Growing evidence is implicating a genetic absis for CKD in African-Americans linked to mutations in the APOL1 gene. A genetic mutation that served sub-saharan Africans well some 10,000 years ago as it confered trypanolytic activity against trypanosoma brucei...but now comes to cost them a susceptibility to non diabetic CKD including primary and secondary FSGS (1).
More recently, it has also become apparent that such mutations in the APOL1 gene may confer increased susceptibility to renal allograft failure; not as much in black recipients but in relation to balck donors. Renal allografts with APOL1 G1 and G2 mutations variants have considerably shorter allograft survival (2).
Consequently, the question is now raised as to whether Blacks with such AOPL1 mutations should donate their kidneys or not? In two respects, first whether such allograft will have a poorer outcome, second, whether the donor, if young, would be susceptible later in life to a nephropathy on his/her remaining kidney. Those may develop the unfavorable CKD/FSGS phenotype later in life.
This concern applies to both living as well as deceased donors. Two (G1 and G2) APLO1 risk variant kidneys may be avoided or used where expanded criteria donor kidneys are considered, as they have a greater probability of early allograft failure.
In the era of rapid sequencing and PCR based genotyping, time may have come for a better genetic evaluation of kidney donors (3).
However, such approach whilst affordable and applicable in high economies is unlikely to be either practical or affordable in low and middle economy countries where most black individuals and those of African ancestry live...all too often medical guidelines and recommendations made in Western countries and Western publications overlook the fact that the world is not confined to the West, but also East and South...in those, genotyping of any kind is not an option, whilst renal transplantation may be a survival option in the absence of other forms of renal replacement therapies such as dialysis. Instead, a more careful clinical and laboratory evaluation of black donors is warranted, with careful family history (of CKD) souhgt, a careful evaluation of their kidney function and microalbuminuria, as well as more cautious, or agressive, management of these potentially higher risk of failure kidneys.
1. Genovese et al. Science 2010;329:841-45.
2. Reeves-Daniel et al. Am J Transpl 2011;11:1025-30.
3. Freedman and Julian. Kidney Int 2015; 87:671-73.
A few months ago I saw an 82 year old lady with very slowly progressive CKD4. She had T2DM, hypertension, a strong history of smoking and was referred by her GP as she had an eGFR of 29 mls/min ( compared to 35 mls/min 5 years ago). Her US showed slightly small kidneys and her dipstick was negative for protein and blood and immunology screen was negative. She was assumed to have ischaemic nephropathy as the cause of her CKD. She had been taking NSAIDs for 20 years for arthritis
Her BP was 152/90 and she was reasonably well - she lived independently with some support from her daughter. When I saw her her main problem was her arthritis - this was severe and she was racked with pain particularly in the morning. The nephrologist who saw her on her prevoius visit had understandbly told her to stop taking NSAIDs ( Ibuprofen 200mg tds) and instructed her family doctor to increase her anti-hypertensive medications by adding in a diuretic
The problems were two fold i) she couldnt tolerate other pain killers ( nausea, constipation and hallucinations) so she was left taking paracetamol which didnt work. ii) She was already on a number of vasodialtors which left her with significant oedema and as she had an overactive, small bladder she found that taking diuretics meant that going out was difficult and so now had to stay at home as she was afraid of being incontinent in public.
What struck when me I saw here was that two very reasonable (from a nephrologists perspective) interventions (ie. stopping NSAIDs and increasing anti-hypertensive medication) had significantly worsened the quality of her life.... which got me thinking what was the actual 'value' we were adding to her quality of life or life expectancy by seeing her? Perhaps they were the following:
i) Reducing her risk of developing ESRD? This ladys risk of developing ESRD in her lifetime is miniscule.. as shown in the GLOMMS study women of this age with no albuminuria virtually never progress to ESRD and so if our goal is to try and reduce the risk of her developing ESRD then we are trying to reduce the risk of someting that is vanishingly unlikely to happen - even if she never sees a nephrologist. This was further brilliantly highlighted in a recent publication extrapolating the effect of a putative intervention that reduces the risk of ESRD by 30% in RCT to an elderly population with CKD. The reality was that the effect would be negligible for most of the elderly as few will progress - again highlighting the importance of interpreting RCT data in the context of the patient on front of you
ii) Stopping NSAIDs will reduce her risk of developing ESRD? Given the fact that she had been taking NSAIDs for 20 years with only a slow decline in kidney function the value of stopping NSAIDs in her case on either her life expectancy or quality of life are negligible - indeed her quality of life was significantly worse after stopping NSAIDs. So perhaps a better approach would have been to tell her to continue taking her NSAIDs (stopping only if she gets intercurrently ill) and to continue monitoring her kidney function regularly. And as a recent systematic review showed the impact of NSAIDs used at a normal dosage on GFR decline is negligible.
