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by Arif Khwaja - Wednesday, 26 December 2012, 11:18 PM
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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


[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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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 (12). 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.


1. Effect of ibandronate on bone loss and renal function after kidney transplantation. Grotz W et al. J Am Soc Nephrol. 2001 Jul;12(7):1530-7.

2.  Effect of pamidronate on bone loss after kidney transplantation: a randomized trial.Walsh SB et al. Am J Kidney Dis. 2009 May;53(5):856-65

3. A 1-Year Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Ibandronate on Bone Loss Following Renal Transplantation.Smerud KT et al. Am J Transplant. 2012 Dec;12(12):3316-3325.

4. Effect of risedronate on bone in renal transplant recipients.Coco M et al J Am Soc Nephrol. 2012 Aug;23(8):1426-37

5. Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation.Mainra R, Elder GJ. Clin J Am Soc Nephrol. 2010 Jan;5(1):117-24.


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by Arif Khwaja - Friday, 14 December 2012, 12:08 AM
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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.

2)  Proteinuria and MA simply reflecting underlying glomerular and endothelial 'health' and improved levels of proteinuria simply reflect improvements in underlying glomerular or vascular disease.
The Altitude study which was published in NEJM recently seriously questions whether strategies designed to improve proteinuria  per se can in themselves have any impact on cardiovascular and renal outcomes. The Altitude study is a large RCT of 8561 patients studying the impact of combining aliskiren (direct renin inhibitor) with an ACEi\ARB on a range of cardiorenal endpoints. Despite a significant reduction in proteinuria and blood pressure, Aliskiren combined with ACE\ARB had no positive effect on any cardio-renal endpoint. This fits in with data from previous interventional (not observational) studies suggesting a disconnect between MA reduction and cardio-renal outcomes. For example in the ROADMAP study of olmesartan in type 2 diabetes showed that despite reducing MA, olmesartan had no effect on cardiovascular morbidity, kidney function and there were significantly more deaths in the treatment group. Similarly the huge ACCOMPLISH study demonstrated significantly superior cardiovascular outcomes with benazepril combined with amlodipine when compared with benazepril combined with a thiazide in hypertensive patients at risk of cardiovascular disease - DESPITE  improved MA in the thiazide group..
Taken together the interventional (as opposed to the observational) data clearly shows that proteinuria and MA are little more than biomarkers for renal and cardiovascular disease. Attempts to target MA per se are futile and as a wise colleague of mine once said MA is little more than a urinary ESR......
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by Arif Khwaja - Tuesday, 11 December 2012, 6:00 PM
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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 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.> *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

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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In this month November 2012, AJKD:

Am J Kidney Dis. 2012 Nov;60(5):804-11. doi: 10.1053/j.ajkd.2012.06.017. Epub 2012 Jul 25.

Albuminuria, Estimated GFR, Traditional Risk Factors, and Incident Cardiovascular Disease: The PREVEND (Prevention of Renal and Vascular Endstage Disease) Study.


Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.



Abnormal levels of both albuminuria and estimated glomerular filtration rate (eGFR) have been reported separately to be associated with cardiovascular risk. This study assessed the contribution of each separately in correctly identifying individuals at cardiovascular risk in the general population beyond traditional risk markers.


Prospective community-based cohort study.


8,507 individuals from the city of Groningen in the Netherlands followed up for 10.5 years for cardiovascular morbidity and mortality.


The contribution of albuminuria and eGFR separately on top of the traditional Framingham risk factors was assessed.


The composite of first occurrence of myocardial infarction, stroke, ischemic heart disease, revascularization procedure, and all-cause mortality.


At the baseline visit, albuminuria was measured in 2 consecutive 24-hour urine samples. eGFR was calculated using the serum creatinine-based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.


In multivariable Cox regression models, albuminuria, but not eGFR, was associated independently with the primary study outcome (HR, 1.08 [95% CI, 1.04-1.12] per doubling of albuminuria). When added to the risk model consisting of Framingham risk factors, albuminuria significantly contributed to better risk stratification, shown by an increase in net reclassification index of 7.2% (95% CI, 3.3%-11.0%; P < 0.001) and increase in relative incremental discrimination improvement of 3.0% (95% CI, 0.9%-5.1%; P = 0.006).


The cohort includes mainly individuals of European ancestry. Therefore, results should not be extrapolated to other ethnicities.


In a general population cohort, albuminuria, but not eGFR, significantly adds to traditional cardiovascular risk factors in identifying individuals at risk of cardiovascular morbidity and all-cause mortality.



