So when I was a medical student I was taught that colloids were the fluid of choice for the management of septic shock. We were not big on evidence in those days.... it was obvious, colloids expanded plasma volume much more effectively than crystalloid so why wouldn't you use colloid. Well now comes the evidence from the 6S study showing that starch is actually inferior to crystalloid. In this really well designed study of fluid resuscitation ICU with either 6% HES (hydroxyethyl starch) or Ringer's acetate ( a crystalloid solution) at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. The headline results are as follows:
At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.4 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.4 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09).
So clearly there is no benefit of expensive colloids over cheap crystalloids and in fact they are harmful. All very similar to the use of renal dose dopamine which made great sense on paper until people did the studies to show it was harmful....
When will nephrologists learn that estimated GFR (eGFR; estimated by the MDRD equation or any other equation) does NOT equate to measured GFR (mGFR) or even calculated GFR (cGFR = CrCl + Urea Cl : 2)?!
This month in NDT, an article by Evans et al from Middlesborough UK reports that Irbesartan delays the progression of nephropathy as measured by eGFR: A post hoc analysis of the IDNT trial.
Wow....some findings...so the data reported by IDNT in the NEJM in September 2001 relating to changes in serum creatinine levels...took 10 years to convert to eGFR.... and show...surprise, surprise...that Irbesartan slows the progression of T2Diabetic Nephropathy!!!!!
When will nephrologists learn that changes in serum creatinine and their beloved eGFR does NOT mean changes in TRUE GFR!?
In fact, the observed changes may well be due to changes in tubular sercretion of creatinine, known to be affected by RAAS inhibition and improved peri-tubular capillary circulation and proximal tubular Creatinine transport, known to be attenuated in DM.
When will nephrologists learn that changes in albuminuria are not solely the result of changes in glomerular loss of albumin?
In the report under discussion, Irbesartan decreased albuminuria, an effect somehow linked to improved outcome?!
Nephrologists need to remember that RAS inhibition also improves peritubular circulation and thus proximal tubukle reabsorption of albumin.
When will nephrologists learn:
That in RCT the progression of CKD and GFR have to be MEASURED not estimated by inappropriate derivative equations....?!
I take the opportunity of this Nephron Digest to let you know that I have now completed my term as Editor of Nephron Clinical Practice.
It has been a great, enjoyable and challenging journey promoting a great journal and reaching for a broader readership.
I hope you enjoyed reading the Nephron Digests and continue to read and follow Nephron. The new Editor of Nephron Clinical Practice is Professor David Wheeler, Reader in Nephrology at University College London, London, UK. I have no doubt that under his stewardship and the guidance of Professor Leon Fine (Chief Editor of Nephron), Nephron Clinical Practice will continue to forge ahead and raise its global profile.
Professor Meguid El Nahas, PhD, FRCP
Editor, Nephron Clinical Practice
Association of Deprivation with Worse Outcomes in Chronic Kidney Disease: Findings from a Hospital-Based Cohort in the United Kingdom (M.P. Hossain, D. Palmer, E. Goyder and M. El Nahas, Sheffield; Nephron Clin Pract 2012;120:c59-c70) The authors report that area level low socio-economic status (SES) is associated with both heavy proteinuria at presentation and rapid progression of CKD. Unskilled professionals were also found to have a marginally significant association with increased risk of mortality. People living in more deprived areas presenting with CKD are likely to be at increased risk of poor outcomes and may need more active management and earlier referral. Such increased risk is likely to be more acute in emerging countries where late referral of CKD patients is a major nephrological healthcare challenge. Most patients who start RRT in these countries are seen within less than 3 months from initiation of therapy. That is the real challenge of CKD in emerging economies, not the early detection and prevention of CKD1 and 2, but the timely referral of CKD3!
