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Anyone in the world

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

In the UK the growth in kidney transplantation in recent years has been predominantly fueled by both increasing live-related transplantation and increasing use of donors after circulatory death (DCDs - or what were previously known as non-heartbeating donors). Around a third of kidneys used in the UK are DCDs, but the use of DCDs has varied across centres with some  being enthusiastic proponents whilst others such as being more cautious. Of course the main concerns amongst clinicians is whether such kidneys are as 'good' as kidneys donated after brain death (DBD), with concerns over the impact of anoxic, warm iscahemia time coupled with prolonged cold ischaemia on long term graft survival. A recent analysis of UK Transplant Registry data by Summers and colleagues in the Lancet sheds some light on what the outcomes are in such kidneys.

The investigators analysed 1768 DCDs and 4127 DBDs transplanted between 2005 and 2010. DCD kidneys had a higher rate of delayed graft function (DGF) than DBDs (49% vs 24%) but patient and graft survival at 3 years were no different. The 12 month eGFR (which maybe a reasonable surrogate for longer term graft survival) was significantly lower in the DCD group vs the DBD group (mean eGFR =48mls/min vs 50mls/min, p<0.04). Kidneys from donors over the age of 60 years were twice as likely to result in graft failure compared to those under the age of 40, irrespective  of whether they were DBDs or DCDs.

In contrast to age, cold storage time (> 24 hours vs<12 hours) did impact adversely on graft survival in DCDs but not in DBDs. i.e. warm ischaemia seems to 'prime' the kidney for further damage resulting from prolonged cold storage. Whilst there has been promising data from a large, well conducted European RCT showing that hypothermic perfusion improves DGF, kidney function and graft survival, this study only included a small number of kidneys were DCDs. In contrast, a UK RCT study specifically evaluating machine perfusion in DCDs, showed no impact of hypothermic machine perfusion on DGF, patient and graft survival at 1 year.

What are the implications of this work?

Well firstly it can reassure clinicians and patients that short-term (i.e. 3 year) outcomes are the same for DBDs and DCDs and that in this timeframe the age of the donor rather than whether they are a DCD or DBD is what matters. Therefore increasing the use of DCDs may increase the overall donor pool and access to transplantation. The price of this maybe slightly worse graft function at 3 years and applying this registry data to individual patient-decision making in the middle of the night will always be fiendishly difficult for transplant surgeons - taking into account recipient comorbidity and age etc will remain paramount.

Secondly its clear that the cold storage time does adversely impact on outcomes of DCDs and this therefore needs to be taken into account when devising an allocation policy for DCDs. Whilst national allocation of DBDs seems sensible, national (rather than regional) allocation of DCDs with inevitable prolongation of cold storage time may simply lead to worse outcomes. This data casts considerable doubt on current deliberations in the UK to move towards a national allocation scheme for DCDs unless guarantees can be made about cold storage time.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

Intensive glucose control improves kidney outcomes in patients with type 2 diabetes.

### Source

The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia.

### Abstract

The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200 μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes.

# Commentary

Kidney International (2013) 83, 346–348; doi:10.1038/ki.2012.431

## Intensive glycemic control in type 2 diabetics at high cardiovascular risk: do the benefits justify the risks?

Sabin Shurraw1,2 and Marcello Tonelli1,2

1. 1Department of Medicine, University of Alberta, Edmonton, Canada
2. 2Alberta Kidney Disease Network, Canada

Correspondence: Marcello Tonelli, Department of Medicine, University of Alberta, Alberta Kidney Disease Network, 7-129 Clinical Science Building, Edmonton, Alberta T6B 2G3, Canada. E-mail: mtonelli-admin@med.ualberta.ca

Top

### ABSTRACT

Perkovic et al. use novel data from the ADVANCE study to report on the potential renal benefits of standard glycemic control, compared with intensive glycemic control (mean hemoglobin A1c 7.3 and 6.5%, respectively). Intensive glycemic control reduced the risk of new-onset microalbuminuria, new-onset macroalbuminuria, and progression of albuminuria. The risk of end-stage renal disease was also reduced in patients treated with intensive glycemic control, although the number of events was small.

Most guidelines, including those from the Kidney Disease Outcomes Quality Initiative (K/DOQI) (National Kidney Foundation), suggest that glycemic control is an important clinical objective for all diabetic patients with and without chronic kidney disease (CKD). These guidelines recommend a target hemoglobin A1c of approximately 7.0% ‘to prevent or delay complications of diabetes, including diabetic kidney disease,’ noting that more intensive treatment improves albuminuria, but evidence for any effect on loss of glomerular filtration rate (GFR) is sparse.1

Perkovic et al.2 (this issue) explore the potential benefits of intensive glycemic control for renal outcomes, using a post hoc analysis of the ADVANCE trial. ADVANCE3 randomly assigned 11,140 patients to standard glycemic control following local guidelines versus intensive glycemic control (target A1c6.5%). Included patients had type 2 diabetes (average duration 8 years) and were more than 55 years old (average age 66 years). Only patients at high risk were included, based on a history of major macrovascular disease, microvascular disease (overt nephropathy or retinopathy), or one major cardiovascular risk factor. After a median duration of 5 years, mean A1c was 7.3 vs. 6.5%, respectively, in the two groups. There was no difference in the risk of macrovascular events between groups (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.84–1.06, P=0.32). However, patients who were in the intensive glycemic control group had fewer microvascular events (HR 0.86, 95% CI 0.77–0.97, P=0.01), primarily due to a 21% reduction in ‘new or worsening nephropathy’ (HR 0.79, 95% CI 0.66–0.93, P=0.006); there was no effect on retinopathy.