This very interesting piece of research from the PREVEND group shows what was suspected and alluded to by others

(Clase et al

and Chang & Kramer, 2010):

that eGFR doesnt improve the predictive value of a Framingham Risk Score (FRS) for CVD and related mortality. This supports what I have argued all along that low eGFR in the community reflects underlying atherosclerosis and ischemic renal damage most often associated with the ageing process.

and therefore it is not surprising that is predicts underlying CVD and their outcomes. CKD is in fact a target organ consequence of CVD. So no surprise that CKD predicts CVD and its outcomes but so does a good history taking, physical examination or a Vascular Risk Score like the FRS.

I argued the same for microalbuminuria; that it is merely a urinary reflection of ill health in the community. The Urine ESR or CRP.... This may also be attributable to age related atherosclerosis and vascular dysfunction. So it would not be suprising that a marker of CVD predicts overt CVD and its complications in the community!!!!

However, the study of Smink and Colleagues from Groningen seem ti imply that albuminuria adds to the predicitve value of the FRS. It improves the Net Reclassification Index (NRI) by 7.2%. Interestingly, it doesnt seem to improve the prediction of those who go on to experience an fact it worsens the FRS predictive value by -2.8% in those.....but it improves the predictive value of those who do NOT experience an event....So my reading would be FRS in the absence of albuminuria is good news!!!!! But adding albuminuria to FRS worsens rather than improve the FRS prediction model?????

So for people in the community at risk of CVD, the FRS is most accurate in predicting major CV events and associated mortality.

Neither eGFR nor Albuminuria improve its positive predictive value.

Take a good history and Examine your patients do derive a good prediction model of CVD and outcomes.

Neither eGFR or microalbuminuria add much to good clinical prediction models. On their own they are predicitive of CVD and related mortality as they reflect underlying CVD in communities, but when compared or added to strong and established CVD prediction models they add nothing or little....!!!!






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by Meguid El Nahas - Wednesday, 21 November 2012, 9:33 AM
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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.








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by Meguid El Nahas - Friday, 16 November 2012, 6:57 AM
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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.


Variability of a biomarker (eg serum Creatinine, or PTH) is the intra-individual coefficient of variation (CVi) without taking into account the analytical variability (due to imprécisison of the measurement = CVa). One could say that the CVi is the variability of a marker or a biological that is "normal" or physiological. It is determined by measuring from the same patients, for example, the marker at 1-week intervals for 6 weeks. The subject is compared each time itself.
The critical difference integrates the CVi and CVa and represents the change needed to be reached for the change in value in the same patient longitudinal monitoring to be considered significant. For example, with serum creatinine, it is around 10-15% (depending on the method used and its CVa). This means that for a given patient, if two successive values ​​of creatinine did not reach 15%, these results are in fact superimposable and "not different".
The critical difference for serum PTH as we have determined (publication pending) is 40-50%! which is huge. This means a difference of more than 50% between PTH values ​​for a patient to say that it has truly changed...!!!!
These concepts are important to grasp to assist with decision making when changes in a biomarker can trigger a clinical management decision.
+ See also the very interesting work of our English colleague EJ LAMB
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by Meguid El Nahas - Monday, 5 November 2012, 3:53 PM
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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 number, NCT00428948.)

n engl j med

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!





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by Meguid El Nahas - Thursday, 1 November 2012, 5:04 PM
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Chronic Kidney Disease—A Challenge for All Ages .

Ian H. de Boer, MD, MS. JAMA. Published online October 30, 2012. doi:10.1001/jama.2012.30761

Context:  Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.

Objective:  To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks.

Design, Setting, and Participants:  Individual-level meta-analysis including 2 051 244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years).

Main Outcome Measures:  Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.

Results:  Mortality (112 325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and ≥75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0-12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.

Conclusions:  Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.


The reported increased risk of mortality associated with low eGFR (<60ml/min) and albuminuria in all age group including the elderly is not surprising.

This is because older patients with low eGFR (<60ml/min) also have underlying CVD, clinically detectable or subclinically, as shown by Park and colleagues recently:

Otherwise, why on earth would an older patient have declining GFR without proteinuria?! The Baltimore Aging Longitudinal Study (BALS) study implied that those whose kidney function decline with age have co-morbidities most often hypertension. Lindeman et al.

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 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...

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....!!!!! 


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by Arif Khwaja - Saturday, 20 October 2012, 11:27 AM
Anyone in the world

Theres a very sensible article about how to use clinical practice guidelines (CPGs) in real world clinical settings in a recent KI. Radhakrishnan and Cattran argue very sensibly that CPGs are not diktats telling the clinician what to do in individual clinical situations but simply provide guidance to help the clinician make decisions.  They highlight how in a practical way one can use CPGs to inform decision making using real cases of patients with glomerular disease. Worth a read especially for those doctors who think guidelines should be /are prescriptive


The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines—application to the individual patient. Jai Radhakrishnan and Daniel C CattranKidney International (2012) 82, 840–856; doi:10.1038/ki.2012.280

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