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What did I learn?

Dr Amy Jane McKnight (Winner of Raine Prize 2012):

Genetics of CKD and DN.

Identified an important genetic association between risk of Diabetic nephropathy, progression as well as tubulointerstitial fibrosis with mutations of the AFF3 gene. AFF proteins are localized in the nucleus and play a role as transcriptional activators with a positive action on RNA elongation and processing of RNA.

She also identified mutations of Haplogroup I on the Y chromosome to be associtaed with CKD as well as CVD in white europeans.

She stressed the potential for changes in DNA methylation on the Y chromosome in the predisposition to CKD.

Prof Jeremy Hughes (Edinburgh):

Gave an excellent talk on experimental ageing.

He highlighted the role of the RAAS in ageing; RAAS inhibition prolongs life span in rodents.

Mitochondrial RAS is mainly directed to the beneficial AT2R during early life and switch to AT1R with ageing. AT1R is linked to the generation of reactive oxygen species (ROS) and tissue damage. RAS blockade decrease ROS generation by mitochondria.

Prof Tom Kirkwood (Professor of ageing in Newcastle):

Reminded us that ageing is a human phenomenon, most other spoecies die before they get too old, excpet man who nowadays lives much longer without the genetic apparatus to prevent ageing. Humans dont have a genetic program for ageing, instead ageing is the direct results of cumulative daily genetic damage. Ageing is caused by damage in the absence of a genetic repair machinery.

Ageing is theresult of random molecular and gentic damage. Consequently, to this daily and random genetic mutations, none of the 100x100million cells in humans are alike as not two cells have the same genome due to endless somatic mutations. Also mtochondrial mutations increase with ageing.

No evidence that calorie restrictions prolongs lifespan in humans in spite of considerable data in rodents but conflicting data in non human primates.

Excercise prolongs lifespan...

Prof Jurgen Floege (Germany):

gave a lecture on vascular calcification in CKD.

Highlighted the protective role of matrix Gla protein (MGP). Warfarin decreases its levels and accelerates vasculkar calcifications.

He argued that Warfarin should not be used in ESRD patients as it often underly lifethreatening calciphylaxis.

He also argues that Vitamin K1 and K2 supplement may be protective against vascular calcification in ESRD. Vitamin K2 attenuates warfarin-induced vascular calcification in experimental models.





[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Arif Khwaja - Saturday, 9 June 2012, 8:21 AM
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So Amgen have posted a press release outlining the results of the EVOLVE study looking at the impact of cinacalcet on death and cardiovascular events in a huge study of over 3000 patients. There was NO effect on mortality or cardiovascular events. Obviously we need to wait for more data but this is yet another negative trial in a dialysis population.  A couple of thoughts come to mind:

1) Amgen actually should be congratulated for investing in the trial but this may well be the last trial of this size we see in a dialysis population - the chances of a 'magic bullet' reducing mortality in a population as complex and diverse as a dialysis population are slim and pharma are unlikely to take the risk....

2) In retrospect a perhaps more modest trial focussing on fractures and cost-effectiveness may have been more useful to practicing nephrologists. In a population where the death rate is high, from multiple aetiologies perhaps we need to start looking at the impact of multiple interventions rather than single interventions.

3) Cinacalcet is an extremely expensive drug.  Whilst there is data on the cost effectiveness of the drug it's rather weak. For those of us who work in an environment where cost is an issue need to think again about who gets the drug..... Or we could hope that in light of this data Amgen could re-evaluate the price of the drug!!!



[ Modified: Thursday, 1 January 1970, 1:00 AM ]
Anyone in the world

The review by Ingelfinger and Nuyt [1] examines current data related to the birth weight hypothesis (that alterations in the intrauterine environment resulting in low birth weight program the individual for future cardiovascular and metabolic disorders).

The authors provide a focused review on plausible mechanisms including environmental and epigenetic forces that may interact in fetal and perinatal development periods with potential longstanding cardiovascular and renal consequences.   

In the 1980s, epidemiologic data by Professor David Barker in which an association was observed between birth weight, as well as placental size, and subsequent cardiovascular disease led to the understanding that the perinatal environment was important in the risk of future disease [2].