The new analysis by Perkovic et al.2 begins by providing us with more insight into the prevalence of preexisting renal disease in the 11,140 ADVANCE participants. At baseline, approximately 27% of patients had microalbuminuria (an inclusion criterion) but only 3.6% had macroalbuminuria. Most patients had no CKD (55%), while CKD stages 2 and 3 was present in 15% and 19% of patients, respectively. Advanced CKD (stages 4 and 5) was present in 0.5% of all patients. As expected based on the main finding of ADVANCE, outcomes related to proteinuria appeared more favorable with intensive glycemic control: new-onset microalbuminuria (33.5 vs. 36.3%), new-onset macroalbuminuria (3.0 vs. 4.3%), and progression of albuminuria by 1 stage (23.3 vs. 25.3%) (allP<0.012). Patients treated with intensive glycemic control had more regression of albuminuria by 1 stage (61.2 vs. 56.3%) and more regression to normoalbuminuria (56.3 vs. 50.2%) (all P0.002).

The authors acknowledge that albuminuria is of questionable reliability as a surrogate marker for renal outcomes and appropriately focus on the risk of end-stage renal disease (ESRD). In these new analyses, the risk of ESRD was significantly reduced in patients treated with intensive glycemic control (vs. standard treatment) (HR 0.35, 95% CI 0.15–0.83, P=0.017). Furthermore, patients with preexisting renal disease seemed to derive more benefit from intensive glycemic control as reflected by a lower number needed to treat (NNT): the NNT was 152 for any albuminuria, 147 for estimated GFR <60ml/min, 85 for estimated GFR <60ml/min per1.73m2 with any albuminuria, and 41 for macroalbuminuria (irrespective of GFR). These findings were consistent in various subgroups, including participants with baseline A1c above or below median (7.2%), with or without retinopathy, in both assigned blood pressure treatment groups (ADVANCE was a two-by-two factorial trial of glycemic and blood pressure control), both men and women, and with age above or below median. On the basis of these data, the authors suggest that intensive glycemic control (presumably A1c <6.5% as targeted in ADVANCE) may be a useful strategy to prevent the development of ESRD in patients with type 2 diabetes.

Before widespread adoption of such a strategy, the reader should consider some important aspects of this post hoc analysis. First, despite an apparent reduction in the risk of ESRD with intensive glycemic control, there was no significant effect on serum creatinine over time—only a non-significant trend toward more frequent doubling of serum creatinine (to >200μmol/l) in intensively treated patients (HR 1.15, P=0.42). The authors propose that doubling of serum creatinine may be an imprecise ‘surrogate’ for progression of diabetic nephropathy to ESRD, as it may capture patients suffering acute kidney injury due to sepsis, shock, and so on. In support of this hypothesis, there was a non-significant trend toward lower risk of sustained doubling of serum creatinine with intensive glycemic control (HR 0.83,P=0.38). Nonetheless, the possibility remains that other factors besides intensive glycemic control per se contributed to the apparent reduction of the risk of ESRD in the treatment group. For example, patients in the (unblinded) intensive treatment arm might have been observed more closely by their treating physician—which in turn could have reduced the risk of acute kidney injury or its consequences.

Second, the number of patients who developed ESRD during ADVANCE was exceedingly low (27 events in 11,140 patients=0.24%). This contributed to the high NNT (445 patients to prevent one case of ESRD over 5 years)—although the NNT was lower in patients with more advanced CKD at baseline, likely because of the higher absolute risk in this group. Despite the high quality of the analyses, the small number of events may reduce confidence in the findings.

The results of ADVANCE and the current analysis by Perkovic et al.2 must be interpreted in the context of other randomized controlled trials that have assessed the impact of intensive glycemic control on clinically relevant kidney outcomes. ACCORD was similar to ADVANCE and enrolled 10,251 patients with type 2 diabetes and high cardiovascular risk (>40 years old with known cardiovascular disease, or >55 years old with anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two cardiovascular risk factors), with randomization to conventional glycemic control (A1c 7.0–7.9%) versus an even more intensive regimen targeting A1c <6%.4 This trial was terminated early (after 3.5 years) because of increased mortality in intensively treated patients. However, a subsequent analysis reported on renal end points at trial’s end.5 Intensive glycemic control resulted in lower A1c at one year (median 6.4 vs. 7.5%) and, similarly to ADVANCE, resulted in a 20–30% reduction in the risk of new-onset micro- and macroalbuminuria, but no reduction in the risk of doublings in serum creatinine (in fact, a significant increase: HR 1.07, P=0.016)—and, in contrast to the results reported by Perkovic et al.,2 no decrease in ESRD (HR 0.95, 95% CI 0.73–1.24, P=0.71). The most recent randomized trial of intensified glycemic control, VADT, was published in 2009 and enrolled 1791 military veterans with long-standing type 2 diabetes (mean duration 11.5 years), 40% of whom had known cardiovascular disease.6 Patients were randomized to standard therapy versus intensified glycemic control to decrease A1c by 1.5%; A1c between groups was 8.4 vs. 6.9%. After a median of 5.6 years, there was no difference in the risk of mortality or microvascular end points, other than a reduced risk of progression of albuminuria; the risks of doubling of serum creatinine and stage 5 CKD were similar between groups (P=0.99 and P=0.35, respectively).

