I have been practicing Medicine and Nephrology for 40 years.
It occured to me that true and major breakthroughs in the management of CKD have been few and far between during these 40-50 years.
In fact, when I started practicing Nephrology and until recently CKD meant: Glomerulonephritis, Pyelonephritis, Reflux nephropathy and Dysplastic Kidney Disease (later called CAKUT), Hypertensive nephrosclewrosis, diabetic nephropathy and PKD (ADPKD).
CKD in the community, with its "epidemic" and all that is the brainchild of KDOQI and KDIGO CKD definitions and classifications that have created a monster out of the decline in kidney function in the over 50 and 60 years...This I will not comment upon here as I have already on many occasions only to dismiss this community CKD (cCKD) and all its ills as the takeover by epidemiologists (rather biostatisticians) and the ones I call "Spreadsheet Nephrologists" of our beautiful profession and specialty...
Back to true Nephrology, and true CKD (previously called Chronic renal failure [CRF]), no biostatistians or epidemiologists needed to tell us that its incidence and prevalence have somewhat increased due to ageing and the associated increase in hypertension and DM - related CKD. Also, more and more elderly present with atherosclerotic and ischemic nephropathies.
But my point here is:
40 years on, has there been any major therapeutic breakthrough in the management of true referred CKD (rCKD)?
My answer is NO:
1. When I started we had a range of anti-hypertensive agents including diuretics and beta-blockers. They treat hypertension effectively with a few other classes of agents including RAAS inhibitors. What matters is the BP control regardless of the agent or class of agents used.
2. For GN primary or secondary, we had immunosuppression with steroids +/- azathioprine/cyclophosphamide. Steroids and Azathioprine/cyclophosphamide remain the cornerstone of the management of GN.
3. For Reflux nephropathy/Pyelonephritis, we had antibiotics prophylactically or otherwise, we still have them, although the clever bacteria we treat or trying to prevent have learned to become more resistant...
3. For ADPKD, still the same treatment, early diagnosis and treatment of hypertension.
4. For HT nephrosclerosis, control hypertension and nil else...
5. For DN, control hypertension and not much more...
So little therapeutic advances that proved superior to those we used 40 years ago...in spite of almost 40-50 years on unabated research and promises to slow CKD progression:
Anti-platelets, anticoagulants, prostaglandins manipulations, nitric oxide manipulations, cytokines, chemokines and growth factors antagonsists, not to mention a number of anti-fibrotic strategies including pirfenidone, collagen synthesis and deposition inhibition etc...and of course TGF-beta1 remains the most fibrogenic of growth factors...and we still have not managed to translate that knowledge (20 years old by now) to the bedside...???!!!
Very disappointing...and worth questioning whether the R&D as well as translation strategies we are relying upon to discover new and more effective therapies to slow CKD progression are effective or at least cost-effective?
May be thats why Nephrologists started to look elsewhere, came up with a new definition of CKD, created new detection tools (eGFR formulas), teamed up with biostatisticians, screened everybody, generated a "CKD Epidemic" to give themselves a new impetus and generate more attention to their dormant specialty...?!
The 3C study presented at this weeks’ World Transplant Congress and published online in the Lancet is an important study, which may in the future inform clinical practice in transplantation. In essence there are two parts to the study. The first part looks at induction therapy and compares induction with alemtuzumab (and anti-CD52 monoclonal antibody that depletes mature lymphocytes and is licensed for the treatment of multiple sclerosis and CLL) vs basiliximab – an IL2- receptor antagonist. Those randomised to alemtuzumab also received tacrolimus (targeting a lower therapeutic 5-7 ng/ml) and low dose mychphenolic acid (MPA 360mg bd) but no steroids. In contrast those randomised to basiliximab received steroids, higher dose tacrolimus (5-12ng/ml) and higher dose MPA (540mg bd). The second part of the study looks at switching patients 6 months post transplant from tacrolimus to sirolimus or continuing tacrolimus.
