We have many unanswered questions about treating renal disease progression. For some the ACEi and ARBs are the “kidney pills” and their beneficial effects are clear and untouchable. For others, the clinical data are not homogeneous and the doctor has to be careful when prescribing such drugs for patients that are not exactly as those selected for trials. In a very good editorial, Charytan & Forman discuss another post-hoc analysis of IDNT and RENAAL studies (ARB in patients with type 2 diabetes and nephropathy) that showed a not surprising fact that low salt diet improves the ARBs effects in proteinuria and renal disease progression (measured as doubling serum creatinina and reaching RRT). However, the editorialists stress a point that the paper´s authors don´t give a proper relevance: for those with high salt intake, ARBs use had not statistically significant, but numerically relevant, more end-points compared to placebo: higher risk of cardiovascular (HR 1.25, 95% CI 0.89–1.75) and renal events (HR 1.37, 95% CI 0.96–1.96). It is already known that low salt diet or adding a diuretic increases the effects of ACEi and ARBs, but it is new that high salt diet could make them harm.
The subject is important because it sheds light in the complexity of renal disease progression where drugs are seen through the lens of trials. Also, I´m more comfortable prescribing low salt diet.
Lambers Heerspink HJ, Holtkamp FA, Parving H-H et al. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. Kidney Int 2012; 82: 330–337.
Both chronic kidney disease (CKD) and osteoporosis are emerging as major public health problems associated with an ageing population. Osteoporosis is characterised by reduced bone strength resulting in an increased predisposition to fragility fracture. Bone strength itself is a reflection of both bone mineral density (BMD) and bone quality. There is significant co-prevalence of osteoporotic fractures and CKD in the elderly population. The qualitative abnormalities in bone in CKD are reflected in the fact that fracture risk is much higher in both the dialysis and the non-dialysis CKD population and the outcomes of fractures are significantly worse with a 2 to 3 fold increase in mortality after hip fracture in the CKD population compared to the general population.
However the management of bone disease in CKD remains uncertain - the fundamental problem being that we simply do not know whether achieving biochemical 'targets' (say PTH, calcium phosphorus) or whether the use of therapeutic agents (such as bisphosphonates, calcimimetics or vitamin D) have any impact on outcomes that matter to patients - like death or fracture rates. Furthermore apart from bone biopsy (which is rarely performed) we don't have any tools to assess bone quality and predict fracture risk.
A recent paper from Yenchek and colleagues is published in this months cJASN and is the first prospective, longitudinal study to specifically test the hypothesis that bone mineral density (BMD) predicts fracture risk irrespective of CKD status. In a cohort of 2754 (of whom 587 had CKD stages 3-5) patients aged between 70-79 years old data was collected on incident fractures over a follow up of 11 years. There were 384 incident fractures and even after adjustment for factors such as age, sex, race, BMI, vitamin D and PTH, low femoral neck BMD as measured by DXA (Dual Energy X-Ray Absorptiometry)was associated with fracture risk irrespective of CKD status. The authors state "This argues against the current KDIGO guideline recommendations and suggests that there may be a role for DXA screening in CKD."
So should we start using DXA to identify fracture risk in CKD and prescribe anti-resorptive therapy to those with reduced BMD? Well I'm not sure I share their view and it is worth considering the following:
i) The study by Yenchek and colleagues is important but only 4% of patients had CKD4/5 so the jury remains out on whether DXA will be useful in CKD4/5
ii) We know from post-hoc analysis from the large registration studies that both Bisphosphonates and Denosumab can reduce fracture risk in osteoporotic patients with CKD3 and CKD4 (down to an eGFR of around 20mls/minute). However, it is worth noting the all patients with abnormal PTH or vitamin D levels were excluded from these studies. Therefore whilst these drugs probably reduce fracture risk in patients with CKD3/4 with 'pure' osteoporosis we simply do not know whether they have any impact in those with evidence of coexistent renal osteodystrophy.
iii) Whilst DXA may identify fracture risk in CKD3 a careful cost/benefit analysis study would need to be performed before such screening could be recommended as routine - indeed it may be cheaper just to focus on non-pharmacological strategies such as reducing risk of falls and improving neuromuscular strength.
iv) A key challenge is how to develop the evidence base for reducing fracture rates in CKD 4 and 5. In the general population huge studies with thousands of patients were required to show a beneficial effect of anti-resorptive therapy. The reality is that it will be almost impossible) to carry out such large studies in the CKD4/5 population - therefore perhaps a more realistic goal is to develop validated surrogate markers of fracture risk in this population (be they biochemical markers of bone turnover combine with bone biopsy data or imaging such as high resolution CT) and then evaluate whether modifying these factors can impact of fracture rates.