What can we conclude about the effect of glycemic control on diabetic nephropathy in type 2 diabetes, and, more broadly, on patient survival and cardiovascular events? We believe that it is reasonable and generally safe to target an A1c of 7%. The UK Prospective Diabetes Study (UKPDS) showed that early, more intensive glycemic control (A1c of 7.0 vs. 7.9%) in patients with newly diagnosed type 2 diabetes safely reduced microalbuminuria and doubling of serum creatinine (as well as retinopathy).7

So, should clinicians routinely target an A1c of 6–7% or lower? As discussed, high-quality data from ACCORD, VADT, and ADVANCE all demonstrate that this strategy will improve proteinuria-based surrogate outcomes, but only the post hoc analysis of ADVANCE by Perkovic et al.2 suggests that such an intensive strategy may reduce the clinically relevant outcome of ESRD. However, adopting an intensive glycemic control strategy may also pose risks to patients. A1ctargets below 6.5% led to increased mortality (largely due to myocardial infarction) in ACCORD and had no significant effect on cardiovascular events or mortality in ADVANCE.

One may speculate that patients enrolled in the latter two trials, most of whom had established type 2 diabetes and major cardiovascular risk factors, were more susceptible to the adverse consequences of hypoglycemia, as opposed to the younger, healthier UKPDS participants. Similarly, observational data suggest that achieved A1c<6.5% is associated with excess mortality in patients with diabetes and established CKD.8

Thus, intensive glycemic control appears to have both risks and benefits—and despite the important findings of Perkovic et al.,2 this strategy cannot be broadly recommended at present. Current data do not allow clinicians to confidently identify patients in whom the risk-to-benefit ratio of tighter glycemic control is especially favorable. Until such data are available, we suggest that an A1c target <6.5% for type 2 diabetes should be used cautiously, if at all—perhaps only in well-informed patients who are younger, at lower risk for hypoglycemia, and free of symptomatic cardiovascular disease.

OLA COMMENTARY:

This is an excellent and balanced review of the recent publication on a posthoc analysis of ADVANCE putting in the context of other intensive v conventional glycemia control stuides in T2DM.

It highlights the facts that in high risk T2DM patients:

1. Intensive glycemia control with HbA1c <7% is either associated with no CVD benefit or increase mortality (ACCORD)

2. Intensive glycemia control has NO effect on renal HARD ENDPOINTS such as decline of GFR or incidence of ESRD

3. Observational studeis also suggest increased mortality with HbA1c<6.5%

The study commenetd upon by Perkovic et al also highlights a number of issues:

1. The concern about endless mining of data to find positive results in posthoc analyses. These are at best hypothesis generating (difficult when considerable data suggest the opposite...) or at worst futile and misleading excercises.

2. The distinction between statistical analysis and the true clinical value of such observations; p vale <0.05 but number needed to treat to prevent 1 ESRD 445 patients over 5 years!!!!!

3. The use of serum creatinine as a marker of progressive CKD/DN, in elderly patients with CVD and a tendency to sarcopenia; thus dissociating further changes in sCr = eGFR and true measured GFR and true progression of Diabetic nephropathy. Intensive glycemia control with its induced side effecst and increased morbidity may be associated with a fall in sCr hence the apparently stable sCR in the Perkovic study in spite of possible worsening of true GFR/kidney function....?!

4. The use of ESRD in the absence of measured GFR as a hard endpoint; this can be misleading and observer baised as the decision to start RRT often has subjective elements to it; a good example of such dissociation was seen in REIN studies where in patients with reduced GFR<45; Ramipril had NO effect on measured GFR decline but decreased the number of those reaching ESRD....!!

http://www.ncbi.nlm.nih.gov/pubmed/10437863

5. Glycemia control may improve/lower sCr through improved on the impaired tubular secretion of Cr observed and associated with DM. http://www.ncbi.nlm.nih.gov/pubmed/15882297

http://www.ncbi.nlm.nih.gov/pubmed/12753302

6. The disconnect between reduction of albuminuria and progression of diabetic nephropathy/CKD; most of the studies showing that intensive glycemia control benefit albuminuria but NOT progression of kidney function decline. This may reflect that glycemia control can affect albuminuria in many ways unconnected to slowing the decline in GFR.

7. Lowering glycemia can improve urianry albumin excretion in the following way:

a. Increasing CVD morbidity and decreasing protein intake due to poor health; this would in turn reduce albuminuria that is often proportional to the protein intake.

b. Affecting glycation and charge of albumin which in turn decrease its filtration and reabsortion rates. http://www.ncbi.nlm.nih.gov/pubmed/9187409

http://www.ncbi.nlm.nih.gov/pubmed/8477883

c. Improving peritubular circulation an dimproving proximal tubular reabsorption of albumin; many beleive that microalbuminuria in DM is a reflection of vascular and fall in peritubular capillary perfusion impacting/decreasing proximal tubular reabsorption of albumin.

http://www.ncbi.nlm.nih.gov/pubmed/22734110

http://www.ncbi.nlm.nih.gov/pubmed/21401356

ALTOGETHER,

IT IS MISLEADING TO CLAIM PROTECTION FROM PROGRESSIVE DIABETIC NEPHROPATHY THROUGH THE REDUCTION IN ALBUMINURIA AND UNRELATED BIOMARKER.