The data presented this week is very early data from the induction part of the study and looks at the impact of a standard basiliximab-based regime vs the steroid-free alemtuzumab-based regime with lower-dose tacrolimus and MPA on biopsy proven acute rejection (BPAR) at 6 months. Groups were well matched though on the whole were of low immunological risk – 92% were first transplants and 4% highly sensitised
The key findings are as follows:
i) There was a significant, 58% proportional reduction in BPAR in the alemtuzumab group (7% of patients) vs the Basiliximab group (16% of patients). Graft function at 6 months was the same in both groups.
ii) The reduction in BPAR was driven by a significant reduction in early cellular rejection. Antibody mediated rejection incidence was 1.9% in the alemtuzumab group but 1.2 % in in the basiliximab group – this was non significant.
iii) There was no difference in CMV viraemia, CMV disease and other opportunistic infections between both groups but BK viraemia was significantly higher in the alemtuzumab group (8% vs 4%). There was no difference in the number of serious infections or hospitalisations
iv) 11 patients died in the alemtuzumab arm compared to 6 in the basiliximab arm. This was not statistically significant but perhaps a little concerning.
v) Leucopaenia was much commoner in the alemtuzumab group – 36% vs 10%.
Like many other clinicians in the UK I have consented patients into the study. To me the interesting points so far are:
i) the 3C study represents a huge success for the UK transplant community in general but in particular for the Oxford Clinical Trials Unit that ran the study. To have recruited so many patients into a study in a relatively short period of time is incredibly difficult and happened because clinicians up and down the country ‘bought’ into the study and the trials unit made it logistically as easy as possible for all investigators
ii) The data is broadly in line with the results of the previous INTAC study which showed that alemtuzumab reduced BPAR in low risk transplant recipients compared to basiliximab whilst enabling an early steroid taper.
iii) The authors emphasise in the discussion that reducing BPAR does not necessarily translate into better graft survival. However the study is powered to detect long-term outcomes and this data will come out in a few years time and we will then be in a position to determine the impact of alemtuzumab induction is on more meaningful outcomes than BPAR.
iv) The results do suggest alemtuzumab-induction does allow for the delivery of steroid-free immunosuppression regimes using lower doses of MPA and tacrolimus – albeit in relatively low risk transplant recipients
v) Although infection rates were broadly similar the ‘big hassle’ of the patients randomised to alemtuzumab was leucopenia which affected a third of patients. There maybe scope to attenuate this by introducing MPA a little later once the lymphocyte count recovers or using a lower dose of alemtuzumab.
vi) Previous retrospective data suggests that alemtuzumab use is associated with an increased risk of antibody-mediated rejection. In the previous INTAC study late acute rejection occurred in 10% of patients in the high-risk group on alemtuzumab vs 2% in the ATG group. Whilst not statistically significant such a difference is worrying. The longer term 3C data will hopefully be able to tease out whether this risk of late rejection (perhaps associated with repopulation of lymphocytes) is a real concern.
In summary the data presented so far are interesting and may clarify a role for alemtuzumab in the delivery of steroid-free immunosuppression once the longer-term outcome data is presented.
This month in the Lancet:
An editorial by Farhat Yaqub on:
Rana Dajani and teh Ethics of Stem cell Research in the Middle East.
The editorial highlights Dr Rana Dajani elevated position in medical and biology research with emphasis on her work in genetics but also the potential of stem cell research to treat many genetic and rare diseases.
Dr Dajani who works at the Hashemite University in Jordan has initiated working and advisroy partiers to explore the potential of stem cell research therapy in medicine and has involved physicians, scientists but also religious and legal experts.
This is a very important step forward in the ethics and governance of medical research in the Middle East and in aprticular in research and potential treatment involving stem cells.
Stem cell therapies like all medical innovcative interventions require considerable governance to translate from basic science to the bedside. Whilst such governance and guidance are often in palce in high economies, the translation of medical adsvances into clinical practice often lacks rigorous governance and good clinical practice (GCP) in emerging countries.
All too often patirents are treated with experiemntal intyerventions before such GCP related steps are implemented and even before ethical and IRB approval or even consideration. This has to be subject of grave concern as patients with geentic conditions, those with orphan and rare disease and others with a range of metabolic abnormalities potentially amenable to stem cell therapies have to be protected against malpractices before they benefit from good practices...
They need to be protected from:
1. being used as guineapigs for greedy scientists and investigators
2. being exploited, and their suffering, by money seeking investigators, physicians and Pharma.
3. being exposed to potential risks before benefiting from potential advances.
4. being duped to beleive their are treated with proven interventions...whe in reality they are subject of research into unproven interventions...after all that is the essence of clinical trials: to Test and Unproven intervention that seems promisiiong...as if it was of proven benefit, it would no longer be ethical to deny its benefits from a control group given placebo....
5. being subjects in poorly controlled and badly conducted "clinical research" that ultimately will yeild no meaningful outcome other than boost the income of the sponsors and investigators of such research...
