User blog: Meguid El Nahas
When will nephrologists learn that estimated GFR (eGFR; estimated by the MDRD equation or any other equation) does NOT equate to measured GFR (mGFR) or even calculated GFR (cGFR = CrCl + Urea Cl : 2)?!
This month in NDT, an article by Evans et al from Middlesborough UK reports that Irbesartan delays the progression of nephropathy as measured by eGFR: A post hoc analysis of the IDNT trial.
Wow....some findings...so the data reported by IDNT in the NEJM in September 2001 relating to changes in serum creatinine levels...took 10 years to convert to eGFR.... and show...surprise, surprise...that Irbesartan slows the progression of T2Diabetic Nephropathy!!!!!
When will nephrologists learn that changes in serum creatinine and their beloved eGFR does NOT mean changes in TRUE GFR!?
In fact, the observed changes may well be due to changes in tubular sercretion of creatinine, known to be affected by RAAS inhibition and improved peri-tubular capillary circulation and proximal tubular Creatinine transport, known to be attenuated in DM.
When will nephrologists learn that changes in albuminuria are not solely the result of changes in glomerular loss of albumin?
In the report under discussion, Irbesartan decreased albuminuria, an effect somehow linked to improved outcome?!
Nephrologists need to remember that RAS inhibition also improves peritubular circulation and thus proximal tubukle reabsorption of albumin.
When will nephrologists learn:
That in RCT the progression of CKD and GFR have to be MEASURED not estimated by inappropriate derivative equations....?!
Susantitaphong and colleagues in Boston have published this month in the June issue of the AJKD a meta-analysis of 16 cohort studies and 1 RCT (n= 1,081,116) relating to impact of the level of GFR at initiation of RRT (HD or PD) on all-cause mortality.
The authors concluded that a higher ESTIMATED GFR (eGFR) was associated with HIGHER mortality.
On the other hand, in a subgroup analysis, higher CALCULATED GFR was associated with LOWER mortality.
Confused you may be...!!!!!
Well, this observation confirms impressions that GFR estimated (eGFR) by the MDRD equation is inaccurate in ESRD as the confounder of serum creatinine leads to this equation, as well as that of Cockcroft-Gault, being more a reflection of the clearance of endogenous creatinine rather than true GFR; clearance of endogenous creatinine is affected by GFR as well as muscle mass and tubular secretion of creatinine. Whilst the authors stress repeatedly that this observation was independent of nutritional parameters; this may reflect visceral nutritional markers such as serum albumin/protein and not necessarily markers of poor somatic nutritional status such as creatinine itself.
On the other hand, calculated GFR derived from a 24h urine collection and the derived mean of urea and creatinine clearances seems to be a better marker of true GFR that is less influenced by muscle mass. Higher calculated GFR, unlike estimated GFR, was in a subgroup analysis (486 patients) associated with LOWER mortality.
This is an important observation putting in context a number of publications on the topic of GFR and timing of RRT. It also warns nephrologists NOT to put too much emphasis on GFR estimation/calculation when deciding when to start RRT but instead use a more holistic approach to the patient and his clinical status as well as co-morbidities.
Lets move away as a profession from these artificial and meaningless equations and go back to the old fashion serum creatinine, serum urea, clinical examination as well as good clinical judgement.
After all we, as Nephrologists, are Physicians and not Mathematicians....
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.
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 JF, , , M.
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.
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 ClinicalTrials.gov 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,
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!
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!?
ERA-EDTA Congress update:
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.
Adam from Paris for GKA 2010
The Theme of this 1st Episode:
Back to Old drugs: Aza, MTx, Hydroxychlorquene.
Less Corticosteroids still do the same action with less S/Es.
Cr Nadir is earlier than Albumin one.
Date: Thursday May 24th 2012
08:30 - 12:30 CME Courses
Rheumatology for nephrologists 46
Peritoneal Dialysis Workshop 47
Title: Rheumatology for nephrologists
Chair: Hans-Joachim Anders, Munich, Germany
David Jayne, Cambridge, UK
i. Welcome and introduction
Hans-Joachim Anders, Munich, Germany
David Jayne, Cambridge, UK
ii. Joint pain in CKD patients: When do we need a joint aspirate?
Hendrik Schulze-Koops, Munich, Germany
1) Sodiumaurate Crystals in Gout is different that those of CPPD crystals in Pseudo gout which may occur in the dialysis population.