iii) Getting better control of her BP will reduce her risk of cardiovascular disease? Putting aside the fact that at the age of 82 with a lifetime of smoking, the dice in terms of CV risk has already been cast, would lowering lowering her blood pressure really improve her CV risk? - well there is increasing evidence that treating to a ‘target’ of less than 140/90 mmHg may not only have no benefit but may for some patients be harmful. In fact the evidence base from interventional studies to support a ‘tight’ BP target in this age group is negligible.
So what did I do…. well I stopped her diuretic, told her to go back on her NSAIDs - Her BP was 152/90 and her eGFR 30mls/min and most importantly she was now happy that she could get out of the house (without worrying about incontinence) and her pain was controlled. When I started talking about CV risk and salt in her diet, her eyes glazed, she leaned forward and said “you do know I’m 82 don’t you...?"
So what did I learn? well without sounding trite the clear learning message from this case is that treating risk is not the same as treating a patient…What matters to us ( e.g reducing proteinuria and BP, stopping NSAIDs) may not matter to the patient and whilst in some cases doing things like tightly controlling BP, reducing proteinuria and stopping NSAIDs will be incredibly important, in other situations they are at at best irrelevant and at worse counterproductive.
This balance between the ‘evidence-based medicine’ and ‘patient-centred care’ has been articulated by a thought-provoking recent article by Ann O’Hare in NDT which continues on from an earlier article stressing the importance individualised rather than disease-based care - a must read for anyone who actually practises medicine and sees real-world pateints.
In other words the certainties and value of guidelines and ‘evidence-based medicine’ are only realised if you can interpret them in the context, society, healthcare system and culture in which you practice and understand their relevance to the patient sitting in front of you. Real-life clinical medicine is still an art - a balance of risks, uncertainties, trade-offs and compromises.
WORLD KIDNEY DAY 2015 AND KIDNEY HEALTH FOR ALL....
Seemed intricately linked to drinking water....every WKD celebration showed people...doctors...nurses...kidney patients...volunteers...shifting case after case of drinking water...bottled of course...mineral some time...and drinking it...photographed drinking water....smiling with a bottle of water in hand...as if at last we have found as a profession the answer to kidney disease....the holy grail...of Nephrology...DRINKING WATER...BOTTLED OF COURSE...!!!!
What is that all about I ask myself...????
Had WKD 2015 addressed the global CKD challenge of kidney stones, I would have understood...some logic then behind drinking a lot...and diuresing a lot to dilute urinary salts and minerals and prevent their precipitation in the millions of worldwide sufferers of kidney stones...
But...KIDNEY HEALTH....and WATER DRINKING...is a different story. No evidence, other than old wives tales, linking kidney health to excessive fluid intake...NO EVIDENCE, as far a I know, linking increased fluid intake with CKD prevention or slowing its progression or improving kidney function in the communities...we target through WKD celebrations!
I am also aware that excessive water intake, aloing with that of salt, in patients with advanced CKD is harmful as it could exacerbate hypertension and precipitate heart failure.
Then, comes an intriguing association/partnership... Danone one of the main ISN and WKD sponsors, and at the same time the greatest producer and exporter of bottled water worldwide...an interesting alliance...and welcomed one...as long as facts are not distorted to link KIDNEY HEALTH to WATER CONSUMPTION...and obviously selling more BOTTLED WATER...
I would like to be proved wrong...that increased water intake...improves kidney health...as this would be the most signifiacnt breakthrough in Nephrology and the cheaper...BUT I COULD FING NO TANGIBLE EVIDENCE.
In the meanwhile, I remain skeptical....and even concerned about our professional society promoting "old wives tales"...and falsehoods...all too easily adopted by global communities...and more concerning still...by ILL INFORMED NEPHROLOGISTS ALL TOO KEEN TO BE SEEN ON PHOTOGRAPHS WITH A GLASS OR BOTTLE OF WATER AND A HAPELESS GRIN...!!!
HAPPY WORLD KIDNEY DAY...I WILL NOT RAISE A GLASS OF WATER!
RARE RENAL DISEASES: NEW FRONTIERS
Rare inherited kidney diseases are increasingly expanding thanks to next-generation sequencing techniques; with new disease entities being discovered and added to this rapidly growing list.