More than in any other field of medicine, stem cell researchj and therapy has raised considerable hopes and expectations amongst the medical profession and those suffering from a wide range of diseases from Daibetes mellitus, heart failure, multiple sclerosis to spinal injury and kidney diseases, but the road ahead is long....and in emerging countries the risk of exploitation is high, thats why the work of people like Rana Dajani has to be commented and followed with great interest.
This Blog aims to raise awareness of the importance of Good Clionical Practice and the Governance and Ethics of Medical Research in Emerging countries;
IT IS NOT ALWAYS AS GOOD AND ETHICAL AS WE WOULD EXPECT...
In this field, as in many others, conflicts of interest between researchers, physicians and Industry is a threat to research and advances integrity. Tight policies have to be in place to safeguard medical practice and patients.
In this field, examples are common of abuse and malpractices that dont live up to ethical or moral expectations:
In this field of stem cells, less regulation may be warranted for basic research but more regulation has to be implemented acroos the board with special attention to emerging countries when it comes to teh translation of basci scientific advances to the bedside and patients' care:
FINALLY WE NEED TO GUARD OURSELVES AND OUR PROFESSION AGAINST USING PATIENTS HOPES AND EXPECTATIONS, TO GENERATE UNWARRANTED HYPE THAT AIMS TO PROMOTE THOSE WHO USE THE POTENTIAL NEW THERAPIES, SUCH AS STEM CELLS, IN UNETHICAL AND IMMOARL WAYS:
PROFESSOR RICHARD GLASSOCK WROTE:
New NICE CKD Guidelines
On July 23, 2014 the National Institute for Health and Care Excellence (NICE) of the United Kingdom released its new 2014 guidance for Chronic Kidney Disease (CKD). This new version updates and revises guidance distributed in 2008.
NICE was one of the first to subdivide CKD Category 3 (eGFR 30-59ml/min/1.73m2) into Categories 3A (eGFR 45-59ml/min/1.73m2) and 3B (eGFR 30-44ml/min/1.73m2) and to add proteinuria (defined as a urinary albumin to creatinine ratio >30mg/mmol) using the KDOQI 2002 classification schema as its base. This new iteration is based extensively upon the 2013 KDIGO CKD classification system.
Many changes have been made and in the interest of space I will comment on only a few. It is worth reading the original at http://www.nice.org.uk/Guidance/CG182.
First, like KDIGO they have reduced the UACR threshold for CKD from 30mg/mmol to 3mg/mmol, embracing the controversial issue of isolated “microalbuminuria” as CKD. I do not happen to agree with this step; but it is generated from the KDIGO 2013 CKD classification system, without a well-reasoned rationale. Prospective studies demonstrating benefits compared to risk for using this threshold is currently lacking.
Second, they have adopted the CKD-EPI creatinine equation (using IDMS standardized serum creatinine values and after adjustments for black vs non-black race and gender) as the standard way of determining eGFR and suggest that all clinical laboratories (including those that are hospital-based based) utilize this equation when reporting eGFR. I have concerns in that the CKD-EPI equation was developed by epidemiologic studies primarily in clinically stable outpatients. The instability of hospital inpatients and the impact of acute and chronic illness on endogenous creatinine generation may make the CKD-EPI equation a less reliable and accurate tool in hospitalized patients, especially those in an ICU environment.
Third, like KDIGO the NICE guidance suggests that eGFR- cystatin C be used as a “confirmatory” test in the subset of subjects with an eGFR-creatinine of 45-59ml/min/1.73m2 who have an UACR of <3mg/mmol and that CKD NOT BE DIAGNOSED in such patients who have an eGFR-cystatin C of >60ml/min/1.73m2. Since eGFR- cystatin C is no more accurate a tool than eGFR- creatinine in providing an accurate estimate of true or measured GFR, any improved identification of CKD (based on prognosis rather than a departure from normality of GFR) is likely to be due to the non-GFR determinants of eGFR-creatinine and/or cystatin C bearing on adverse events, such as CV disease.
Fouth, the guidance suggests that “opportunistic screening” for CKD (presumably during encounters with the health care system), be offered to those at increased risk of CKD, regardless of age (such as diabetes, hypertension, CV disease, multisystem disease or a family history of CKD). Importantly, older age per se is not regarded as a sufficient reason for such testing. This differs dramatically form recommendation for US organization, such as the National Kidney Foundation. Wisely, NICE took no position on population-based screening for CKD--- a position generally agreed upon by other agencies such as the US Preventative Services Task Force.