The data mesh well with the hypothesis put forth nearly concomitantly by Brenner and colleagues, who hypothesized that the final number of nephrons, which is fixed by term birth in humans, might explain subsequent hypertension and chronic kidney disease [3].

PHENOTYPIC INDUCTION was later suggested as a better term for the subtle changes that occur in the perinatal period but have long-ranging effects, a label that may better combine the various forces at work—both environmental and epigenetic that lead to time-spanning changes in the individual.

Nephrogenesis and renal vascularization are intimately linked. Both glomerular and tubular epithelia are induced by the ureteric bud, with a condensation of mesenchymal cells, which ultimately develop into glomeruli. Concomitantly, the vasculature develops, and if coordination is not synchronized, the kidneys are markedly abnormal.

Many strategies have been employed to examine the impact of challenges to the maternal-fetal environment including: total caloric restriction, low-protein diet, high-fat diet, vitamin A and D deficiencies, high-salt diet, ethanol exposure, trace metal deficiencies, and glucocorticoid exposure or interruption to endogenous glucocorticoids.

I.   Both experimental models and epidemiologic data suggest that intrauterine events can affect both VASCULOGENESIS and ENDOTHELIAL FUNCTION, as well as vascular wall structure. Both endothelium-independent and-dependent vasodilatation (well-recognized precursors of hypertension and atherosclerosis) may be impaired in low-birth weight infants and may persist to adult life. Low birth weight and premature birth are associated with increased arterial stiffness (relatively increased collagen and reduced elastin content) when tested later as adults (key factor in increased systolic and pulse pressure) Elastin synthesis in vessels peaks in late gestation, decreases rapidly after birth, and is minimal in the adult aorta.

II.   The inverse relationship between BIRTH WEIGHT and blood pressure is not present during the neonatal period or very early childhood, but it has been reported from the age of 4 and appears to increase with age.

In a study of 430 Swedish men, aged 49 years, the authors estimated that every additional week of gestation achieved before birth was associated with a decrease in adult systolic blood pressure of 7.2 mm Hg [4].   Interestingly, in many studies, IUGR participants do not seem to differ from those who were born at an appropriate size for gestational age, within both the premature and term groups, suggesting that preterm birth per se plays an important role in the programming of later-life cardiovascular function.

III.   Growing evidence suggests that EPIGENETIC MODIFICATIONS might explain many of the changes noted in perinatal programming. Epigenetic changes consist of modifications to nucleic acids that do not change the sequence of base pairs. Such changes consist mainly of chemical reactions e.g. methylation, phosphorylation, etc.

In a series of experiments in a rat model, Vaiman and colleagues examined epigenetic regulators, imprinted genes, and chromosome- specific alterations of gene expression and concluded that many alterations would be permanent, affecting organ function well into adult life.  In general, organs that develop function late are affected more severely than are those that function early. For example, the kidney would be more markedly affected than the heart [5].

In immature newborns, exposure to supplemental oxygen can halt microvessel growth in the lung and retina, leading to serious short-term complications such as bronchopulmonary dysplasia and retinopathy of prematurity. The possible long-term consequences of early-life vascular OXIDATIVE INJURY in susceptible individuals are only starting to be explored, and experimental data indicate a premature arrest in cell proliferation in developing organs with accelerated differentiation and oxidative DNA damage.


Evidence so far indicate that enhancing vasculogenesis postnatally can be promoted by exercise with significant increase in  the number of circulating progenitor cells. Therefore, the common sense healthy life habits (limiting calories and regular exercise) can be particularly critical for the significant proportion of children and adults who were born with low birth weight or prematurely.

Practical means of assessing VASCULAR AND NEPHRON ENDOWMENT during early infancy in humans are still needed to identify infants at risk of developing HTN and renal disease as adults!


1. Ingelfinger JR, Nuyt AM. Impact of Fetal Programming, Birth Weight, and Infant Feeding on Later Hypertension. J Clin Hypertens (Greenwich). 2012 Jun;14(6):365-71.

2. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986;1:1077–1081.

3. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure.Less of one, more the other? Am J Hypertens. 1988;1:335–347.

4. Siewert-Delle A, Ljungman S. The impact of birth weight and gestational age on blood pressure in adult life: a population-based study of 49-year-old men. Am J Hypertens. 1998;11:946–953.