Many of these diseases are monogenic affecting not only children but also adults. At least 10% of adults and nearly all children who receive renal-replacement therapy have an inherited kidney disease.
This calls for challenging current clinical practice to maintain high index of suspicion, to promote precise clinical phenotyping, and to update diagnostic paradigms thereby ultimately improving rare disease diagnosis.
Rare kidney diseases are the perfect example of multidisciplinary approach necessitating close collaboration between pediatric nephrologists, geneticists, adult nephrologists, other physicians, nurses, social workers, and dietitians.
Clinical practice guidelines are usually built up on the basis of evidence-based medicine, nevertheless this is commonly lacking in orphan diseases. Alternatively, objective face-to face discussions of expert groups, where consensus between experts in the field of the disease is obtained, is seemingly an acceptable way to balance personal experience and available (as few as it might be) evidence.
Advances in genetics are expected to guide targeted interventional treatment and pharmacological orphan therapeutics. On the other hand, they have raised many ethical concerns regarding genetic counseling, geographical distribution of medical care, and health equity.
Happy Rare Disease Day February 28, 2015
IN THE LANCET THIS WEEK:
What is high quality science? Rigorous, accurate, original, honest, and transparent were the words selected by scientists who took part in the UK Nuffield Council on Bioethics' project to assess the ethical consequences of the culture of research. The project surveyed 970 scientists and held several discussion events in the UK as well as meetings with funding bodies, publishers, editors.
Scientists reported that they were motivated to do research to make discoveries that benefit society and to improve their own knowledge and understanding. However, they raised concerns that their working environment did not support their goals and visions. Worryingly, for some, the culture of research in the UK was such that it even encouraged poor quality research practices, such as rushing to finish and publish research and employing less rigorous research methods. High levels of competition for funding and jobs and promotions were noted as driving factors for these behaviours.
The Research Excellence Framework (REF) results (to be released on Dec 18), which inform allocation of core funding to higher education institutes, were a key issue for those surveyed. Despite a change in format since the last such exercise (eg, REF assessment panels were instructed not to make any use of journal impact factors in assessing the quality of research outputs), REF still causes researchers much anxiety, and misperceptions and mistrust about the system exist. Scientists still think that publishing in high-impact journals is the most important element in determining funding, jobs, and promotions, along with article metrics such as citation numbers.
The Lancet Series on Research: increasing value, reducing waste also noted problems with reward systems—they incentivised quantity more than quality and novelty more than reliability. “Research rewards and integrity: improving systems to promote responsible research” is the theme of the 4th World Conference on Research Integrity (May 31–June 3) in Rio de Janeiro, Brazil, 2015. Critical examination of rewards systems is warranted by all those involved in the research enterprise since existing approaches are putting immense pressure on scientists and could be damaging the very practice of science itself.
Research culture based on pressurising scientisits to produce results, most often positive results, as many perceive a negative result as a failure..., is most harmful. Such pressured environment has been, and remains, the essence of biomedical research in the UK and elsewhere. Publish or Perish...type of philosophy is destructive and dangerous.
It leads to short termism in research endaveours., with lack of continuity and longterm perspective...
It leads to a rush to publish preliminary findings that many misinterpret as definitive...and that are often contradicted by more in depth research and analysis...
It also leads, most importantly, to fraud...scientific fraud is common in such a pressured research environement where lack of publication, means lacks of subsequent funding, which in turn means loss of livelihood...all too often scientists cheat and manipulate their results to prodcue positive findings that allows publications and garantee their job security...Castles built on Sand...
ROFESSOR KIM SOLEZ (CANADA) WROTE:
IN aswer to the shortage of Nephrology trainees in US
Highly significant and related to what I have been writing and saying about the need for further engagement between nephrology and regenerative medicine!
To put the situation succinctly, the stem cell generated kidney is the "moon shot" of regenerative medicine, substantially harder to pull off than the stem cell generated liver or heart. Nephrologists possess the unique knowledge that can make this "moon shot" happen, but they are running scared from regenerative medicine because their leaders are telling them "this will make everything we do redundant"! They need to embrace renal regenerative medicine as a logical extension of what they are already doing, and once they do that the best and the brightest young people will once again be competing to enter the field! I can think of no bigger issue than this right now in nephrology.
Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy.
