Circulating urokinase receptor as a cause of focal segmental
- Nature Medicine
- 952–960, 2
For Review read: McCarthy ET, Sharma M, Savin VJ.Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010 Nov;5(11):2115-21.
Dr Arif Khwaja wrote:
Results from the ORION study are published in this months AJT. This study involved 469 de-novo standard risk allografts who were randomised to either
1) Sirolimus and Tacrolimus aiming for Tacrolimus withdrawal at 3 months.
2) Sirolimus +MMF
3) Standard therapy with Tacrolimus and MMF.
All groups got Daclizumab induction and steroids. Due to higher rate of rejection the MMF+Sirolimus arm was terminated early in the study. The primary endpoint was Nankivell GFR at 12 months and there was no difference between standard therapy (group 3) and CNI withdrawal in group 1. The CNI-withdrawal group did not have any advantage over standard therapy with tacrolimus and MMF: patient (97.0% vs. 94.4%) and graft survival (95.4% vs. 88.5%), renal function (62.0% vs. 59.1 mL/min), rejection prophylaxis (12.3% vs. 17.4% biopsy-proven rejections), discontinuations (35.2% vs. 65.1%) representing overall tolerability and adverse events such as oedema (36.7% vs. 51.3%), anaemia (36.0% vs. 40.8%), hyperlipidaemia (20.1% vs. 36.8%), proteinuria (6.5% vs. 11.2%) and wound healing disorders including lymphoceles (14.4% vs.32.8%). Dyslipidaemia and thrombocytopenia and acne were significantly worse in the CNI withdrawal group whilst other secondary outcomes such as proteinuria whilst worse in the CNI withdrawal group did not reach significance.
Overall the study is consistent with the prevailing belief that Tacrolimus and MMF should be the standard therapy in renal transplantation at the moment both in terms of outcomes and tolerability. whether there is a role for switching from CNI to Sirolimus at a later date is not clear and is an issue that is being explored by the 3C Study in the UK which is evaluating the role of Alemtuzumab and steroid avoidance followed by switching from Tacrolimus to Sirolimus at 6 months. For the time being the role of Sirolimus in transplant immunosuppression remains unclear. (see Flechner SM et al. American Journal of Transplantation. Volume 11, Issue 8, pages 1633–1644, August 2011)