Finally, and most disappointingly from my perspective, NICE did not suggest that the eGFR thresholds for defining CKD be age calibrated. This position is identical to that of KDIGO 2013 and both systems ignore the normal decay of renal function with organ senescence. This mistake, in my view, will lead to an ever-increasing prevalence of falsely defined CKD as the population ages, and will lead to unnecessary referrals and testing in the older adult without abnormal albuminuria. As stated previously and until more prospective interventional information is available, I prefer to define abnormal albuminuria as >30mg/mmol persisting for 3 months or more, but I fully recognize that this is a minority position at present.
Notwithstanding these criticism of the NICE 2014 guidance, the overall document is well-written in clear and easily understandable language. I agree with many things in the document, such as when to employ an accurate and precise measured GFR, use of reagent strips to define haematuria instead of urinary sediment, how to identify progression of CKD based on repeated eGFR determinations and not recommending low-protein diets (<0.6-0.8gg/kg/d) in patients with CKD, and scrupulously avoiding the use of combinations of RAS antagonists in people with CKD.
I am confident that these new guidance statements from the highly-regarded NICE organization will elicit an interesting and informative debate in the months ahead. I look forward to reading the comments of others in this BLOG space.
Richard J. Glassock, MD
Laguna Niguel, CA
July 29, 2014
High impact journals tend to focus on clinical trial data that are likely to impact on practice. So it was nice to see a very simple but elegant piece of ‘bench to bedside’ work published in this weeks’ NEJM from Canaud and colleagues from INSERM, Paris looking at the role of mammalian target of rapamycin (mTOR)signalling in the pathogenesis of proliferative vascular lesions and fibrosis in patients with in patients with Anti-Phospholipid Syndrome (APS). APS is characterised not only recurrent thrombosis but also by proliferation of vascular smooth muscle cells and fibrosis of the vascular intima and media. i.e. vasculopathy exists in APS even in the absence of significant thrombosis.
mTOR is a serine/threonine protein kinase that belongs to the PI3-Kinase family that integrates a variety of intracellular and extracellular signalling pathways that control cell metabolism, growth, proliferation and survival. mTOR is the catalytic subunit of 2 distinct complexes mTORC1 and mTORC2 that localise to distinct subcellular compartments and have differing biological function. Inhibitors of mTOR such as sirolimus or everolimus are widely used in kidney transplantation and there is increasing interest in their use in polycystic kidney disease and general organ fibrosis. Of course their anti-proliferative, anti-fibrotic effects in kidney transplantation manifest clinically as impaired wound healing but potentially beneficial effects on tumours such as skin cancer. Similarly sirolimus eluting coronary stents have been shown to inhibit recurrent vascular stenosis and therefore the group hypothesized that mTORC pathway may be involved in the lesions in APS.
They looked at 35 patients with APS (25 of whom had lupus) who had undergone kidney transplantation and compared with 74 case-controls. Immunohistochemistry and immunofluorescence for phosphorylated S6 ribosomal protein (S6RP – a marker of mTORC1 activity) and phosphorylated Akt (a marker of mTORC2 activity) provided an assay of mTORC activity in kidney biopsies. Colocalisation experiments were also performed using markers of endothelial cells and vascular smooth muscle cells.
The key findings were:
i) significantly increased activation of both mTORCs in endothelial cells and vascular smooth muscle cells from patients who had APS- nephropathy – there was also increased proliferation of both endothelial and vascular smooth muscle cells in kidney biopsies
ii) Anti-phospholipid antibodies isolated from serum from patients with APS markedly upregulated mTORC1 and mTORC2 in a human endothelial cell line (HMEC-1 cells) and this activation was abolished by preincubation of cells with mTOR inhibitors including sirolimus. This upregulation did not appear to be due to anti-HLA antibodies as these antibodies were equally prevalent in the control patients who did not have evidence of increased mTORC activity. Control human IgG did not upregulate mTORC activity.