Background Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown. Methods Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis. Results Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1-negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic membranous nephropathy who were seropositive for anti-PLA2R1 antibodies, from the 76 patients with other glomerular diseases, and from the 44 healthy controls reacted against this antigen. Although this newly identified antigen is clearly different from PLA2R1, it shares some biochemical features, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions. Mass spectrometry identified this antigen as thrombospondin type-1 domain-containing 7A (THSD7A). All reactive serum samples recognized recombinant THSD7A and immunoprecipitated THSD7A from glomerular lysates. Moreover, immunohistochemical analyses of biopsy samples from patients revealed localization of THSD7A to podocytes, and IgG eluted from one of these samples was specific for THSD7A. Conclusions In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition. (Funded by the French National Center for Scientific Research and others.).
More and more autoantibodies are being identified in patients with idiopathic membranous nephropathy:
Anti-Aldose Reductase (AR)
Anti-Thrombospondin Type1 D7A (abstract above)
These anti-Podocytes antibodies, mostly IgG4, are most likely to represent, in my opinion, a paraphenomenon of podocyte injury with subsequent damage of the podocyte and exposure or enhanced antigenecity of these cytoplasmic and cell surface proteins and enzymes with a secondary auto-immune response.
It would be most unlikely that all these, overlapping and often correlating auto-antibodies are the primary auto-immune event in IMN. This would be the first disease, toi my knowledge, that is triggered simultaneously by 4 or 5 auto-immune antibody...the hypothesis that I put forward that these are events secondary to a primary podocytic insult/injury with subsequent injurious amplification loop is more plausible.
Unless, as suggested by the author of the publication above, there are different and distinctive subgroup of patients with IMN initiated by different auto-antibodies...seems less likely to me!
The Future Burden of CKD in the United States: A Simulation Model for the CDC CKD Initiative.
BACKGROUND:Awareness of chronic kidney disease (CKD), defined by kidney damage or reduced glomerular filtration rate, remains low in the United States, and few estimates of its future burden exist.
STUDY DESIGN:We used the CKD Health Policy Model to simulate the residual lifetime incidence of CKD and project the prevalence of CKD in 2020 and 2030. The simulation sample was based on nationally representative data from the 1999 to 2010 National Health and Nutrition Examination Surveys.
SETTING & POPULATION:Current US population.
MODEL, PERSPECTIVE, & TIMELINE:Simulation model following up individuals from current age through death or age 90 years.
OUTCOMES:Residual lifetime incidence represents the projected percentage of persons who will develop new CKD during their lifetimes. Future prevalence is projected for 2020 and 2030.
MEASUREMENTS:Development and progression of CKD are based on annual decrements in estimated glomerular filtration rates that depend on age and risk factors.
RESULTS:For US adults aged 30 to 49, 50 to 64, and 65 years or older with no CKD at baseline, the residual lifetime incidences of CKD are 54%, 52%, and 42%, respectively. The prevalence of CKD in adults 30 years or older is projected to increase from 13.2% currently to 14.4% in 2020 and 16.7% in 2030.
LIMITATIONS:Due to limited data, our simulation model estimates are based on assumptions about annual decrements in estimated glomerular filtration rates.
For an individual, lifetime risk of CKD is high, with more than half the US adults aged 30 to 64 years likely to develop CKD. Knowing the lifetime incidence of CKD may raise individuals' awareness and encourage them to take steps to prevent CKD. From a national burden perspective, we estimate that the population prevalence of CKD will increase in coming decades, suggesting that development of interventions to slow CKD onset and progression should be considered.
We are mystified and deeply troubled by what appears to be a "fear mongering" simulation of the life-time risk of developing what is unreasonably called "CKD" recently published on-line in the AJKD (Hoerger, TJ; Simpson, SA; Yarnoff, BO; Pavkov, ME; Ríos Burrows, N; Saydah, SH; Williams, DE; Zhuo, X. The Future Burden of CKD in the United States: A Simulation Model for the CDC CKD Initiative Am. J. Kidney Dis., 2014- on-line- December 6, 2014). Both the authors and the reviewers of this paper clearly accept the notion that as humans age the GFR falls. They must also realize that the application of a fixed, absolute and arbitrary threshold of GFR as a definition for "CKD", without reference to other manifestations of kidney disease (such as overt albuminuria) will always and predictably lead to an increase in "CKD" as one grows older and GFR falls. Thus, it is expected and unsurprising that as populations and individuals age the incidence and prevalence of "CKD", defined in this fashion, will rise in a commensurate fashion. Does this mean that life expectancy is curtailed to any significant extent by this age-related" and artificially-created "pseudo-CKD"? No! Does this mean that the new label imposes any special burden on the person so labeled? No!, except for the anxiety and fear that it engenders and the resulting “medicalization” of ageing and associated events such as falling GFR.
