User blog: Meguid El Nahas

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by Meguid El Nahas - Thursday, 15 December 2011, 10:56 AM
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A number of publications have recently linked AKI to the development or progression of CKD.

In the November issue of cJASN:

Thakar et al as well as an editorial on the topic highlight this important issue.

Thakar and colleagues report the increased incidence of CKD in elderly diabetics who develop one or more episodes of AKI.

This publication along with another 5 reviewed in the editorial by Bydash and Ishani stress teh association between AKI and CKD.

In the Thankar et al paper, elderly diabetics with CKD3 and significant proteinuria were at the highest risk.

I ask myself, what do T2DM, with CKD and heavy proteinuria have in common?

The answer is the "Elephant in the Room" that everybody chooses to ignore... INHIBITION OF THE RAAS!!!

So I suspect that these older diabetics with CKD3 ar eall on the dreaded ACE inhibitors, ARBs or a combination of both when in reality they have significant underlying atherosclerosis, CAD  as well as peripheral vascular disease; also most likely to be suffering from atherosclerotic renovascular disease and ischemic nephropathy.

I therefore urge the authors of these publications to examine the medication these patients are on and the relationship between RAAS inhibitors and the development of AKI/CKD.

Also, I urge Nephrologists to spare their older patients with T2DM and atherosclerotic manifestations (that most have) the use of inhibitors of the renin angiotensin aldosterone system (RAAS). These are often immediately detrimental to these patients kidney function. They may also accelerate the decline of kidney function as shown many years ago by Suissa and colleagues in Canada and by Onuigbo and colleagues in the US.

BUT also, they may constitute an added risk to elderly patients who have an AKI insult thus further compromising their acute insult and further compromising their pre-existent CKD.

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by Meguid El Nahas - Saturday, 26 November 2011, 8:10 PM
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In an editorial comment on the article appearing this month in NDT: Rajan T, Barbour SJ, White CT, Levin A. Low birth weight and nephron mass as a role in the progression of chronic kidney disease: a case report on identical twins with Alport disease.Nephrol Dial Transplant. 2011 May 12. [Epub ahead of print].

I highlighted that although identical twins sharing the same genotype share the same predisposition to nephropathies, that the course of a given nephropathy can vary due to the superimposed environmental factors including the severity of hypertension, its impact on proteinuria, smoking and compliance.

Genetic background impacts on susceptibility to diseases including CKD, but additional hits are needed to trigger and progress the disease. The article published this month in NDT describing the difference course of two identical twins affecetd by Alport's disease makes this point. The authors attributed the different CKD outcome in the two brothers to differences in birth weight with a disadvantage in the twin born with a low birth weight (LBW). I begged to differ...!!!! 

 

In conclusion, as far as the progression of CKD in these two twins is concerned, the devil is in the details . . . or should I say the devil is in the confounders . . . LBW  may have been one of the determinants, but others, possibly related or unrelated, such as hypertension, its control and treatment and albuminuria may have had the overwhelming impact on the observed differences in CKD progression. Nature provides good experiments, but life’s confounders make such experiments often less than perfect. Perhaps nature is not perfect or understandable after all!

El Nahas Meguid. Twins and CKD: confounding nature’s experiments! NDT November 2011.

Read full article in OLA's library

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by Meguid El Nahas - Thursday, 10 November 2011, 10:32 AM
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Control of Blood Pressure in Chronic Kidney Disease: How Low to Go?
Anadil Faqah, Tazeen H. Jafar. Nephron Clin Pract 2011;119:c324-c332 (DOI: 10.1159/000331066)

My comments:

The minireview by A. Faqah and T.H. Jafar exposes the issues related to BP target values in CKD. Numerous statements suggested that the lower the BP, the slower the progression of CKD. A number of guidelines have stipulated target values around 130/80 mm Hg and even lower in patients with diabetes and those with proteinuria. The evidence upon which these guidelines were based relied primarily on observational data as well as secondary or post hoc analyses of clinical trials and systematic and meta-analyses of heterogeneous data. This review exposes the weakness of such evidence. As so often in nephrology, evidence is gathered from observational studies that remain unsubstantiated by subsequent attempts at confirmation by RCTs. So often in nephrology, evidence is sought from secondary and post hoc analyses not intended or powered to answer the question raised...! So often in nephrology, dogma prevails enforced by unsubstantiated guidelines...!

Most RCTs mentioned in the review that attempted to answer whether intensive BP control is beneficial in slowing the progression of CKD failed to show a significant difference in renal functional outcomes. Furthermore, concern about harm has been raised in those submitted to intensive treatment with increased morbidity and mortality.