iii)Biopsies performed at 3 and 12 months after transplantation revealed markedly increased phosphorylation of S6RP and AKT (i.e. increased mTORC activity) in APL patients compared to controls. Furthermore APL patients on Sirolimus had significantly reduced evidence of mTORC activation compared to those APL patients not on sirolimus and this was associated with a significant reduction in the development of vascular lesions on biopsy (as characterised and quantified by fibrous intimal hyperplasia)
iv) The improved vascular histology in APS patients on sirolimus was associated with better graft survival and eGFR post-transplantation compared to those APS patients not on sirolimus – although the numbers are very small. All patients with APS were anticoagulated
The biopsy staining as well as the in vitro data with anti-phospholipid antibodies from patient sera suggest that the vascular lesions in APS post-transplantation are mediated by activation of mTORC by antiphospholipid antibodies. One has to be careful about making clinical recommendations on the basis of this kind of work but the data does seem to suggest that sirolimus maybe a better agent than a CNI for APS patients post-transplant. Whilst there are clearly lots of questions about delineating the precise mechanism of how anti-phospholipid antibodies activate mTORC and how this translates into a particular histological phenotype, the work presented is a very elegant example of applying basic science to better understand a clinico-pathological phenotype.
Experiences Obtaining Insurance After Live Kidney Donation
The impact of kidney donation on the ability to change or initiate health or life insurance following donation is unknown. To quantify this risk, we surveyed 1046 individuals who donated a kidney at our center between 1970 and 2011. Participants were asked whether they changed or initiated health or life insurance after donation, and if they had any difficulty doing so. Among 395 donors who changed or initiated health insurance after donation, 27 (7%) reported difficulty; among those who reported difficulty, 15 were denied altogether, 12 were charged a higher premium and 8 were told they had a preexisting condition because they were kidney donors. Among 186 donors who changed or initiated life insurance after donation, 46 (25%) reported difficulty; among those who reported difficulty, 23 were denied altogether, 27 were charged a higher premium and 17 were told they had a preexisting condition because they were kidney donors. In this single-center study, a high proportion of kidney donors reported difficulty changing or initiating insurance, particularly life insurance. These practices by insurers create unnecessary burden and stress for those choosing to donate and could negatively impact the likelihood of live kidney donation among those considering donation.
See Original Source http://goo.gl/2k87QW
Sadly this is most likely the consequence of the eGFR-CKD hysteria...those who donate and end up with an eGFR<60 are automatically labelled as suffering from CKD and consequently have difficulties getting life insurances.
It is high time that this eGFR-CKD mislabelling of these otherwise healthy individuals is addressed.
It is high time it is recognised that their life expectancy is in some instances higher than the general population, due to better health and better follow-ups.
It is also high time that mislabelling, otherwise healthy individuals, as suffering from CKD based on an eGFR calculation is stopped if we dont want to put people off kidney donation.
The eGFR based CKD classification of otherwise normal older people and kidney donors with eGFR<60 as suffering from a disease (CKD3) is one of the sad consequences of the eGFR-CKD hysteria and bandwagon that need to be stopped at once.
Nephrology practice, research and publications seem to have been highjacked by spreadhseet nephrologists and biostatisticians who are changing the face of Nephrology and its practice.
They have created a bubble with CKD…; global epidemic of CKD....that never was...Global healthcare threat....that is misunderstood and misrepresented...not to mention the medicalization of the normality of millions of asymptomatic mostly older individuals who suddenly find themselves labelled as suffering from a disease, CKD, they never had…
The Spreadsheet nephrologists and their Biostatistician colleagues went to action some 10-12 years ago, armed with a new CKD classification (KDOQI 2002) based on estimated GFR (eGFR), the new holy grail of Nephrology….
The KDOQI and more recently the KDIGO CKD classifications are based on eGFR and false assumptions emanating from spreadsheet nephrologists and biostatisticians misinterpretation of insufficient and seriously flawed and invalid data.
Most of the KDIGO CKD Cohorts, upon which the new 2012 proposed classification is based, are seriously flawed:
Individuals all over the world, in excess of a million... tested only once, inaccurately with non validated or standardised biochemistry, with wrong assumptions of chronicity who have their data put on spreadsheets and given to biostatisticians sitting in front of their computers crunching these inaccurate data...to come up with all sorts of prediction models and false assumptions....
“Epidemic of CKD”....Wrong!....just an epidemic of misleading biostatistics in an ageing population....
eGFR/Albuminuria powerful and independent predictors of death...Wrong!....just a misinterpretation of the data....data that even those who have put it forward have argued plausibly that it was weak, flawed and not validated to predict mortality or cardiovascular disease....
But this doesnt deter the spreadsheet nephrologists and the Biostatisticians who carry on regardless...and claim in one paper that mortality increases with CKD regardless of individuals' age....