This publication, by suggesting that individuals can all look forward to a 1:2 chance of developing "CKD" over our lifetimes and that our societies can anticipate a secular increase in the prevalence of "CKD", carries with it a deep responsibility to explain the origins of these phenomena to the reader in a clear and unequivocal way. After all, the lifetime chance of dying is 1:1 and we all intrinsically understand what this means; namely, that death is inevitable, the process is biological and begins at the time of birth. Similarly, the decline GFR, in those who survive over 65 years of age, is also a biological process that will affect an increasing percentage of the ageing population. In addition, no cogent explanations are offered for the huge gaps in prevalence of “CKD” between Category 2 and Category 3A and Category 3B—if the CKD Categories represent some kind of naturall progression why do these discrepancies occur?
It is disappointing that the extremely worthwhile aspects of the CKD concept are being twisted in such an unhelpful way that obfuscates the real risks of meaningful (treatable) CKD. An obvious solution would be to age-calibrate the thresholds of eGFR used for defining CKD (in the absence of other disease defining features), in the first place. One might anticipate that if this were done the frightening characteristics of the simulation would take on a more subtle, less dramatic hue. Only then will life-time risks of CKD assume meaningful significance to individuals, populations and societies.
Richard J. Glassock
Meguid El Nahas
The biggest problem facing around 13,000 kidney professionals attending this huge annual meeting of the American Society of Nephrology was to decide which talks and sessions to attend among the very rich program where too many interesting sessions were running in parallel.
In her address at the opening plenary session, the American Society of Nephrology (ASN) President Sharon M Moe, MD crafted a road map "BUILDING NEW PATHS TO KIDNEY HEALTH" in light of the changing healthcare landscape and rapidly advancing science. She pointed out that nephrology is now almost facing a mid-life crisis and that focusing on kidney health instead of disease would get it back on the glamorous path it once was on; giving it a face lift.
State-of-the-Art Lecture “Stem cells to understand and treat diabetes” by Douglas Melton, PhD, Professor from Harvard merely reflects enhancing the basic science content of this meeting where he presented the pioneering work of his lab in studying the genes and cells that differentiate into functioning islet beta cells to treat diabetes. Also, Eske Willersslev, DSc an expert in ancient DNA and evolutionary biology unveiled some secretes in his interesting talk “What we can learn from the genetic past”.
To further emphasize the pivotal role of basic research and genetic studies in kidney health and disease, the acclaimed researcher received the Homer W. Smith Award Professor Friedhelm Hildebrandt, MD from Harvard and delivered an address “Single gene defects elucidating the mechanisms of CKD”. He smoothly introduced the huge audience into the fascinating and exciting world of monogenic kidney diseases. He also presented that his group identified more than 50 novel causative genes for CKD and delineated the related pathogenesis.
Given the above, I have to respectfully disagree with Dr. Moe. I am not very enthusiastic about the nephrology middle age crisis and face lift theory. On the contrary, I believe nephrology is yet to mature and grow up with the rapidly accumulating data on molecular basis of kidney health and disease. We will grow when we conquer all the challenges ahead. As researchers continue to unravel basic pathogenic mechanisms of many, yet enigmatic, kidney diseases, our therapeutic options would undoubtedly change heading strongly towards a whole new era of personalized medicine
FROM PROFESSOR GLASSOCK AT ASN 2014:
HALT-PKD- study a showed the a lower BP goal slows rate of increase of total kidney volume (TKV), reduces LVH, reduces albuminuria but has no effect on decline in eGFR (no mGFR reported. Dual ACEi + ARB neither beneficial or harmful. High uncertainty whether the short-term benefits on TKV change and LVH will have a benefit on Survival or ESRD.
Disconnect between BP lower targets and reduction in LVH/albuminuria AND PKD progression in terms of decline of eGFR.
This raises questions regarding the assumption (made for instance in mTOR inhibitors in ADPKD) that a reduction in TKV (Total Kidney Volume) would translate into slowewr ADPKD progression.
Also raises questions regarding the assumption that a reduction in LVH would imrpove CKD survival (by analogy here...a higher hematocrit improves LVH but doesnt survival...).
Clinical trials in Nephrology are a huge challenge:
1. Surrogate markers are unpredictable at best in terms of outcomes.
2. Hard endpoints would take 5-10 years to reach.
UNLESS, BETTER RISK STRATIFICATION OF THOSE INCLUDED IN RCTs. CHOOSING ESTABLISHED AND PREDICTABLE PROGRESSORS (if possible) WHERE A RESPONSE TO AN INTERVENTION WOULD BE MORE LIKELY.