5. Vaiman D, Gascoin-Lachambre G, Boubred F, et al. The intensity of IUGR-induced transriptome deregulations is inversely correlated with onset of organ function in a rat model. PLoS One. 2011;6:e21222.


[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Arif Khwaja - Friday, 8 June 2012, 8:26 AM
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There is a nice debate in this months JASN between Rifkin and Hsu about whether AKI leads to CKD. This is timely as the recent KDIGO guidelines have suggested that AKI be considered a risk factor for CKD - the logical implication of this being that all patients with AKI (including those who have completely 'recovered') be monitored for life for CKD. Rifkin and colleagues pint out that whilst its certainly biologically plausible for AKI to lead to CKD, there may be common risk factors of kidney injury that independently predispose to both AKI or CKD and furthermore its entirely plausible that CKD itself may predispose to AKI. In many ways I find the argument a bit sterile... have we not known for many years that if the AKI 'hit' is severe enough then people may be left with residual CKD whilst those wilth mild AKI appear to recover fully. As Rifkin and colleagues point out more than 500,000 AKI events occur in in the USA every year and the the vast majority recover without any significant longterm complication. The idea that all these patients need lifelong monitoring in case they get CKD is neither economically viable nor based on sound clinical judgement. An obviously pragmatic approach would be to monitor those who had severe or dialysis dependent AKI for a few years to see if CKD develops. In contrast its hard to believe that those whos have mild AKI that resolves quickly (with no comorbidity) will benefit from lifelong screening for CKD. Clearly longterm observational studies if AKI may help resolve this debate but in the meantime I suspect most nephrologist will be able to get buy just using clinical common sense....  

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Meguid El Nahas - Wednesday, 6 June 2012, 5:48 PM
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It is 30 years since we put forward the hypothesis that lipids were nephrotoxic and that dyslipidemia contributed to progressive CKD.

30 years on, a new era of APOL1-associated CKD suggest that a link may indeed exist between genetic mutations affecting HDL cholesterol concentrations and the pathogenesis of nephropathies as variants of ApoL1 proteins associate with circulating HDL.

The association between apoliporotein L1 (APOL1) gene mutations and CKD is becoming increasingly evident with APOL1 variants considered initiating factors for most hypertension-attributed nephropathies in African Americans (AA) as well as a spectrum of renal disease in hispanic as well as European Americans. Variations in APOL1 appears to be strongly associated with kidney disease historically labelled as hypertensive arterioslosclerosis in AA. 

It is intriguing to realise that APLO1, a disease associated gene, has persisted in AA. However, it is of interest to realise that one copy of the APOL1 G1 or G2 nephropathy risk variant confers protection from the deadly African Sleeping Sickness while not necessarily being associated with a nephropathy as for the latter to develop a second hit is often necessary. HIV infection is one of many such second hits initating APOL1-associated nephropathy in susceptible individuals with one or two gene variants.

Of interest, individuals with two APLO1 gene variants develop ESRD at a younger age than those with zero or one gene variants. A single gene variant, G1 but not G2, also leads to an earlier onset of ESRD albeit later than those with G1 and G2 variants. This may be due to the fact that tghose with 2 APLO1 gene variants progress to ESRD at a faster rate.

It is likely that the MYH9-APOL1 gene region on chromosome 22q contains additional risk loci that may be difficult to detect due to the high degrees of linkage desiquilibrium.

Clearly, a new era of understanding non diabetic glomerulosclerosis with APLO1-MYH9 genetic mutations providing suceptibility and second hits/modifiers genes leading to initiation and progression of CKD.

Perhaps, after all, we were right when in 1982, we suggested that lipo- and apo- lipoprotein abnormalities may underly the initiation and progression of CKD.



Moorhead JFChan MKEl-Nahas MVarghese Z.

Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease.

Lancet. 1982 Dec 11;2(8311):1309-11.

Kanji et al. genetic variations of APOOL1 associated with younger age at hemodialysis initation. JASN 2011; 22:2091-97.

Tzur et al. APOL1 allelic variants are associated with lower age at dialysis initiation...

NDT 2012; 27:1498-1505.