Only to contradict themselves, using the same biostatistics and spreadsheets...., to say that life expectancy is not different between individuals with normal renal function and those with reduced GFR (down to 45ml/min):
Clearly, premature conclusions regarding the incidence, prevalence and prognosis of CKD based on false and invalid assumptions made by spreadsheet nephrologists and biostatisticians who probably never saw a CKD patient beyond their computer spreadsheet and databases…
Same with eGFR, an approximate calculation of true GFR, that is at best confusing and at worst misleading:
eGFR is at the basis of the false assumptions made about CKD prevalence and prognosis.
Based on eGFR <60, millions have CKD; when in reality the measure is at best imprecise and at worst inaccurate...
Mostly, labelling seemingly healthy older individuals as suffering from a disease, CKD, they never had...they just have a slow and expected decline in their organ function including age-related decline in kidney function…a dangerous and misleading medicalization of an growing ageing population…with unwarranted consequences!?
Then, the spreadsheet nephrologists and their biostatisticians tells us that eGFR, with its endless variety of formulas, predicts all sorts of ills...cardiovascular disease (CVD), mortality etc...when in reality all it does...badly...is reflect the prognostic value of its components:
Mostly, Age and Gender, those two integral part of the eGFR formulas and the strongest predictors of CVD and death....
And serum creatinine, which along with Cystatin C, are better predictors of outcomes than their unnecessary formulation into an eGFR:
In fact, eGFR adds little if nothing to standard CVD and mortality prediction models such as the old fashion Framingham Risk Score (FRS):
Beyond the spreadsheet nephrologists, eGFR offers little to jobbing clinical nephrologists:
1. It underestimates true GFR in early CKD
2. It overestimates GFR in late CKD
3. It is useless at reflecting CKD progression
4. Inaccurate in timing RRT as serum creatinine can decrease by up to 20% in CKD5 due to ESRD and its metabolic consequences.
5. Unhelpful in AKI; as useless and not applicable in absence of a steady state
6. Unhelpful in renal transplantation, confounded by medication
So who is eGFR for, other than spreadsheet nephrologists and biostatisticians…???
Perhaps, non nephrologists who don't know the normal range of serum creatinine and make the wrong assumptions based of normal renal function faced with serum creatinine levels that are raised for a given age…mostly older individuals…better knowledge of serum creatinine norms, their population based percentiles and distribution would suffice;
if not just dividing 1 by the serum creatinine level (mg/dl) would give the non-nephrologists a useful enough approximation of GFR to adjust drug dosage and avoid unnecessary nephrotoxicity, without the false pretense of accurate GFR estimation by eGFR...
But perhaps, and after all….eGFR may also be helpful to clinical nephrologists..., as by playing around with formulas they can cure people from CKD…if you have CKD with the MDRD formula, then apply CKD EPI and you are cured…if not try the Virga equation...; after all the prevalence of CKD in the community varies from 5.8% (MDRD), to 3.6% (CKD EPI) to even 1.8% (Virga)…in one stroke the prevalence of CKD can be reduced to a quarter of its original value with the help of...eGFR formulas…and... biostatisticians!!!! ;)
Longitudinal changes in estimated and measured GFR in type 1 diabetes.
Estimation of GFR from serum concentrations of creatinine and cystatin C has been refined using cross-sectional data from large numbers of people. However, the ability of the improved estimating equations to identify changes in GFR within individuals over time has not been rigorously evaluated, particularly within the normal range of GFR. In cross-sectional and longitudinal analyses of 1441 participants in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study with type 1 diabetes, we compared GFRestimated from creatinine (eGFR(Cr)), cystatin C (eGFR(Cys)), or both (eGFR(Cr+Cys)) with iothalamate GFR (iGFR), including changes in each over time. Mean (SD) iGFR was 122.7 (21.0) ml/min per 1.73 m(2). In cross-sectional analyses, eGFR(Cr+Cys) estimated iGFR with the highest correlation (r=0.48 versus 0.39-0.42), precision, and accuracy. In longitudinal analyses, change in eGFR(Cr+Cys) best estimated change in iGFR; however, differences between estimates were small, and no estimate accurately classified change in iGFR. Over a median 23 years of follow-up, mean rate of change in eGFR was similar across estimates of eGFR(Cr), eGFR(Cys), and eGFR(Cr+Cys) (-1.37, -1.11, and -1.29 ml/min per 1.73 m(2) per year, respectively). Associations of BP and hemoglobin A1c with change in eGFR were strongest for eGFR(Cys) and eGFR(Cr+Cys). Together, these results suggest that the addition of cystatin C to creatinine to estimate GFR may improve identification of the causes and consequences of GFR loss in type 1 diabetes, but may not meaningfully improve the tracking of GFR in clinical care.