Finally, the assumption that one size fits all with target systolic levels of <130 or 120 mm Hg is preposterous. Age, race and comorbidities may dictate different target levels. This is becoming apparent in patients on hemodialysis where older and diabetic individuals had higher mortality rates at lower (<140/70 mm Hg) BP levels. More remarkable was the observation in this cohort analysis that survival did not seem to be harmed by higher systolic and diastolic values [1]. In conclusion, it is high time that BP-related guidelines in CKD are reviewed; this is currently underway by KDIGO. It is also high time that nephrologists base their practice on substantiated guidelines.... It is also high time that nephrologists critically appraise the data submitted to them by ‘experts’ and refute assertions based on secondary and post hoc analyses as weak at best. We have a long way to go!

Reference 1.

Myers OB, Adams C, Rohrscheib MR, Servilla KS, Miskulin D, Bedrick EJ, Zager PG: Age, race, diabetes, blood pressure, and mortality among hemodialysis patients. J Am Soc Nephrol 2010;21:1970–1978.


 

 

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by Meguid El Nahas - Tuesday, 8 November 2011, 9:13 AM
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A recent article by Chan et al (KI November 2011) review the outcome of >22,000 Chronic hemodialysis (CHD) patients and examine their survival and the impact of use of ACEi, ARB or a combination of both.

It concludes that the combination of an ACEi + ARB increases the risk of death. This combination was associated with the highest risk of CVD and all-cause mortality.

This observation goes along that of ONTARGET in patients with DM and high CVD risk.

These observations undoubtedely lead to caution in the overzealous use of such combination all the more so since there is little if NO evidence of an additional advantage of combining these agents in CKD.

The mechanisms of such increased mortality on CHD are potentially many:

1. Increased hyperkalemia with rapid and dramatic changes in potassium levels on HD and increased related mortality.

2. Overzealous reduction in BD, that may be detrimental in older patients on HD; recent observations suggest that lowewring BP below 140/90mmHg in HD patients is associated in certain subgroups( Older and diabetics) with increased mortality, Myers O et al. JASN 2010.

 

Myers OBAdams CRohrscheib MRServilla KSMiskulin DBedrick EJZager PG. Age, race, diabetes, blood pressure, and mortality among hemodialysis patients.J Am Soc Nephrol. 2010 Nov;21(11):1970-8. Epub 2010 Oct 14.
 
3. An editorial in the same issue of KI argues that such a combiantion would increase the potential toxicity of Renin and the pro-renin receptor (PRR). This is a more esoteric explanation, that could be considered when the more likely explanations (1 and 2) could be ruled out or controlled for in a RCT.
 
The authors, Chan and colleagues, acknowledge the limitations of their retrosepctive observation, including the confounding by indication, and suggest that a RCT would be necessary. I very much doubt that we will ever see a RCT exposing CHD patients to a potentially dangerous and unjustfiable combination of agents.
 
 

 

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A recent article by Kim et al from the Hammersmith Hospital Renal unit in London, UK (KI 2011;80:851-860) suggests that short term Vitamin D (Cholecalciferol) supplementation of patients with CKD 2-4 due to diabetic nephropathy (T2DM) decreases albuminuria (overt 2-4months).

This observation supports the VITAL study data in T2DM whose albuminuria (ACR) decreased, albeit marginally, upon treatment with a vitamin D analogue: paricalcitol. It also supports recent observations made in Asia in IgA nephropathy.

Whilst all these studies are open label proof of concept and hypothesis generating studies, they are consistent and somewhat encouraging.

 Until one realises, that Albuminuria is estimated bu urinary albumin:creatinien ratio (ACR); in other words the intervention effect lowering ACR could be EITHER due to a decreased urinary ALBUMIN excretion

OR an increased urinary CREATININE excretion

The authors seem oblivious to the effects of vitamin D supplementation on muscle structure and function. Furthermore, they seem to ignore the effect of vitamin D supplementation on creatinine generation, increased serum creatinine levels and subsequently the urinary excretion of creatinine! This in spite of a large body of data relating to this subject with emphasis in some publications on Asian and Vegetarian populations. An increased urinary creatinine excretion in this study is all the more likely since there was little change in urinay Ca:Cr ratio as one would expect Vitamin D supplementation to increase both...!!!

Once more, eminent and experienced nephrologists overlook the fact that measuring ACR is a measure of two variables and that a reduction of urianry ACR following a given intervention may eb due to either a fall in urinary albumin excretion OR an increased urinary creatinine excretion. 

Undoutedly, urine ACR is a convenient and easily measurable urine parameters as long as its limitations are known and its interpretation correct. 

An alternative interpretation of the Kim and colleagues study could be:

"Oral Cholecalciferol increases creatininuria in aptients with T2DM..." ?!

 

 

Agarwal RHynson JEHecht TJLight RPSinha AD.Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular filtration rate.Kidney Int. 2011 Jun 29. doi: 10.1038/ki.2011.207.