[ Modified: Thursday, 1 January 1970, 1:00 AM ]
Anyone in the world


Effect of Frequent or Extended Hemodialysis on Cardiovascular Parameters: A Meta-analysis

Paweena Susantitaphong, MD,1,2,3 Ioannis Koulouridis, MD,1,2 Ethan M. Balk, MD, MPH,2,4 Nicolaos E. Madias, MD,1,2 and Bertrand L. Jaber, MD, MS1,2

Background: Increased left ventricular (LV) mass is a risk factor for cardiovascular mortality in patients with chronic kidney failure. More frequent or extended hemodialysis (HD) has been hypothesized to have a beneficial effect on LV mass.

Study Design: Meta-analysis.

Setting & Population: MEDLINE literature search (inception to April 2011), Cochrane Central Register of Controlled Trials and using the search terms “short daily HD,” “daily HD,” “quotidian HD,” “frequent HD,” “intensive HD,” “nocturnal HD,” and “home HD.”

Selection Criteria for Studies: Single-arm cohort studies (with pre- and post-study evaluations) and trials examining the effect of frequent or extended HD on cardiac morphology and function and blood pressure parameters. Studies of hemofiltration, hemodiafiltration, and peritoneal dialysis were excluded.

Intervention: Frequent (2-8 hours,

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Meguid El Nahas - Wednesday, 30 May 2012, 10:38 AM
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Survival in Daily Home Hemodialysis and Matched Thrice-Weekly In-Center Hemodialysis Patients

Eric D. Weinhandl,* Jiannong Liu,* David T. Gilbertson,* Thomas J. Arneson,* and Allan J. Collins*†

*Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota; and †Department of Medicine, University of Minnesota, Minneapolis, Minnesota


Frequent hemodialysis improves cardiovascular surrogates and quality-of-life indicators, but its effect on survival remains unclear. We used a matched-cohort design to assess relative mortality in daily home hemodialysis and thrice-weekly in-center hemodialysis patients between 2005 and 2008. We matched 1873 home hemodialysis patients with 9365 in-center patients (i.e., 1:5 ratio) selected from the prevalent population in the US Renal Data System database. Matching variables included first date of follow-up, demographic characteristics, and measures of disease severity. The cumulative incidence of death was 19.2% and 21.7% in the home hemodialysis and in-center patients, respectively. In the intention-to-treat analysis, home hemodialysis associated with a 13% lower risk for all-cause mortality than in-center hemo- dialysis (hazard ratio [HR], 0.87; 95% confidence interval [95% CI], 0.78–0.97). Cause-specific mortality HRs were 0.92 (95% CI, 0.78–1.09) for cardiovascular disease, 1.13 (95% CI, 0.84–1.53) for infection, 0.63 (95% CI, 0.41–0.95) for cachexia/dialysis withdrawal, 1.06 (95% CI, 0.81–1.37) for other specified cause, and 0.59 (95% CI, 0.44–0.79) for unknown cause. Findings were similar using as-treated analyses. We did not detect statistically significant evidence of heterogeneity of treatment effects in subgroup analyses. In summary, these data suggest that relative to thrice-weekly in-center hemodialysis, daily home hemodialysis asso- ciates with modest improvements in survival. Continued surveillance should strengthen inference about causes of mortality and determine whether treatment effects are homogeneous throughout the dialysis population.

J Am Soc Nephrol 23: 895–904, 2012. doi: 10.1681/ASN.2011080761 


Once more, these authors, like those before them reporting on the Frequent HD Network, fail to consider the fact that perhaps the Frequent HD group had more HD (in terms of duration/hours per week and in terms of higher weekly KT/V).

Once more, the authors do not seem to distinguishe between Frequent HD and Longer HD.

The Tassin group implied 20 years ago that longer hours on HD per week was good for HD patients, now the whole bandwagon of Frequent HD is rolling without considering that the adequate control group should be:

Group A: Frequent HD

Group B: Thrice weekly HD, BUT with same duration of HD per week copmpared to group A.

That is the propensity analysis that these studies should undertake; comparing hours on HD not how frequent people get on the machine...

Then the modest difference will be even more modest...non-existent!

Even the editorial by David Wheeler doesnt seem to get the point of longer hours versus More Frequent; the FHN study was all about longer hours and better KT/V not too mention better ultrafiltration.

What do we expect the average reader to conclude if even the editorial board doesnt get it!