IT IS MISLEADING TO EQUATE CHANGES IN SCR INDEPENDENTLY OF THE HARD ENDPOINT OF MEASURING GFR.

START OF RRT/ESRD IS DIFFICULT TO INTERPRET IN THE ABSENCE OF HARD DATA RELATING TO TEH RATE OF DECLINE OF KIDNEY FUNCTION.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

Last year I wrote a blog outlining the results from the Dutch CONTRAST study which was a large RCT which failed to show any benefit of online-haemodiafitration (OL-HDF) when compared with haemodialysis in terms of mortality. Recently 2 further large RCTs have been published comparing OL-HDF to haemodialysis which add significantly to theevidence base about he relative merits of OL-HDF when compared to conventional HD.

Firstly, the Turkish Hemodialfiltration Study was recently published in NDT. In this RCT, 782 patients were randomised to receive either high-flux HD or OL-HDF. At 2 years there was no significant difference in survival between the two groups - 77.6% in OL-HDF versus 74.8% in the high-flux group, P = 0.28. Its worth pointing out here that here that the authors stated that 'statistical power for this analysis was lower than hypothesized during the design of the study'  in part due to a lower than expected event rate in the control group. In a post-hoc analysis of those in the OL-HDF group who actually achieved substitution volumes of >17.4 litres per session there was a mind-boggling 46% reduction in overall mortality and 71% risk reduction for cardiovascular mortality when compared to high flux HD. However its worth pointing out that those in the OL-HDF group who achieved high convective volumes were less likely to be diabetic, had higher serum albumin and higher blood flow rates. Whilst this was controlled for in the analysis it is entirely possible that better survival rates in those who achieved convective volumes >17.4l were simply 'healthier' patients.

The second study is the ESHOL study sponsored by the Catalonian Society of Nephrology,  which was a multicentre, RCT that randomised 906 patients to receive either OL-HDF or haemodialysis (92% of those randomised to the haemodialysis arm received high-flux HD) and has just been published in JASN. The headline figures are impressive and are in striking contrast to both the CONTRAST and the Turkish HDF studies which both failed to achieve their primary endpoints. Those assigned to OL-HDF had a 30% lower risk of all-cause mortality, a 33% lower risk of cardiovascular mortality, and a 55% lower risk of infection-related mortality. The reduction cardiovascular mortality was primarily driven by a reduction in the number of strokes. The estimated number needed to treat suggested that switching eight patients from hemodialysis to OL-HDF may prevent one annual death which suggests that OL-HDF was having an astonishing clinical impact.

So why the striking difference between the ESHOL and Dutch/Turkish studies? The answer is not obvious to me but it is worth considering the following:

i) In the ESHOL study no formal statistics are done on the baseline characteristics of each group but its worth noting that there are baseline differences between the two groups. 7.5% of the OL-HDF group dialysed via a line compared to 13.1% of the HD group. The mean age was 66.3 years in the HD group vs 64.5 years in the OL-HDF group and 22.8% of the OL-HDF group were diabetic compared to 27.1% of the HD group. The Charlson Comorbidity Index was 6 in the OL-HDF group and 7 in the HD group. What I genuinely dont understand is why there was no statistical analysis to see if these baseline differences were statistically significant. Instead these variables were included in multivariate analyses and then treatment risk estimates were calculated in all subgroups. I assume this is an accepted statistical approach but I am just left with this nagging doubt that the 55% reduction in infection related mortality in the OL-HDF group is in part related to the fact that were nearly 40% less lines in this group than in the HD group.

ii) the reduction in strokes with OL-HDF accounted for most of the reduction in cardiovascular risk and this may well have been related to the significant reduction in intradialytic hypotension that was observed in this group compared to the HD group.

iii) a consistent theme that emerges from all three studies is that that actual replacement volume delivered seems to matter. The median replacement volume in the ESHOL study was around 21 litres/session compared to 17 litres/session in the Turkish Study and around 20 litres/session in the CONTRAST study. Indeed post-hoc analyses of both the Turkish and CONTRAST studies showed higher convective volumes did associate with better survival. This was also seen in a post-hoc analysis in the ESHOL study where those with >25 litres/session of convective volume had a 45% reduction in mortality. However what isn't clear is why some patients who are randomised to OL-HDF are able to achieve high convection volumes and others aren't. In particular I wonder whether factors such as quality of access and  cardiac function may somehow select out those who are able to achieve high convection volumes. Thus its plausible that those who can tolerate high volume OL-HDF are simply those with better cardiac function

iv) many will be surprised at the scale of the impact of OL-HDF in the ESHOL study. There have been so many negative RCTs in large dialysis populations it is surprising to see that simply switching 8 patients from high-flux HD to OL-HDF can prevent one death per year.. I am not sure if this is plausible particularly given the fact that most of the reduction in mortality is driven by a reduction in infections and if this is due to OL-HDF how is OL-HDF reducing the risk of infections? Furthermore I'm not sure if the scale of impact seen in ESHOL will be translated to having a similar impact  in routine clinical practice. For example in the UK, the centre that has been using OL-HDF for the longest period of time is Stevenage and they published their rather impressive experience here in cJASN  - yet UK Registry Data does not suggest that patients in Stevenage have better survival than other centres in the UK that don't routinely use OL-HDF