 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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In this month AJT:
Treatment of Kidney Transplant Recipients With ACEi/ARB and Risk of Respiratory Tract Cancer:
A Collaborative Transplant Study Report by G. Opelz and B. Dohler
 
Conclusion:
In patients with a history of smoking, however, the risk of respiratory/intrathoracic tumors was 2.77 (95% CI 1.19–6.43, p = 0.018) in
patients without ACEi/ARB treatment as compared to 7.10 (95% CI 3.27–15.4, p < 0.001) in patients treated with ACEi/ARB. Our data indicate that in kidney transplant recipients, ACEi/ARB treatment is associated with a significant increase in the rate of respiratory/intrathoracic tumors in the subpopulation of patients with a history of smoking. In non transplanted CKD, it had been argued that smokers benfit most of ACE inhibition in terms of slowing the progression of CKD.
 
Comments:
ACE inhibition has been promoted over the last 10 years as the optimal anti-hypertensive treatment for hypertensive recipients of renal allograft. This would have been all the more indicated in those with CAN with hypertension and proteinuria.
 
Now, the above cited publication based on a survey of  around 24,000 allograft recipients shows that those on ACEi/ARB are at considerably higher risk of intrathoracic and respiratory tumours specially if they were smokers. There was no significant increase in teh risk of other malignacies. The risk of developing respiratory malignancy was the highest in patients who continued to smoke.
 
This study raises the questions of whether ACEi/ARB should be contraindicated in renal transplanted patients in particular those who smoked or continue to smoke?!
 
 
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by Meguid El Nahas - Tuesday, 11 October 2011, 7:36 PM
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Risk Profile in Chronic Kidney Disease Stage 3: Older versus Younger Patients (Natasha McIntyre and colleagues, Derby; Nephron Clin Pract 2011;119:c269-c276).

The authors studied 1,741 CKD3 participants and observed that subjects 75 years or older had a significantly lower eGFR than younger subjects and a higher risk profile characterised by greater albuminuria, more arterial stiffness and higher serum uric acid levels. They concluded that older subjects with CKD3 had a higher risk profile for CKD progression and cardiovascular events than younger patients. Such an observation highlights once more that CKD in the older population is a manifestation of a systematic cardiovascular disease involving most vascular beds including the kidneys. For more information about CKD and Aging see the Nephron Special Issue 2011 Aging and Chronic Kidney Disease edited by J.R. Glassock, Los Angeles, Calif., and D.G. Oreopoulos, Toronto

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by Meguid El Nahas - Tuesday, 11 October 2011, 3:31 PM
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Doubling of Serum Creatinine a Valid Clinical 'Hard' Endpoint in Clinical Nephrology Trials? (H.J. Lambers Heerspink and colleagues, Groningen and Sydney; Nephron Clin Pract 2011;119:c195-c199) The authors address the important issue of endpoints in clinical trials on CKD progression and examine the value of the commonly used endpoint, namely the doubling of serum creatinine. The review reminds the readers of the limitations of such a measurement as serum creatinine estimation in CKD can be affected by a number of factors including creatine/creatinine intake, metabolism, filtration and secretion. All too often changes in serum creatinine are solely equated with measured GFR! I remember all too well the plethora of clinical trials in the 1970s and 1980s that relied on changes/fall in serum creatinine levels to argue for a beneficial effect of low-protein diets on the progression of CKD, overlooking the impact of such diets of creatinine intake, metabolism and muscle mass. Unfortunately, these lessons have not been learned as serum creatinine, and derived GFR calculations continue to be used in large clinical trials to argue for a beneficial effect on GFR! Nephrologists have been criticized over the years for the quality of the clinical trials undertaken - all too often underpowered with inadequate sample size. This has been largely addressed over the last decade with larger trials. Nowadays, we could still be criticized for using inappropriate single or composite endpoints including serum creatinine measurements or derived eGFRs!

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by Meguid El Nahas - Tuesday, 11 October 2011, 8:19 AM
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The IMPACT study showed that a 200 day prophylaxis with valgancyclovir is superior to 100 day prophylaxis for CMV viremia and disease in renal allograft recipients.

One caveat to this study is the variable follow-up time in the two groups:
those treated for 100 days were followed up for 9months
Those treated for 200 days were followed up for 6 months
?!

Has this publication changed your practice?
 

 

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by Meguid El Nahas - Saturday, 8 October 2011, 2:30 PM
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I am currently on an academic visit in Tehran having conducted a Master Class on behalf of the Global Kidney Academy.

I took this opportunity to further familiarise mysef with the Iranian Transplantation model.

I was most impressed with the efforts made by the National Transplantation team at the Tissue Bank of the National Renal Centre under the leadership of Professor Mitra Mahdavi-Mazdeh to promote Brain Death Donations (BDD). It is remarkable that in excess of 20% of all renal transplants now undertaken in Iran are from cadaveric donors. This growing program warrants recognition and support.

The Iranian unrelated living donor transplantation program, inspite of its limitations, has allowed thousands of ESRD patients to be transplanted in this country. Opinions are divided on its merits but we should all have open minds when it comes to saving ESRD lives and providing them with improved outcomes after renal transplantation.

More debate is warranted on the optimisation of organ donation in emerging countries.

 

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