Disappearance of Association in Diabetic Patients on Hemodialysis between Anemia and Mortality Risk: The Japan Dialysis Outcomes and Practice Pattern Study (M. Inaba and colleagues, Kyoto and Tokyo; Nephron Clin Pract 2012;120:c91-c100) Inaba and colleagues report a significant association between hematocrit with all-cause mortality in non-diabetic ESRD patients after adjustment for age, gender, BMI, hemodialysis duration, SBP, DBP, albumin, total cholesterol, calcium, phosphorus, and intact PTH. This association disappeared in diabetic patients suggesting that the association between anemia (lower hematocrit) and higher mortality disappeared in DM hemodialysis patients, in contrast with non-DM counterparts. Once more, an observational study highlights the fact that the higher the hematocrit, the better in terms of outcomes and survival in HD patients. This has not been confirmed by randomized clinical trials when raised hematocrit beyond a certain level (around 36%) has been associated with increased cardiovascular risk. Hence guidelines defining target hematocrit for HD patients between 33 and 36%. However, guidelines do not take into consideration the complexity and heterogeneity of HD patients, as they don't distinguish for instance between diabetic and non-diabetic patients, or young and older patients, and as shown in the paper by Inaba et al., different hematocrit targets may have different implications according to underlying comorbidities.
Non-Calcium-Containing Phosphate Binders: Comparing Efficacy, Safety, and Other Clinical Effects (J.M. Frazao and T. Adragao, Lisbon; Nephron Clin Pract 2012;120:c108-c119) The authors review the potential of non-calcium-containing phosphate binders in patients with CKD. They conclude that sevelamer and lanthanum carbonate are effective at reducing serum phosphorus levels to those recommended by international guidelines. They also suggest from a small number of studies that sevelamer (Renagel) may have therapeutic advantages in terms of reducing vascular calcifications. This was suggested in the RIND (Renagel in New Dialysis) and TTG (Treat to Goal) studies but not by others such as BRiC and CARE2. Such analysis is of considerable interest and highlights a number of issues: First, the jury is out on the superiority of Renagel over calcium-containing phosphate binders in terms of vascular calcifications. Second, the use of vascular calcifications as surrogate endpoint may be subject to analytical confounders and variability and does not negate the need for hard end-points such as major adverse cardiovascular events (MACE) or more importantly, mortality. Of interest, in that respect, in the DCOR study, in 12,100 chronic hemodialysis patients, there was no difference in all-cause mortality between sevelamer and calcium-based phosphate binder therapy over a 3-year observation time. Third, as often in nephrology, smaller clinical trials and observational studies tend to show promising effects of interventions that are all too often disappointed by larger studies. Fourth, a cost analysis is needed to support the cost:benefit of non-calcium-containing binders, including sevelamer. As so often in nephrology, tempered enthusiasm is warranted for newer agents compared to older ones, but enthusiasm should not replace critical analysis of available evidence as well as the requirement for hard and meaningful clinical endpoints. These remain lacking to favor newer phosphate binders.
Susantitaphong and colleagues in Boston have published this month in the June issue of the AJKD a meta-analysis of 16 cohort studies and 1 RCT (n= 1,081,116) relating to impact of the level of GFR at initiation of RRT (HD or PD) on all-cause mortality.
The authors concluded that a higher ESTIMATED GFR (eGFR) was associated with HIGHER mortality.
On the other hand, in a subgroup analysis, higher CALCULATED GFR was associated with LOWER mortality.
Confused you may be...!!!!!
Well, this observation confirms impressions that GFR estimated (eGFR) by the MDRD equation is inaccurate in ESRD as the confounder of serum creatinine leads to this equation, as well as that of Cockcroft-Gault, being more a reflection of the clearance of endogenous creatinine rather than true GFR; clearance of endogenous creatinine is affected by GFR as well as muscle mass and tubular secretion of creatinine. Whilst the authors stress repeatedly that this observation was independent of nutritional parameters; this may reflect visceral nutritional markers such as serum albumin/protein and not necessarily markers of poor somatic nutritional status such as creatinine itself.
On the other hand, calculated GFR derived from a 24h urine collection and the derived mean of urea and creatinine clearances seems to be a better marker of true GFR that is less influenced by muscle mass. Higher calculated GFR, unlike estimated GFR, was in a subgroup analysis (486 patients) associated with LOWER mortality.
This is an important observation putting in context a number of publications on the topic of GFR and timing of RRT. It also warns nephrologists NOT to put too much emphasis on GFR estimation/calculation when deciding when to start RRT but instead use a more holistic approach to the patient and his clinical status as well as co-morbidities.