Therefore the evidence from these 3 studies is a bit mixed.   ESHOL showing remarkable effects that some may think are 'too good to be true' whilst the CONTRAST and Turkish-HDF studies failing to meet their primary endpoint. If OL-HDF is to be used than the actual convective volume delivered seems to be critically important if its going to have an effect.  The key question has to be whether OL-HDF is cost-effective (both economically and environmentally). If the cost-effectiveness analysis stacks up then clearly Ol-HDF should be standard therapy - as yet a quality of life analysis of CONTRAST has failed to show a positive impact of OL-HDF.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world
The KDIGO 2012 CKD guidelines which were recently published are available for all to read. Here are my immediate thoughts:

i) There are 2 chapters on defining and identifying CKD and progression and only one chapter on the management of progression of CKD and its complications. This tells you all you need to know about the obssession with epidemiological data in the nephrology literature at the moment. This is true of not only CKD but AKI as well

ii) Worth reminding ourselves that there is not one single licensed therapy for preventing the progression of CKD - its disappointing that of all the research recommendations made not one focussed on the need for licensed therapies in progressive CKD and how to collaborate with industry/academia to deliver this

iii) The classification system is absurdly complex and is a great example of  the dangers of taking an epidemiologically useful tool for research and putting it into the clinical arena. I gave a talk to some family doctors last week and went over the KDIGO classification system... all of them found it confusing, complex and nobody could understand why there needed to be another revision of the staging system. One of the doctors just looked at the classification and said " that just gives me a headache".....

iv) has anybody met a busy practicing nephrologist who thinks that microalbuminuria should be considered as a sole definer of CKD?

v) Can anyone explain how differentiating between CKD 1 and 2 based on current eGFR equations a) makes sense and b) will change patient management and improve outcomes
vi) as discussed the age neutrality of the classification simply does not stand up to any scrutiny... we all know that an eGFR of 40mls/min means different things in a 20 year old and a 70 year old as was powerfully shown by O'Hare and colleagues several years ago

vii) I have yet to see a convincing rebuttal to the critique of the CKD classification system put forward by the likes of Glassock and Winnearls and others several years ago

vii) KDIGO either needs to remove the term 'Global' from its title or start addressing the healthcare needs of the global population. The earlier guidelines on transplantation did discuss models of care in low income countries yet here there is no such discussion here. Its great to talk about patient activation, psychosocial support and the need for conservative care for those of us who work in affluent societies. Yet we know large swathes of the global population have no access to any kind of nephrology care. To provide absolutely no discussion or direction for how low/middle income societies should deal with CKD at best displays a lack of imagination and at worst just highlights the academic and geographical myopia of those who wrote guidelines.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

Prevalence of Diagnosed Cancer According to Duration of Diagnosed Diabetes and Current Insulin Use Among U.S. Adults With Diagnosed Diabetes Findings from the 2009 Behavioral Risk Factor Surveillance System

Authors :CHAOYANG LI,GUIXIANG ZHAO,XIAO-JUN WEN,EARL S. FORD, LINA S. BALLUZ,
org DIABETES CARE
Diabetes Care Publish Ahead of Print, published online January 8, 2013

this article recently published in diabetes care raises suspicious about long term insulin use in T2DM and cancer .
The aim of the study was to To determine whether longer duration of diagnosed diabetes and current insulin use are associated with increased prevalence of cancer among adults with diagnosed diabetes,
Authors analyzed a large population-based sample from the 2009 Behavioral Risk Factor Surveillance
System (BRFSS) in the U.S. The BRFSS is a standardized telephone survey that assesses key
behavioral risk factors, lifestyle habits,and chronic illnesses and conditions among adults aged $18 years in all U.S. RESULT :There were a total of 34,424 adults with diagnosed diabetes participating in the survey with the diabetes module. Of them, 8,460 had missing data on diabetes age, insulin use, and selected covariates. Among adults with diagnosed diabetes and with complete data on cancer and diabetes-related covariates (n = 25,964), there were 11,165 men (weighted percentage, 52.8%), 18,673 NH whites (65.3%), 3,575 NH blacks (16.0%), 2,348 Hispanics (13.1%), and 1,368 participants with NH other race/ ethnicity (5.6%). Approximately 4.7% of adults with diagnosed diabetes were estimated to have type 1 diabetes (n = 491 men and 721 women), 70.5% were type 2 diabeticwithout current insulin use (n = 7,820 men and 10,475 women), and 24.8% were type 2 diabetic with current insulin use (n = 2,854 men and 3,603 women). The mean age was 58.6 years (median 59.0 years). The mean age at diabetes diagnosis was 47.6 years (49.0 years). The unadjusted prevalence for cancers of all sites among men with type 2 diabetes and current insulin use was higher than those with either type 1 diabetes (P , 0.001) or those with type 2 diabetes and no current insulin use (P , 0.001) among both men and women. After adjustment for age, the difference in the prevalence estimates for cancers of all sites remained between adults with type 2 diabetes with current insulin use and those with type 2 diabetes with no current insulin use among men (P , 0.001) and women (P , 0.001). Among both men and women with type 2 diabetes, the prevalence estimates for cancers of all sites were significantly higher among those who had diabetes >15 years than among those who had diabetes ,15 years after adjustment for all selected covariates . Specifically,the prevalence was estimated to be significantly higher among adults who had diabetes$15 years for colon cancer, melanoma, nonmelanoma skin cancer, and cancer of urinary tract among men and the cancers of the breast, female reproductive tract, and skin among women than those who had diabetes ,15 years. Among both men and women with type 2 diabetes, the prevalence estimate for cancers of all sites was ~1.5 times higher among those who used insulin than those who did not use insulin after adjustment for demographic characteristics and selected health risk factors.
current insulin
use remained significantly associated with increased prevalence of cancers of all sites among both men and women and increased prevalence of skin cancer (both melanoma and nonmelanoma) among men and cancer of the reproductive tract .