2) The Take Home message in unclear monoarthrits; Do Not Wait; and do Aspirate; however;
3) Synovial fluid aspirate is a sterile procedure; however; the risk of complication by sepsis is 1/10,000; which cost a famous German athelet his career by causing septic arthritis for a procedure which is considered in his case may not be justified.
iii. Proteinuria in the patient with arthritis
Volker Vielhauer, Munich, Germany
4) Proteinuria in patients with arthritis include these following 5 main Topics: either Association, Complication, Manifestation, Toxicity and the fifth and the Last but not the least is Co-morbidity.
5) This need Reply: A 34 yrs old male diagnosed as Behcet and was on CsA and CS. Developed proteinuria 2.8 g/24hrs, Cr 88um/L, with Dysmorphic RBCs, Hence referred to the Nephrologist; with a Bx showed IgA in A Behcet Disease with eGFR 60 ml, with no Cresents and no Fibrosis. How to manage? Opinions so to tell you what happen and what they did?
6) Assoicated Renal Disease in Behcet include mainly Amyloidosis 69/156, and GN in 51/152 cases. IgA deposition was found in 22% of GN with Behcet.
7) Associated Renal Disease in RA include: Mesangial GN 40/110, Renal Amyloidosis 33/110 and MN 19/110 cases.
8) The 2012 “standard of care” in lupus nephritis – referral,
drugs and monitoring
Frédéric A. Houssiau, Brussels, Belgium
8) LN is a very heterogenous disease which varies from single shot, or relapsing 1/3 or refractory 1/5 of the cases.
9) Poor prognostic factors include many; but on the top of the lists are Race (AA), non-observance to Rx, Absence of primary response to IS.
10) Poor prognostic factors in the pathology; beyond Roman numerals include fibrinoid necrosis, partial cresents and circumferential cresents.
11) Renal Bx is not a routine procedure in all SLE patients. However; Low C3, High Anti-DNA, or renal involvements include Pr > 0.5 g/24hrs and/or Active sediment are red flagged.
12) You may need Renal Bx so as not to miss APL-related Disease.
13) Which LN patients should be immunosuppressed? Class I, II NO ---, III & IV (both have Endo/extra capillary cellularity and sub-endo ID: YES ---, V in Selected Cases. However; wait for
my 2nd Episode from the EDTA concerning ISN/RPS 2003 Classification for more Info and critic by Ian Roberts.
14) LN: Towards no Steroid regimen? By Imperial College of Kidney and Tx Institute in London UK; by Liz Lighstone et al. Giving on Day 1 and 15th : 500 mg MPS + 1g RTx. Then only use MMF with no steroids. Claiming optimal renal protection.
15) Euro Lupus Nephritis Trial showed LD is equivalent to HD of CYP for induction in LN.
16) The cost of MMF is more than 10 times that of CYP for induction of Rx in LN.
17) Both AZA and MMF have similar effect as maintenance Rx for LN as proved by two trials ALMS (David Wafsy; especially if the two arms were induction with IV CYP) and MAINTAIN.
18) Never forget Plaquanil (Hydrochlorequene) in LN not only in SLE. Nephrologists are reluctant to consider it.
19) This need Reply: A Pregnant Lady with Acute flare of SLE; which IS Rx you recommend? Either with or without LN? and Do you recommend Abortion to save the mother from being ESRD or more complication?
v. Non-renal flares in lupus nephritis patients – new options
Falk Hiepe, Berlin, Germany
20) Bortezomib can cause clinical improvement in severe and refractoy SLE. This proteasome inhibition markedly reduced plasmablasts and plasma cells from the peripheral blood and bone marrow.
David Jayne, Cambridge, UK
viii. ANCA-associated vasculitis - an update on therapeutic
Alan Salama, London, UK
Wait for my 2nd Episode of the Pathology.
The Theme is:
New Pathological Dx with still invalid clinical Significance.
Recent pathological classification of LN 2003 are more confusing than older one and may be wrong.
Criteriae necessary for Dx may not be necessary anymore. (ABMR with C4d –ve).
Wait for my 3rd Episode of the Opening Cermony and Pioneers in European Nephrology .
The Theme is:
There are two "REFRAINS" in the opening Cermony: Continuity and Memory.
Modesty and The Patient is what Kept the Pioneers so Pioneers.