Lets move away as a profession from these artificial and meaningless equations and go back to the old fashion serum creatinine, serum urea, clinical examination as well as good clinical judgement.
After all we, as Nephrologists, are Physicians and not Mathematicians....
There is a great recent post by Ajay Singh, Professor of Nephrology at Harvard on his blog The Kidney Doctor talking about the importance of communication with patients. He cites data showing that only 23% of patients are allowed to finish their opening statements when talking to doctors and astonishingly the average time to interruption is only 18 seconds!!
Yet the cost of poor communication remains high. I was reflecting on this as I did my on-call ward rounds this weekend. As in most nephrology units there were a core of dialysis patients for whom dialysis neither improves the quality of life nor life expectancy. These were mostly elderly patients with significant comorbidity many of whom were diabetic. The history was invariably one of recurrent admissions with infections, access problems and fluid overload. All foreseeable and predictable yet patients still ended up in a cycle of recurrent admissions and functional deterioration. Of course the economic cost is significant - a recent analysis of healthcare costs and mortality over the last 200 years at the Massachusetts General Hospital showed some interesting findings. Mortality has fallen precipitously since around 1970 though healthcare costs have risen exponentially. Interestingly whilst costs have continued to rise in the last 10 years mortality no longer seems to be falling - one could speculate that this is perhaps because doctors are losing the art of recognising dying patients and subjecting them to endless interventions with little benefit.
Few of us (myself included) talk about withdrawing treatment until relatively late in the course of treatment and while we like to all talk about patient choice we perhaps need to discuss conservative therapy more openly and honestly.This has been known for many years as Farrington and colleagues showed in Stevenage, UK that dialysis offered no survival advantage in the elderly with significant co-morbidity. Similarly data from the Royal Free Hospital in London showed that those elderly patients with comorbidity who opted to have dialysis did have a survival advantage... Yet virtually all this "extra-time" was spent in hospital. And we know from a large analysis of nursing home residents in the USA that 58% of patients died and only 13% maintained functional status at 1 year.
The clear message is that for many elderly patients with comorbidity, dialysis neither makes people feel better nor makes them live longer. Of course we have known this for years and as it turns out that nephrologists are actually very good at predicting who does badly on dialysis - but many (including myself) need to start listening more to patients and being much more honest with them about dialysis and recognise that whilst dialysis may be palliative for all patients, for some patients dialysis simply doesn't palliate....
1. Two Hundred Years of Hospital Costs and Mortality — MGH and Four Eras of Value in Medicine Gregg S. Meyer, M.D., Akinluwa A. Demehin, M.P.H., Xiu Liu, M.S., and Duncan Neuhauser, Ph.D. N Engl J Med 2012
2. Is Maximum Conservative Management an Equivalent Treatment Option to Dialysis for Elderly Patients with Significant Comorbid Disease? Rachel C. Carson*, Maciej Juszczak†, Andrew Davenport†, Aine Burns. CJASN
3. Smith C, Da Silva-Gane M, Chandna S, Warwicker P, Greenwood R, Farrington K: Choosing not to dialyse: Evaluation of planned non-dialytic management in a cohort of patients with end-stage renal failure. Nephron Clin Pract 95: c40– c46, 2003
4. Functional Status of Elderly Adults before and after Initiation of DialysisManjula Kurella Tamura, M.D., M.P.H., Kenneth E. Covinsky, M.D., M.P.H., Glenn M. Chertow, M.D., M.P.H., Kristine Yaffe, M.D., C. Seth Landefeld, M.D., and Charles E. McCulloch, Ph.D. N Engl J Med 2009; 361:1539-1547
5. Utility of the “Surprise” Question to Identify Dialysis Patients with High Mortality Alvin H. Moss* †, Jesse Ganjoo*, Sanjay Sharma*, Julie Gansor*, Sharon Senft*, Barbara Weaner*, Cheryl Dalton*, Karen MacKay*, Beth Pellegrino*, Priya Anantharaman*, Rebecca Schmidt* CJASN September 2008 vol 3 , no 5. 1379-1384
What did I learn?