- Yenchek RH, Ix JH, Shlipack MG, Bauer DC, Rianon NJ, Kritchevsky SB, Harris TB, Newman AB, Cauley JA, Fried LF, for the Health, Aging, and Body Composition Study: Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol 7: 1130–1136, 2012
- Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE: Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res 20: 2105–2115, 2005
- Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A, Cummings SR: Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res 22: 503–508, 2007
- Jamal SA, Ljunggren O, Stehman-Breen C, Cummings SR, McClung MR, Goemaere S, Ebeling PR, Franek E, Yang YC, Egbuna OI, Boonen S, Miller PD. J Bone Miner Res. 2011 Aug;26 (8): 1829-35
In the June issue of cJASN Rahman and colleagues from the ALLHAT Collaborative Group report the long-term (9 year) renal and cardiovascular outcomes of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
This is a randomised, double blind, multicentre clinical trial that compares the impact of 5 year treatment with an ACE inhibitor (lisinopril), a calcium antagonist (Amlodipine), an alpha blocker (Doxazosin) and a thiazide diuretic (Chlorthalidone) on the incidence of major coronary heart disease (CHD) in high risk hypertensive patients. The initial analysis over a 5 years observation and follow-up period showed that neither lisinopril not amlodipine were superior to the diuretic chlorthalidone. The Doxazosin arm had to be discontinued earlier due to side effects and increased mortality (ALLHAT Collaborative Research Group: JAMA 283:1967-1975, 2000).
The current posthoc analysis reports on 31,350 participants followed up for up to 9years, based on hospitalisation records, in term of cardiovascular outcomes; total mortality, CHD, CVD, Stroke, Heart Failure and ESRD.
In the whole study group, there was no difference between lisinopril, amlodipine and chlorthalidone isn relation to CVD or renal outcomes/ESRD. Subgroup analysis of pateints with CKD and an eGFR<60 (with minimal proteinuria), also showed no difference in renal or cardiovascular outcomes between the groups. Of interest, the morbidity and mortality from CVD causes was similar to those observed in the RENAAL and AASK trials.
The authors conclude that independently of BP lowering effect, no antihypertensive drug class has significant advantage over others in preventing CVD; morbidity and mortality. Of note amlodipine was less effective than chlorthalidone in preventing heart failure; although this may simply reflect that the former favours fluid retention whilst the latter minimises it...!!!
This observation agrees with a review of controlled trials by Segall et al (J Nephrol 2008;21:374-383) that showed no specific benefit of anti-hypertensive drug class beyond BP control. Other studies suggested a therapeutic advantage of RAAS inhibition on CVD but it was unclear whether this was independent from improved BP control. Of note the much quoted HOPE study, also failed to dissociate the CVD protective effect of Ramipril from its antihypertensive impact. More recently, HOPE study posthoc analysis based on 24h ambulatory BP Monitoring failed to convincingly dissociate cardioprotection from improved BP control (Svensson et al. Hypertension. 2001;38:e28-e32).
From the above one is entitled to ask whether the much publicised cardioprotective effect of RAAS inhibitors is real or a bais generated by:
1. Poorly designed clinical trials (RCT); with unequal BP control between groups
2. Inadequate BP measurements in RCT; with occasional office BP measurements now known to be poorly reflective of 24h BP recordings measuring nocturnal BP and nocturnal dip in BP, both known to be closely associated with CV events.
3. An industry led brainwashing of ill informed Nephrologists; who follow the trend without asking questions....?!
I suspect the answer lies in all three...!!!
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!!!