2013 will see the publication of numerous guidelines aiming to improve the outcomes of patients with kidney disease. Whilst there will be heated debate about the merits of the CKD classification system or the setting of lipid targets in CKD, it's striking that major international nephrology organisations such as KDIGO and the ISN generally ignore the major elephant in the room when it comes to global nephrology care - namely the right of all citizens around the world to have high quality care irrespective of their ability to pay for such healthcare.
The argument that nephrology care is expensive and many countries cannot afford such care simply doesn't stand up to scrutiny. For example in oil-rich Nigeria or in booming India, end stage renal disease is simply a death sentence for patients who can't afford care. Despite being the 10th largest economy in the world, data from the WHO shows that the government of India only spends 1.1% of its GDP on healthcare. Tazeen Jafar wrote movingly in the New England Journal of Medicine about the death of a Pakistani tailor in 2006 as a result of developing ESRD secondary to type 2 diabetes - bankrupting his family in process. Yet there is nothing 'inevitable' about such deaths - it is too easy to dismiss these deaths as a consequence of poverty rather than a direct consequence of political choices and priorities made by governments. Again data from the WHO shows that the government of Pakistan chooses to spend only a derisory 0.8% of its GDP on healthcare whilst military spending attracts four times as much funding. In contras there are developing countries that choose to make healthcare a priority. For example, Mauritius has been highlighted by the Nobel prize-winning economist Joseph Stigilitz as a role model for many developing countries - it's government spends 6% of GDP on healthcare and has provided free dialysis for all its citizens since 1997.
The problem of health iniquity is not of course just limited to the developing world and is not just about the amount of money spent on healthcare but how it is spent. 16% of Americans have no health insurance resulting in an estimated 45,000 extra deaths a year and this is despite the US spending an astonishing 17.9% of its GDP on healthcare. Of course it is the poor who suffer with Hispanics and African-Americans being particularly affected. As I pointed out in an earlier blog, lack of funding for long term immunosuppression post-kidney transplantation in Medicare insured patients may partially explain the worse outcomes in those insured by Medicare. Similarly a recent small cohort study of African-American live kidney donors published in AJT showed that at nearly 7 years 15.5% had developed an eGFR<60mls/min/1.73m2 and 5.8% had microalbuminuria. Depressingly 52.4% of those donors that had developed hypertension remained untreated. Whilst these differences in outcomes amongst different racial groups effect in part genetic risk factors for disease, it is likely that access to care may also impact on outcomes. Similarly prior to he 'fistula-first' campaign, American dialysis patients were more likely to be subjected to an arteriovenous graft even though the outcomes were known to be worse with a graft, simply because reimbursement favoured the use of grafts.
I am fortunate to work in the UK where the NHS provides free healthcare for all, irrespective of their ability to pay. The NHS was founded in 1948 and was recently memorably celebrated by Danny Boyle in the opening ceremony of the London 2012 Olympics. Like the BBC and the Open University, the NHS is a brilliant, quintessentially British public institution. Of course it is not perfect and there have been issues with quality of care. Yet its strength is that it is valued, cherished and used by a broad swathe of society irrespective of socioeconomic class. It continues to develop with a relatively sophisticated primary healthcare system that is well placed to deal with the epidemic of non-communicable diseases and is widely recognised as being one of the most efficient, cost-effective healthcare systems in the world. It is worth noting that the inception of the NHS was bitterly opposed by medical organisations such as the BMA which worried about the impact of a publicly funded health system on the salary of doctors, prompting the then Health Secretary Nye Bevan to admit that to get the agreement of doctors he had to " stuff their mouths with gold!"
So while national societies and international organisations such as KDIGO and the ISN do great work to promote nephrology care worldwide it is important that we don't lose sight of the bigger picture - early detection of kidney disease and clinical guidelines count for nothing unless governments fund healthcare appropriately. At the moment governments in both the developing and developed world are getting this wrong and are simply not giving adequate priority to publicly funded healthcare and national and international nephrology societies need to start pushing hard on this issue. Universal access to high quality healthcare is a human right not a privilege - now that really is a message worth promoting on World Kidney Day
Bone disease post-transplantation remains a difficult clinical problem with an evidence base that can be difficult to interpret. In the landmark osteoporosis studies demonstrating benefit of bisphosphonates in the general population the sample size was huge (many RCTs with around 5000 subjects) in order to show a positive effect on patient fracture. Clearly such studies are not possible in the transplant population but several studies have shown significant loss of bone mineral density (BMD) particularly in the first 12-18 months after transplantation (1, 2). Furthermore bisphosphonates have been shown to significantly attenuate the decline in BMD in the early post-transplantation period (1, 2). Whilst BMD is accepted as a reasonable surrogate marker in the general population it cannot capture the qualitative changes in bone histomorphometry that characterise CKD-MBD and so may not be a particularly useful surrogate post transplantation. Crucially the 'standard care' aspect of management post-transplantation may impact on BMD loss and a few recent studies have highlighted this.