Dr Amy Jane McKnight (Winner of Raine Prize 2012):
Genetics of CKD and DN.
Identified an important genetic association between risk of Diabetic nephropathy, progression as well as tubulointerstitial fibrosis with mutations of the AFF3 gene. AFF proteins are localized in the nucleus and play a role as transcriptional activators with a positive action on RNA elongation and processing of RNA.
She also identified mutations of Haplogroup I on the Y chromosome to be associtaed with CKD as well as CVD in white europeans.
She stressed the potential for changes in DNA methylation on the Y chromosome in the predisposition to CKD.
Prof Jeremy Hughes (Edinburgh):
Gave an excellent talk on experimental ageing.
He highlighted the role of the RAAS in ageing; RAAS inhibition prolongs life span in rodents.
Mitochondrial RAS is mainly directed to the beneficial AT2R during early life and switch to AT1R with ageing. AT1R is linked to the generation of reactive oxygen species (ROS) and tissue damage. RAS blockade decrease ROS generation by mitochondria.
Prof Tom Kirkwood (Professor of ageing in Newcastle):
Reminded us that ageing is a human phenomenon, most other spoecies die before they get too old, excpet man who nowadays lives much longer without the genetic apparatus to prevent ageing. Humans dont have a genetic program for ageing, instead ageing is the direct results of cumulative daily genetic damage. Ageing is caused by damage in the absence of a genetic repair machinery.
Ageing is theresult of random molecular and gentic damage. Consequently, to this daily and random genetic mutations, none of the 100x100million cells in humans are alike as not two cells have the same genome due to endless somatic mutations. Also mtochondrial mutations increase with ageing.
No evidence that calorie restrictions prolongs lifespan in humans in spite of considerable data in rodents but conflicting data in non human primates.
Excercise prolongs lifespan...
Prof Jurgen Floege (Germany):
gave a lecture on vascular calcification in CKD.
Highlighted the protective role of matrix Gla protein (MGP). Warfarin decreases its levels and accelerates vasculkar calcifications.
He argued that Warfarin should not be used in ESRD patients as it often underly lifethreatening calciphylaxis.
He also argues that Vitamin K1 and K2 supplement may be protective against vascular calcification in ESRD. Vitamin K2 attenuates warfarin-induced vascular calcification in experimental models.
So Amgen have posted a press release outlining the results of the EVOLVE study looking at the impact of cinacalcet on death and cardiovascular events in a huge study of over 3000 patients. There was NO effect on mortality or cardiovascular events. Obviously we need to wait for more data but this is yet another negative trial in a dialysis population. A couple of thoughts come to mind:
1) Amgen actually should be congratulated for investing in the trial but this may well be the last trial of this size we see in a dialysis population - the chances of a 'magic bullet' reducing mortality in a population as complex and diverse as a dialysis population are slim and pharma are unlikely to take the risk....
2) In retrospect a perhaps more modest trial focussing on fractures and cost-effectiveness may have been more useful to practicing nephrologists. In a population where the death rate is high, from multiple aetiologies perhaps we need to start looking at the impact of multiple interventions rather than single interventions.
3) Cinacalcet is an extremely expensive drug. Whilst there is data on the cost effectiveness of the drug it's rather weak. For those of us who work in an environment where cost is an issue need to think again about who gets the drug..... Or we could hope that in light of this data Amgen could re-evaluate the price of the drug!!!
There is a nice debate in this months JASN between Rifkin and Hsu about whether AKI leads to CKD. This is timely as the recent KDIGO guidelines have suggested that AKI be considered a risk factor for CKD - the logical implication of this being that all patients with AKI (including those who have completely 'recovered') be monitored for life for CKD. Rifkin and colleagues pint out that whilst its certainly biologically plausible for AKI to lead to CKD, there may be common risk factors of kidney injury that independently predispose to both AKI or CKD and furthermore its entirely plausible that CKD itself may predispose to AKI. In many ways I find the argument a bit sterile... have we not known for many years that if the AKI 'hit' is severe enough then people may be left with residual CKD whilst those wilth mild AKI appear to recover fully. As Rifkin and colleagues point out more than 500,000 AKI events occur in in the USA every year and the the vast majority recover without any significant longterm complication. The idea that all these patients need lifelong monitoring in case they get CKD is neither economically viable nor based on sound clinical judgement. An obviously pragmatic approach would be to monitor those who had severe or dialysis dependent AKI for a few years to see if CKD develops. In contrast its hard to believe that those whos have mild AKI that resolves quickly (with no comorbidity) will benefit from lifelong screening for CKD. Clearly longterm observational studies if AKI may help resolve this debate but in the meantime I suspect most nephrologist will be able to get buy just using clinical common sense....