Comments from Professor Pierre Delanaye:
An extremely interesting study as the authors looked at the patients with type 1 DM with a "normal" GFR (average 123 ml / min) and changes in GFR with time comparing measured GFR to eGFR.
977 patients had GFR measured by iothalamate at least more than once on an average of 3.1 years (average between 1 and 6 years follow-up). The formulas used are those of the CKD-EPI consortium. The results show that all formulations (eGFR) are not suitable to reflect the slope of true GFR decline with time.
Cystatin C based equations brings a little more compared to creatinine based equations but thats probably clinically insignificant.
The most illustrative result seems to me that: 297 patients had a measured GFR that decreased by >15 ml/min.
By contrast:CKD-EPI based on creatinine showed that only 46 patients had a GFR decline of >15 ml/min, CKD-EPI based on cystatin C gave 54 patients and CKD-EPI combining Cr + CysC gave 47 patients.
The agreement between measured GFR and eGFR was poor in terms of revealing individuals with T1DM who had a decline in GFR.
This implies that whilst eGFR formulas may agree with measured GFR to a certain extent in cross-sectional studies, they are very poor in estimating changes in GFR with time.
This important observation confirms a growing body of evidence that the estiamtion of changes in GFR with time whether in longitudinal observational studeis or in interventions clinical trials is misleading.
eGFR in this study serioulsy underestimated patients with progressive decline in kidney function.
This agrees with the observationsmade by Ruggenenti et al in 2012 who showed that in patients with ADPKD the MDRD as well as the CKD EPI eGFR formulas underestimated GFR changes by 50%. The authors stressed that direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research.
It is time to review our underestanding and evaluation of the progression of CKD and related progression intervention trials relying on eGFR, with a critical eye based on the above observations.
Increasingly, I ask myself what is eGFR useful for...????
Not accurate in individuals with normal or near normal GFR as they underestimate true GFR...
Not accurate in CKD4-5 as they overestimate true GFR...
Not accurate in predicting CKD progression as they underestimate progressors...
Not accurate in predicting timing of RRT...
Useless in AKI...
Not very helpful after renal transplantation...
It seems to me that eGFR is only useful for "Spreadsheet Nephrologists/Biostatisticians" who want to publish weak and unvalidated data dressed up as "high science"...in Nephrology journals that are too uncritical to accept their manuscripts...
For me as a clinical nephrologist, I can live happily without eGFR!
DR SAMAH IDRISS REPORTED FROM EDAT-ERA 2014:
EUROTOX GRAND SESSION
PROF R Vanholder and G. Glorieux
Uremic toxins are more like established Gut Kidney axis with effect on mechanisms with impact on survival and quality of life of CKD patients :
progression of CKD
Protein bound uremic toxins :
1-Hippurate ( inhibits uremic glucose utilization and involved with muscle weakness in uremic patients, also in CSF responsible for neurological symptoms in old literatures !!!! )
New studies on Rat models of CKD shows that it accelerate tubular injuries , glomerular dysfunction and glomerulosclerosis..
2- Phenylacetic acid impairs macrophage functions and involves in inflammation -oxidative burst theory and inhibiting iNOS .
GUT KIDNEY AXIS determinants :
Nutrient availability (Carbohydrates and Nitrogenous molecules ) +colonic transit time ( specially with HD patients having prolonged colonic transit time )+ composition of colon microbiota (CKD alters intestinal flora )
Possible interventions :
Protein restriction(CKD 3-5 ND)
food supplement (pre and pro synbiotics ) !!!
pharmacological therapies to alter GI physiology(acarbose)
Avoiding therapies slowing down the transit time /
removal of protein bound toxins by combined fractional plasma separation and adsorption techniques (FRAD vs HF HD)
As many are of microbial origins so to prove causal relations for sure ... we should focus on intestinal generation , tubular secretion ,novel approaches in dialysis to decrease the circulating levels .