In a study from Norway, Smerud and colleagues allocated 129 patients to receive either ibandronate or standard treatment (calcium and calcitriol supplementation) (3). Lumbar spine BMD was increased at 12 months in both groups and the change in BMD did not significantly differ between the patients who received ibandronate therapy and those who received placebo. Ibandronate did improve femoral BMD but interestingly there was no statistically significant loss in BMD at the femur in the placebo group. Coco and colleagues randomised 42 live related transplant recipients to either risedronate or placebo and found no significant impact on BMD (4) - nor did they find any evidence of adynamic bone disease, which remains an important theoretical concern when giving bisphosphonates to patients with CKD. Thus the more recent studies of bisphosphonates tend to show lesser loss in BMD in the control arm than the earlier studies. This probably relates to the fact the cumulative steroid exposure is less in the current era and that treatment with calcitriol and calcium in itself has a beneficial effect on BMD.
So where does this leave us in practical terms? Well it seems reasonable to ensure that all transplant patients should be kept vitamin D replete and levels should be monitored in the first year post-transplantation. Whether BMD should be measured in all patients is difficult to know but it would certainly be sensible to do in all those who are maintained on steroids. Given the fact that there will never be an adequately powered RCT looking at fracture rates in the post-transplant period I suspect the best that centres can do is develop local protocols based on risk factors such as vitamin D and steroid exposure with active audit to determine the utility of such protocols. A very practical approach was proposed by Mainra and Elder in Sydney, Australia who have developed an individualised approach to bone loss that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment (5). In the absence of definitive evidence this kind of approach seems very pragmatic.
Again, this is discussed in a recent paper (http://dx.doi.org/10.1111/j.1532-5415.2012.04203.x) by Sabayan et al. This is an observational study of frail elderly 85-year-old followed up to age 90. The group in the higher tertile of systolic blood pressure (162-215 mmHg) had a better Mini-Mental status and lesser physical and cognitive decline.
It is not easy to draw conclusions from the study, once that could be a surviving population from cardiovascular events. Also, comorbidities, as heart failure, could explain the lower blood pressure on those with a worst evolution (systolic BP, 110-146). However, it raises more concerns about treating arterial hypertension in this population and again underlines the concept that blood pressure levels should be tailored for each individual. I guess that this findings would be similar if the authors looked at the renal function decline.
In the last week I have seen 2 patients who have had steroid resistant nephrotic syndrome due to minimal change disease. Both have had various immunosuppressives without success and have continued to have nephrotic range proteinura for 5 years. Despite this they both have normal kidney function!! Thus the obsession with microalbuminuria (MA) as a risk factor for progression in CKD is something I have always found puzzling. There has been a plethora of publications over the last 10 years focussing on the association between microalbuminuria (MA) and adverse renal and cardiovascular outcomes and its likely that MA identfcaton wll be central to the KDIGO approach to CKD. In simple terms there are two schools of thought as regards proteinuria and CKD:
1) proteinuria in itself is nephrotoxic (based predominantly on in vitro and in vivo studies showing evidence of inflammatory and fibrogenic effects on tubular epithelial cells) and cardiotoxic and so reducing proteinuria will positively impact on both cardiovascular and renal endpoints.
There is some interesting data published from Stevenage, England in this months cJASN describing differences in outcomes between patients on RRT and those opting Conservative Kidney Management (CKM). Observational data from the UK has already shown that in those elderly patients with significant co-morbidity RRT offers litlle survival advantage over CKM. Furthermore data from the Royal Free Hospital, London had suggested that much of the survival advantage that such comorbid patients get from RRT is at the price of days spent in hospital and the actual, 'hospital-free' days gained was marginal. Whats interesting about the current study is that it focuses on endpoints that matter to patients - namely objective quality of life measures using tools such as SF-36 and Hospital Anxiety and Depression Scale on a 3 monthly basis in a cochort of patients with CKD4/5. In their cohort of 170 patients 30 elected for CKM. Unsurprisingly these patients had more comorbidities and poorer functional status. Serial quality of life measures demonstrated no change from baseline EXCEPT a decline in life satisfaction associated with those starting dialysis. Median survival (after adjustment for comorbidity) was 13 months shorter in the CKM group.