It is 30 years since we put forward the hypothesis that lipids were nephrotoxic and that dyslipidemia contributed to progressive CKD.
30 years on, a new era of APOL1-associated CKD suggest that a link may indeed exist between genetic mutations affecting HDL cholesterol concentrations and the pathogenesis of nephropathies as variants of ApoL1 proteins associate with circulating HDL.
The association between apoliporotein L1 (APOL1) gene mutations and CKD is becoming increasingly evident with APOL1 variants considered initiating factors for most hypertension-attributed nephropathies in African Americans (AA) as well as a spectrum of renal disease in hispanic as well as European Americans. Variations in APOL1 appears to be strongly associated with kidney disease historically labelled as hypertensive arterioslosclerosis in AA.
It is intriguing to realise that APLO1, a disease associated gene, has persisted in AA. However, it is of interest to realise that one copy of the APOL1 G1 or G2 nephropathy risk variant confers protection from the deadly African Sleeping Sickness while not necessarily being associated with a nephropathy as for the latter to develop a second hit is often necessary. HIV infection is one of many such second hits initating APOL1-associated nephropathy in susceptible individuals with one or two gene variants.
Of interest, individuals with two APLO1 gene variants develop ESRD at a younger age than those with zero or one gene variants. A single gene variant, G1 but not G2, also leads to an earlier onset of ESRD albeit later than those with G1 and G2 variants. This may be due to the fact that tghose with 2 APLO1 gene variants progress to ESRD at a faster rate.
It is likely that the MYH9-APOL1 gene region on chromosome 22q contains additional risk loci that may be difficult to detect due to the high degrees of linkage desiquilibrium.
Clearly, a new era of understanding non diabetic glomerulosclerosis with APLO1-MYH9 genetic mutations providing suceptibility and second hits/modifiers genes leading to initiation and progression of CKD.
Perhaps, after all, we were right when in 1982, we suggested that lipo- and apo- lipoprotein abnormalities may underly the initiation and progression of CKD.
Moorhead JF, , , M.
Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease.
Lancet. 1982 Dec 11;2(8311):1309-11.
Kanji et al. genetic variations of APOOL1 associated with younger age at hemodialysis initation. JASN 2011; 22:2091-97.
Tzur et al. APOL1 allelic variants are associated with lower age at dialysis initiation...
NDT 2012; 27:1498-1505.
Paweena Susantitaphong, MD,1,2,3 Ioannis Koulouridis, MD,1,2 Ethan M. Balk, MD, MPH,2,4 Nicolaos E. Madias, MD,1,2 and Bertrand L. Jaber, MD, MS1,2
Background: Increased left ventricular (LV) mass is a risk factor for cardiovascular mortality in patients with chronic kidney failure. More frequent or extended hemodialysis (HD) has been hypothesized to have a beneficial effect on LV mass.
Study Design: Meta-analysis.
Setting & Population: MEDLINE literature search (inception to April 2011), Cochrane Central Register of Controlled Trials and ClinicalTrials.gov using the search terms “short daily HD,” “daily HD,” “quotidian HD,” “frequent HD,” “intensive HD,” “nocturnal HD,” and “home HD.”
Selection Criteria for Studies: Single-arm cohort studies (with pre- and post-study evaluations) and trials examining the effect of frequent or extended HD on cardiac morphology and function and blood pressure parameters. Studies of hemofiltration, hemodiafiltration, and peritoneal dialysis were excluded.
Intervention: Frequent (2-8 hours,