1-The relation between Insulin use and cancer needs more attention and further .Further research may be warranted.
2-The major strength this study was the use of a large population-based sample,
which enabled investigators to provide stable estimates of cancer prevalence among adults with diabetes in the general population.
3- There were also several limitations , the study is a cross-sectional study in which persons who self-reported diagnosed cancer were cancer survivors and included those who were newly diagnosed and those who had a preexisting condition. Persons who died of cancer were excluded in this self-reported cross-sectional survey. Therefore, these results based on the prevalence of diagnosed cancer suggest crosss ectional associations and preclude causal associations between duration of diagnosed
diabetes or current insulin use and cancer.
4-Age at diagnosis of diabetes or cancer, current insulin use, and cancer types were self-reported by survey participants; thus, recall bias may be possible.
5-duration of diagnosed diabetes may not represent actual duration of exposure to diabetes because people may be asymptomatic for many years before medical diagnosis.

However and again this study raised the red flag between possible association between insulin and cancer that was raised before for Lantus.

Professor Alaa Sabry
[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

American Society for Critical Care Medicine (Puerto Rico): January 22, 2013

GFRs Overestimated in ICU Patients with AKI

Glomerular filtration rates (GFRs) of critically ill patients with acute kidney injury (AKI) are routinely overestimated, data presented at the Society for Critical Care Medicine's 2013 annual meeting suggest. Investigators believe urine output should be used instead of creatinine-based equations to assess kidney function in oligoanuric ICU patients.

The average baseline serum creatinine level was 0.9 mg/dL, and 10% of subjects had a documented history of chronic kidney disease. On each of the first four days of AKI, patients were between 1.8 and 3.7 liters fluid positive. Ten percent of the patients were prescribed trimethoprim.

The researchers assumed that the patients had a true GFR of less than 15 mL/min/1.73 m2. They compared this to the patients' estimated GFRs (eGFRs) calculated from six existing equations. The equations were the Cockcroft-Gault using actual body weight (CG-ABW), Cockcroft-Gault using ideal body weight (CG-IBW), Jeliffe, Modified Jeliffe, the four-variable Modification of Diet in Renal Disease (MDRD-4) study formula, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations.

Results of all six equations significantly overestimated GFR, even after the researchers adjusted for patients' daily variation in creatinine clearance. The closest approximation of the true GFR was given by the CG-IBW, which yielded a day-adjusted eGFR of 32 ml/min/1.73m2. The next-most accurate was the CG-ABW, with a day-adjusted eGFR of 51 ml/min/1.73m2. The least accurate was the Jeliffe equation, with a day-adjusted eGFR or 65 ml/min/1.73m2. Statistically and clinically significant overestimation of true GFR persisted out to the fourth day of AKI.

The findings echo those of previous studies. For example, a multicenter observational study published in 2010 showed the CG-ABW, MDRD and Jeliffe equations overestimated urinary creatinine clearance by 80%, 33% and 10%, respectively (Nephrol Dial Transplant 2010;25:102-107).

Clearly, this doesnt fully appreciate that:

1. eGFR (Regardless of the CR based Formula used) is NOT applicable to AKI!

2. eGFR is NOT applicable to non-steady state situations!

3. eGFR is NOT applicable to sick patients with malnutrition and sarcopenia!

4. Serum Creatinine is an UNRELIABLE marker of true GFR/Kidney Function in AKI!

Other Biomarkers are not much better and a circular argument goes that they rise before serum Cr goes up....but serum creatinine is an unreliable marker of AKI...so in the absence of Gold Biomarker for AKI, clinical judgement is key to the Diagnosis and Management of AKI!

http://ndt.oxfordjournals.org/content/early/2012/10/31/ndt.gfs380.full.pdf+html

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world
The UK Membranous Nephropathy Trial which I had blogged on in an earlier post here has now been published in The Lancet. Most of the data was presented at The ASN and is covered in my earlier blog but its worth reiterating a few points. 108 patients who had at least a 20% decline in excretory renal function over 2 years  were randomised to chlorambucil+ steroids, ciclosporin monotherapy or supportive care. No data was provided about ARBs but 82% of the cytotoxic group, 92% of the CyA group and 100% of the supportive care group were on ACEi. The primary endpoint was a  further 20%  decline in excretory renal function. 58 % of the cytotoxic group experienced this compared to 81-84% of the other 2 groups. The outcomes with CNI and supportive care were comparable. 36 months after randomisation the greatest mean reduction in proteinuria was in the cytotoxic group of 2.2g/24 hours. Serious adverse events were much more common in the cytotoxic group (61%) vs 49% in the CyA group and 42% in the supportive care group. Most of these adverse events were related to haematological complications from myelosuppression with chlorambucil and metabolic disturbances with steroids. Its worth noting that at randomisation the kidney function was reasonable in all three groups with a creatinine clearance of around 50mls/min.