Of course this data is observational and subject to signficant confounding bias but then there is never going to be an RCT comparing outcomes between RRT and CKM.
However it adds to what we already know - patients with poor functional status or comorbidity get little benefit from RRT either in terms of survival or quality of life. Making individual patient decisions about RRT is very difficult but in the UK, NHS kidney care have lauched an online decision aid to help patients make decisions about RRT ( see http://sdm.rightcare.nhs.uk/pda/established-kidney-failure/)... the decision aid incorporates the values and aspirations of individual patients to help them come to a decision and will hopefully help decision making in the UK.
Its important to bear in mind that this kind of data is almost certainly irrelevant for those practicing in emerging countries as the patient population and social care will be very different making it impossible to extrapolate such data to those countries. I am struck that in certain parts of the world there seem to be cultural barriers to CKM even though in selected cases it appears associated with a better quality of life and equivalent survival. The key here is to get *LOCAL* data starting probably with survival data for those starting RRT as accurate information is essential to help patients make decisions. Without that any discussions of the pros and cons of RRT are meaningless......
1. Quality of Life and Survival in Patients with Advanced Kidney Failure Managed Conservatively or by Dialysis. http://www.ncbi.nlm.nih.gov/pubmed/22956262> *Da Silva-Gane M*, Wellsted D, Greenshields H, Norton S, Chandna SM, Farrington K. Clin J Am Soc Nephrol. 2012 Dec; 7 (12) 2002-2009.
2. Is there a rationale for rationing chronic dialysis? A hospital based cohort study of factors affecting survival and morbidity. Chandna SM, Schulz J, Lawrence C, *Greenwood* RN, *Farrington K*. BMJ. 1999 Jan 23;318(7178):217-23.
3. Is maximum *conservative* management an equivalent treatment option to dialysis for elderly patients with significant comorbid disease?Carson RC, Juszczak M, Davenport A, *Burns A*.Clin J Am Soc Nephrol. 2009 Oct;4(10):1611-9.
4. Dialysis or not? A comparative survival study of patients over 75 years with chronic kidney disease stage Murtagh FE, Marsh JE, Donohoe P, *Ekbal NJ*, Sheerin NS, Harris FE. Nephrol Dial Transplant. 2007 Jul;22(7):1955-62.
5. Conservatively managed patients with stage 5 chronic kidney disease--outcomes from a single center experience.Ellam T, *El-Kossi M*, Prasanth KC, El-Nahas M, Khwaja A. QJM. 2009 Aug;102(8):547-54
The UK ADDITION study of value of screening for DM has reported its findings in the Lancet.
This was a clinic level cluster randomised trial.
>16,000 high risk individuals were screened in general practice in the UK between ages of 40-69 for type2 diabetes mellitus.
3% were found to have DM upon screening.
Follow-up of 10 years of these cohorts showed no difference in mortality between screening and control group.
Moratlity hazard ratios for death from CVD, cancer and diabetes did not differ either.
The study has not reproted on microvascular complications and their incidence.
The low prevalence of 3% of T2DM in this high risk population may be a reason why the overall impact of screening on mortality has been limited. In populations with higher prevalence of obesity and T2DM, screening of those at risk may prove cost-effective.
Also, screening may allow to detect early complications of T2DM such as renal, cardiovascular, neuropathic and ocular involvements. These may take more than 10 years to fully express their morbidity and the associated mortality. Early detection may impact on progression of microvascular complications and overall outcomes in the longer term. Such secondary prevention of complications have not been reported by the ADDITION study yet.
Ultimately, the issue of obesity and T2DM is a societal one and one that involves primary prevention. Here lifestyle changes are key to outcomes but implementation of societal lifestyle changes take much more that mere encouragement to eat well and excercise....!!! Also barriers for implementation of lifestyle and metformin treatment for prevention of T2DM has previously been discussed on OLA.
Finally, lifestyle changes require huge economical commitments from governments with changes in internal migration, westernisation as well as urbanisation. It also requires urban planning with changes in the configuration of our communities and cities...In the current financial climate of recession and austerity, governments have other priorities on their minds....
Interesting to read in the Lancet this week about New York city efforts to reduce NCDs:
As New York City Mayor Michael Bloomberg has noted, “while government action is not sufficient alone, it is nevertheless absolutely essential. There are powers only governments can exercise, policies only governments can mandate and enforce, and results only governments can achieve. To halt the worldwide epidemic of non-communicable diseases, governments at all levels must make healthy solutions the default social option. That is, ultimately, government’s highest duty.