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Meguid El Nahas - Tuesday, 29 May 2012, 10:51 AM
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Rituximab, a chimeric monoclonal anti-CD20 antibody, has now been extensively used in the management of autoimmune diseases including SLE and lupus nephritis as well as AASV (ANCA associated systemic vasculitis).

Concern has been expressed about the association of immunosuppressants, including Rituximab, and the increased risk of Progressive multifocal leukoencephalopathy (PML). The signal and association with Rituximab is of concern and warrants vigilance.

Whilst rare, such an association may be overlooked when considering teh RISK:BENEFIT of rituximab in autoimmune renal disease. However, the devastating nature of PML warrants careful follow-up and vigilance. This, all the more, since the benefit of Rituximab in conditions such as LN (LUNAR study) and ANCA associated vasculitis (RAVE INT & RITUXIVAS studies) is not superior to current therapies!

A recent article in the NEJM, this month, also shows an increased risk of PML with another monoclonal antibody Natalizumab (anti-integrin a4), with increased risk in those who have a positive status in respect to anti-JC virus antibodies, prior use of immunosuppression and duration of treatment.

Perhaps, we should screen the patients we treat willi nilly with Rituximab.. for anti-JC (John Cunningham) antibodies?!

Perhaps, we should use  Rituximab less often when evidence supports its indication!?



[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Arif Khwaja - Monday, 28 May 2012, 7:45 PM
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Once I have had a chance to digest the KDIGO guidelines I will post some thoughts. I note there has been much interest on the KDIGO guidelines on this site. A few things caught my eye - like the suggestion for fish oils in IgA nephropathy. This is based on data by Donadio and colleagues showing a beneficial effect. This has never been reproduced anywhere else and the control group in that study did extraordinarily badly - around 40% ended up on  RRT. KDIGO not unreasonably suggest that fish oils are relatively safe and therefore make a 2D recommendation about their use.

In fact 36% of all the statements in the glomerulonephritis guidelines are 2D. And to remind ourselves what does 2D mean? Well '2' is a suggestion and '1' is a recommendation. D means that the quality of evidence that the suggestion is made is ' very low - the estimate of the effect is very uncertain and often will be far from the truth'  - to me 2D sounds a lot like opinion and theres nothing wrong with opinion but we need to recognise it as opinion and not fact. If we are going to get the most out of guidelines we need to learn how to read them or perhaps just have guidelines about things for which there is good evidence.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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ERA-EDTA Congress update: 
New discovery!
Searching for molecular mediators
N-acetyl-D-mannosamine could represent a new non immunosuppressive therapeutic agent in the treatment of minimal change nephropathy.

Minimal Change Disease (MCD), Despite being nearly a century old disease, the first molecular mediator behind the structural and functional changes in MCD was only recently discovered. Angiopoietin- like-4 (Angptl4), a glycoprotein secreted from podocytes in large amounts, is now shown to mediate most of the above mentioned characteristic features of MCD. This upregulation in podocytes is glucocorticoid sensitive, and declines with glucocortcoid treatment. it was shown that Angptl4 secreted from podocytes binds to the GBM and induces albuminuria even before the development of foot process effacement.

A precursor of sialic acid, N-acetyl-D-mannosamine (Man- NAc), leads to improved sialylation of podocyte-secreted Angptl4 and significantly reduced proteinuria. ManNAc is relatively non-toxic, and could represent a new non-immunosuppressive therapeutic agent in the treatment of MCD, if shown to be effective in future clinical trials. It is the first potential drug for MCD that primarily affects protein structure, and could be used alone or synergistically with glucocorticoids, that work at least partly by reducing Angptl4 gene upregulation in podocytes.

Treatment with ManNAc improves other parameters of nephrotic syndrome in PAN rats and also reduces proteinuria in Zucker diabetic fatty rats. One important characteristic of the podocyte that favors the further development of ManNAc as a novel therapeutic agent for nephrotic syndrome is its inability to divide. Since ManNAc crosses cell membranes easily and is also rapidly excreted in the urine after an oral or parenteral dose, it is most likely to accumulate in a non-dividing cell like the podocyte even at small doses without significant systemic effects in other organs composed primarily of dividing cells. 

In summary, the discovery of Angptl4 may lead the way to future therapeutic approaches for MCD.

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