My thoughts are as follows:

i) this is an excellent RCT that establishes that cytotoxic therapy should be the preferred therapy for those with progressive membranous nephropathy. This adds to a body of earlier work from Jha and Ponticelli that suggests that cytotoxic therapy is the treatment of choice for those with progressive disease who dont undergo spontaneous remission. There is no role for CNIs in such patients.
ii) as acknowledged in the excellent discussion the adverse events with such therapy is a problem but its also worth noting that adverse events are also pretty common in the supportive care group suggesting the disease itself can be fairly disabling
iii) there was no data presented on progression to ESRD although given the trajectory of the data presented I think its safe to assume that cytotoxic therapy would reduce the risk of progression to ESRD. Given the time it took to conduct this study I dont think one can reasonably expect there to be a study of membranous that has ESRD as its endpoint!
iv) the authors themselves state that Ponticelli has showed (subsequent to the start of the study) that cyclophosphamide and chlorambucil are equally effective.
v) Clearly as phospholipase a2 receptor antibody testing starts to be introduced into clinical practice future trials in membranous maybe able to better identify those who would benefit from immunosuppressive therapy.
vi) Finally given the positive observational data of Rituximab from the Remuzzi group and from the Mayo Clinic the next obvious trial to do in membranous would be to compare rituximab to cytotoxic therapy not only in terms of remission and progression but also evaluating safety and cost-effectiveness. Until such data is available it is difficult to justify using Rituximab as first line therapy as there have been no studies comparing it with simple supportive care or with active cytotoxic therapy.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

Mohan and colleagues in the December issue of JASN report on the prognostic value of pre-transplant DSA (Donor Specific Antibodies) measured by solid phase assays (SPA) in relation to renal allografts outcomes. Mohan et al. JASN 2012;23:2061-2071.

They undertook a systematic review of cohort studies comprising a total of 1119 patients inclduing 145 with isolated DSA-SPA.

They noted that in the presence of negative Complemenet dependent cytotoxicity (CDC) crossmatch, a positive DSA-SPA (such a Luminex) doubles the risk of antibody-mediated rejection (AMR) and increases the risk of long term graft failure. This suggests that recipients should be checked for DSA regardless of a negative cross match. Of interest, the negative impact of a positive DSA-SPA test at transplantation on outcomes was noted regardless of the SPA titre (mean fluorescence index: MFI, low 1000).

This observation is in agreement with previous publications:

For instance, Lefaucheur and colleagues in 2010 showed that patients with MFI >6000 had >100-fold higher risk for AMR compared to those with MFI <465. The presence of HLA-DSA did not affect patients survival. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938596/

Gary Hill and colleagues in Paris showed that DSA+ recipients have a three fold increase incidence of renal arteriosclerosis. Such accelerated arteriosclerosis was noted early within teh course of the allograft (3-12 months after transplantation). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083319/

1. Interesting observation consistent with the literature on the topic.

2. How would routine DSA-SPA screening affect outcomes?

This may stratify patients into higher risk warranting stronger initial/induction immunosuppression with ATG/Alemtuzumab.

It may also trigger closer monitoring of DSAs after transplantation and lead to related maintenance immunosuppression related strategies.

Alternatively, DSA screening would be undertaken if and when AMR is suspected; onset of albuminuria for instance!

3. Is routine DSA-SPA of all transplant recipients cost effective?

4. Are all DSAs harmful?

5. Is detection of DSA-SPA antibodies of unknown significance create unecessary investigations, excessive testing and unecessary patients' anxiety?

Is this a luxury few renal transplantation centres can afford or is it a game changer in renal transplantation?

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

Professor Richard Glassock wrote:

Thank Dr Khwaja your for your passionate plea for declaring that access to high-quality healthcare (including life-extending procedures such as dialysis and transplantation for those who suffer from ESRD) is a human right not a privilege.  Such a position was codified 65 years ago in the Universal Declaration of Human Rights adopted by the UN General Assembly (Article 27)—mentioning adequate but not high-quality health care and avoiding the issue of cost.

In the face of limited resources, difficult choices must be made on how to extend this right of access toadequate health care to the maximum extent possible across the broad spectrum of health problems in a given society (the burden of disease).

Surely the socio-economic status of individuals suffering from the consequences of ill-health should never be a criterion for making such difficult choices in a civilized society. Nevertheless, the winners in the lottery of life (the affluent) will always have a privileged status in regards to their access to the health care game.  What you have written about is the dilemma of what to do for those who did not win the lottery of life, by virtue of birth or circumstances.