LIFESTYLE CHANGES....EASIER SAID THAN DONE...AND SUSTAINED....SPECIALLY AMONGST THE MOST DEPRIVED!!!!
This is a post by Dr Pierre Delanaye posted on OLA French that I translated and share in view of its importance:
Biological variability and critical difference are concepts of clinical biology nephrologists often poorly familair with, but are essential for clinicians and clinical decision making.
Tolvaptan in Patients with Autosomal
Dominant Polycystic Kidney Disease
Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D.,
Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D.,
Jared J. Grantham, M.D., Eiji Higashihara, M.D., Ph.D., Ronald D. Perrone, M.D., Holly B. Krasa, M.S., John Ouyang, Ph.D., and Frank S. Czerwiec, M.D., Ph.D., for the TEMPO 3:4 Trial Investigators*
The course of autosomal dominant polycystic kidney disease (ADPKD) is often associ-
ated with pain, hypertension, and kidney failure. Preclinical studies indicated that
vasopressin V -receptor antagonists inhibit cyst growth and slow the decline of kidney
In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we ran- domly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V2-receptor antagonist, at the high- est of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.
Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow- up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (recip- rocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher dis- continuation rate (23%, vs. 14% in the placebo group).
Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercial- ization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.)
n engl j med nejm.org
The New England Journal of Medicine November 2012.
Very exciting and promising results on the slowing of the progression of ADPKD with preserved kidney function by a ADH V2 receptor antagonist; Tolavptan.
Previous interventions with mTOR antagonists (Sirolimus and Everolimus) have shown that kidney size increase can be pharmacologically manipulated, improved, in ADPKD. Tolvaptan is also effective in that respect.
However, the TEMPO study shows, that unlike mTOR antagonists, V2 blockage by Tolavptan can slow the progression of CKD in ADPKD.
Some reservations regarding the latter point:
1. The impact on kidney function was not a primary endpoint, so the study may not be fully powered to look at that variable?!
2. Glomerular filtration rate was NOT measured but instead calculated (eGFR). It was shown by Remuzzi and his colleagues that such analysis can be misleading in ADPKD :
3. The study was also conducted on ADPKD patients with normal kidney function where the estimated GFR tend to be at best inaccurate.
4. The effect of ADH antagonisms on tubular secretion of creatinine is unknown? Could the observed effect related to changes in tubular handling of creatinine rather than GFR. After all ADH impacts on tubular secretion of uric acid another OCT mediated tubular handled substance.
It is high time nephrologists and their sponsor who undertake multimillion pounds/dollars RCTs on CKD progression MEASURE CKD progression.....not serum creatinine!
Ian H. de Boer, MD, MS. JAMA. Published online October 30, 2012. doi:10.1001/jama.2012.30761
The problem with the above study is that underlying CVD, and in particular hypertension, are not factored in these analyses of hazard risk in relation to low eGFR and mortality. Hypertension, for example, is neither adequately diagnosed, treated or controlled worldwide; to take the US example, only around 60% of hypertensive individuals are treated....and 35% are controlled....as shown by Chobanian:
Furthermore, in most of the studies quoted in the above analysis, BP is seldom measured and when it is, it is not measured adequately. It is measured at the office and casually, measurements known to be of little correlation with CV outcomes and mortality. Night time, home and 24h ambulatory BP measurements are nowadays thought to be more predictive of CVD outcomes when compared to office BP monitoring.
So it is not surprising that older individuals with poorly treated and uncontrolled hypertension have a higher prevalence of target organ damage including CKD. It is also not surprising that they have a higher risk of CVD and related death.
So my take on this paper is that those older people who are at higher risk of death because of low eGFR, are at higher risk because low GFR is a MARKER of underlying CVD NOT a maker of risk....I would also argue that underlying CVD is not properly, if at all, assessed in these individuals.
When CVD risk is properly assessed the NIR (added predictive risk) of renal markers (eGFR and albuminuria) to the standard CVD risk markers is NIL... http://www.ncbi.nlm.nih.gov/pubmed?term=Chang%2C%20Kramer%2C%20Nephron
As to low level albuminuria, it is probably a reflection of underlying hypertension or diffuse vascular damage!
So once more, the authors do not seem to discern the fact that CKD most likely reflects underlying age-related atherosclerosis/CVD and hypertension (clinical or subclinical-diagnosed or undiagnosed) and therefore it is not surprising that older people with these abnormal markers have a higher mortality....!!!!!