UREMIC TOXINS...THE LOCH NESS MONSTER OF NEPHROLOGY...REARS ITS HEAD EVERY NOW AND THEN...AND THEN DISAPPEARS WITHOUT TRACE OR IMPACT....WHEN WILL THOSE WHO SEARCH FOR THE HOLY GRAIL OF UREMIA TO REALISE THAT CKD IS NOT A SINGLE MOLECULE DISEASE BUT INSTEAD...A COMPLEX MULTISYSTEM...MUTLI-MEDIATORS...INTER-RELATED SYSTEMIC DISEASE....
I RECALL THE LATE PROFESSOR JONAS BERGSTROM IN THE 70-80s...SEARCHING FOR THE UREMIC TOXIN(S)...IN THOSE DAYS...MIDDLE MOLECULES...FOR SOME REASON...NOT SMALL...NOT LARGE...BUT MIDDLE MOLECULES...WAS THE ANSWER TO ALL OUR TROUBLES WITH UREMIA...
HE LIVED....PUBLISHED...AND DIED...AND MIDDLE MOLECULES ADDED NOTHING BUT CONFUSION TO NEPHROLOGY...
I FEAR THE SAME MAY BE SAID ABOUT PROF VANHOLDER ONE DAY...I SINCERELY HOPE TO BE PROVED WRONG...
THE URMEIC TOXINS CHASERS ARE CHASING RAINBOWS...
OR THE LOCH NESS MONSTER (please note that I am on holiday near a Scottish Loch...hence this analogy...)
PROFESSOR PIERRE DELANAYE WROTE FROM THE EDTA-ERA CONGRESS IN AMSTERDAM:
Le Docteur Block, bien connu pour ses nombreuses études dans le domaine CKD-MBD, a montré les premiers résultats avec un nouveau chélateur à base de Fer, le Zerenex° qui est en fait du citrate de Fer. L’idée de chélater le phosphore avec des composés ferriques ne datent pas d’hier mais finalement peu d’études randomisées existent. Il s’agit de patients en pré-dialyse. Les critères d’inclusion sont les suivants : Hg entre 9 et 12 g/dl, la ferrtitine devait être inférieure à 300, la saturation inférieure à 30% et le phosphore entre 4 et 6 mg/dL. Les patients transfusés, traités par EPO ou pas Fer IV étaient exclus. Le traitement est administré à ds patients américains (66 ans, eGFR à 26 ml/min). L’étude est randomisée, contre placebo, « double-blinded ». Sont inclus 75 patients dans le groupe traité et 74 dans le groupe placebo (1 perdu de vue, compliance OK). L’étude porte sur une courte période de 12 semaines. Globallement, on observe une augmentation significative dans le groupe traité de la saturation en transferrine (20 à 30%), de l’hémoglobione 10.4 à 10.9 g/dl et une diminution du phosphore de 4,5 à –de 4 (les chiffres sont à considérer prudemment, c’est plus une estimation, un « trend » car les chiffres précis ne sont pas donnés mais estimés d’après les graphes présentés). De manière intéressante le FGF23 (intact et Cterminal) diminuait significativement dans le groupe traité. Le traitement parait bien supporté avec, comme c’est le cas pour tous les chélateurs, des effets secondaires surtout intestinaux (diarrhée). Aucun effet secondaire sévère n’était décrit.
Bien entendu, l’étude devra être complétée dans un plus grande population et surtout plus longtemps mais ce traitement semble faire d’ « une pierre deux coups » avec des effets bénéfiques sur l’Hg et le phosphore en prédialyse. Aucune idée du prix de la médication mais théoriquement (si on met de côté le « marketing »), cela pourrait être moins cher…
This presentation shows in CKD4-5 that iron containing chelators of phosphate reduce serum phosphorus levels and improve iron status.
This offers the dual advantage of serum Pi control and anemia management (iron repletion).
Iron containing phosphate chelators have been around for a while.
It is surprising that an iron containing chelator that is meant to be minimally absorbed improves iron stores. It would be interesting to knwo how much iron is absorbed in thse patients with advanced CKD who normally dont absorb much oral iron never mind that chelated to phosphate?
A previous study showed that iron uptake is indeed minimal in thse patients when given orla iron chelators: Median iron uptake (range) was 0.06% (0.008 - 0.44%), 0.02% (0 - 0.04%) and 0.43% (0.16% - 1.25%) in the nondialysis-dependent CKDpatients, hemodialysis patients and healthy subjects, respectively. 0.06% in CKD ND, hardly enough to correct iron stores or increase ferritin???
But the true question is:
DO WE NEED MORE PHOSPHATE BINDERS....????