Societies and the governments they form must make these difficult choices for the populations they are entrusted to serve (or oppress as the case may be).  We all recognize that chronic kidney disease (CKD) and its end-stages can be a debilitating and devastating development for individuals, but on a population basis it ranks rather low compared to other common non-communicable health issues, and it tends to disproportionately affect the elderly.  According to the Global Burden of Diseases (2010) study recently reported in Lancet (volume 380, December 15, 22, 29, 2012) in a landmark series of papers, CKD ranked 39th for years lived with disability among 289 diseases and injuries (average of 58 years lived in disability per 100,000 population--low back pain and major depression ranked 1st and 2nd).  In 2010 CKD ranked  24th in a list of 235 causes of death (up from 32nd in 1990) in terms of global years of life lost, but 7th among non-communicable disease (up from 10th in 1990). Not surprisingly, ischemic heart disease ranked  1st in this category.  Among the top 10 ranked disorders in terms of global years of life lost, 6 were communicable, 3 were non-communicable and 1 was related to injury.  The global ranking of CKD (including ESRD), in terms of years of life lost, ranged from 6th (in Central Latin America) 36th (in Central sub-Saharan Africa.

While these details do not truly reflect the degree of human suffering brought about by CKD or any other disease, they do provide a useful perspective in the challenging arena of choice-making from the societal perspective. Resource-rich countries such as North America and Western Europe have adopted a variety of strategies to deal with the burden of disease in their unique regions.  The United Kingdom adopted a strategy of universal access and “free” at the point-of- car for all of its citizens after WW II (The National Health Service; NHS); whereas the United States more recently adopted a  non-universal, capitalistic (free-market) framework, focusing on the elderly, the disabled and the poor.  The Affordable Care Act (“Obamacare”) is extending this reach into a broader range of its citizens, but it still does not approach the NHS in terms of universality of access, except in the arena of ESRD care. Many resource-poor countries have naturally focused on common health issues arising from communicable diseases, such as water potability, vaccination, and endemic infectious diseases (e.g. HIV and Malaria).  The ever-present threats or realities of war have also had a bearing on allocation of scarce resources for health. Many countries are now in transition from a pre-occupation with communicable diseases to the non-communicable ones, especially as their populations age, consequent to lower birth rates and better control of  life-threatening infectious disease.

Yes, the percentage of gross domestic product allocated to diagnosis and treatment of disease varies widely among the countries of the world.   The large amounts of money spent in resource-rich countries does not always result in a uniformly high quality of life and excellent outcomes of care.  Also, in a capitalistic society there is always the opportunity for fraud and abuse and in socialist schemes the implicit risk of rationing by the queue. Universal care cannot be equated with “free” care- it is merely a formalized way of redistributing capital in the form of taxation policies.  As we are learning in the USA, if we are to guarantee access of high-quality health care to everybody, either our taxes must increase or the cost of the care-provided, in aggregate, must come down. The latter means fewer units of care and /or a lower cost per unit.  Where does care for CKD or ESRD fit in this new equation, and how will other less affluent populations grapple with the disconnect between the burden of care, in its varied forms, and the ability of governments (or individuals) to sustain the funding of care, without the prospect of insolvency?  A middle ground must be sought, but some form of rationing, implicit or explicit, seems inevitable.

In the case of CKD and ESRD, like ischemic heart disease, stroke and COPD, an effort to prevent disease or slow its progression is certainly a wise choice, considering the alternatives.  Improvements in the care of patients with ESRD already under treatment with dialysis or transplantation, will improve the quality of life, but will also steadily increase the number of patients treated (like better survivorship with cancer chemotherapy), at least until some new balance is achieved between incidence rate and death rates among the treated population.  Global screening of asymptomatic persons for the presence of CKD in the population as a whole does not seem to be a viable option at the present, but efforts to detect and control Obesity, Diabetes and Hypertension may be a cost-effective way of lowering the burden of CKD in vulnerable populations, and would have the added benefits of addressing issues in ischemic heart disease, stroke, blindness, amputations and congestive heart failure that contribute so much to the global burden of disease.  Such an approach need not have CKD as it central theme.

An organized, coherent, simple and universally-agreed upon system of classification, nosology and staging of CKD is a highly desirable goal- and much progress has been made by KDOQI in 2002 and KDIGO in 2012.  However, this system must in the final analysis, in the perspective of optimal allocation of resources in rich and poor countries alike, accurately identify those individuals most likely to benefit from interventions and at the lowest achievable cost.   There should be a low tolerance for both “false positives” and “false negatives”, especially when disease labeling can have untoward consequences and when erroneous reassurance leads to damaging delays in appropriate treatment.

You make a plea that organized Nephrology couple their advocacy for logical classification of CKD (largely based on prognosis) and clinical guidelines with a strong message that care for patients with kidney disease be universally available, publically supported (“free” at the point-of –care) and of the highest-quality.

Assuredly, you must recognize that such advocacy, on a global stage, creates the necessity for agonizingly difficult decisions involving prioritization among a list of equally or more pressing problems of health in an environment of limited or soon-to-be limited resources. In addition, other social issues such as education, poverty, war and its prevention are competitive to health issues.  Surely access to adequate health care is a right, and not a privilege for the fortunate few, but the expression of this right by populations, through their governments should be leavened by reason and by the ethical principle of the providing the greatest good for the largest number, without consideration of the social worth of the individual.  Physicians adhere to the traditional medical ethic of “rendering to each patient a full measure of service and devotion” Foregoing such a “full measure” can be easily justified when the treatment is useless or unnecessary.  Similar decisions can be fraught with much difficulty (and risk) when such “full measure” competes with broader social issues.  It is the tension in this complex arena that you address in your poignant and passionate essay.

Richard J. Glassock, MD, MACP

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

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