User blog: Meguid El Nahas

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In this month Lancet, Zhang et al report a cross-sectional analysis of CKD in China and conclude that 10.8% of the population has CKD; eGFR<60 = 1.7% and Albuminuria (ACR) = 9.4%.

As it is published in the Lancet, I assumed it was a well conducted analysis and became concerned that 119.5 million chinese suffer from CKD!

I was totally wrong on two accounts:

1. Publishing in the Lancet does not garantee quality

2. The study is badly conducted.

Major criticism:

1. A cross-sectional survey of a chronic disease is a contradiction in terms; testing 1x does NOT define CKD according to the current KDOQI definition requiring 2 of 3 positive tests over a period of 3 months....the authors and reviewers seem to have overlook this small fact, although it is mentioned in the discussion....!

2. Urine ACR is as much a marker of raised albuminuria than low creatininuria; malnourished rural chinese are likely to suffer from the latter rathen than the former...

3. A number of studies including our own show that repeat albuminuria testing leads to a steady decline in prevalence; the authors should have re-tested!  They should also b eaware that microalbuminuria is an acute phase abnormality that regresses with an infection or inflammation subsides! Re-testing is essential!

3. Hypertension is common in China 27-43% and poorly controlled and is a major cause of albuminuria in that study...

4. So what we have is a publication on the high prevalence of hypertension in China with consequent albuminuria if albuminuria exists at all in this sample size... and the answer is:

Perhaps the CKD epidemic in China is easily reversible and curable as one expects albuminuria to regress with control of hypertension.

This article should have been entitled: Uncontroilled hypertension in China as a cause of albuminuria!

This article will be undoubtedly quoted repeatedly byu those on the bandwagon of the "CKD epidemic..."; here in OLA we got off this bandwagon a long time ago when we realised how poor research in this field was. This recent publication reinfoces our conviction! 

 

Reference:

Zhang et al. Prevalence of chronic kidney disease in China: a cross-sectional analysis. Lancet 2012;379:815-822.

 

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by Meguid El Nahas - Tuesday, 28 February 2012, 6:15 PM
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In this month issue of Nephron: Garcia  /Harden  /Chapman: The Global Role of Kidney Transplantation:

This review raises important issues and in particular the fate of those suffering from ESRD in Emerging countries. Limited healthcare and Nephrological resources makes long term renal replacement therapy by dialysis unavailable. Transplantation is often the sole option for those at risk of death due to ESRD. This year’s WKD raises issues related to transplantation in emerging countries including major and justifiable concern over organ commercialisation.

The authors state: “There remain major challenges to providing optimal treatment for ESRD worldwide and a need, particularly in low income economies, to mandate more focus on community screening and implementation of simple measures to minimize progression of CKD”

Whilst Detection and Prevention of CKD is a healthcare priority worldwide, general population screening is unlikely to be a universal option and targeted screening is likely to be more beneficial and cost/effective. Screening should focus on the two main causes of CKD: Diabetes and Hypertension! Most hypertensive individuals and those suffering from diabetes are often diagnosed very late in emerging countries and poorly controlled hence a higher rate of cardiovascular complication including CKD.

Also, it is important not to overlook the fact that the majority of those reaching ESRD in Emerging countries are seen within 90 days or less from starting RRT; Emphasis should therefore be on timely referral of those suffering from CKD to Nephrologists. Perhaps, screening and appropriate referral of those suffering from CKD3 should also be a priority.

  The authors state: “The recent  designation of renal disease as an important non-communicable disease at the UN High Level Meeting on NCDs is one step in this direction. But early detection and prevention programs will never prevent ESRD in everyone with CKD, and kidney transplantation is an essential, viable, cost-effective and life-saving therapy which should be equally available to all people in need. It may be the only tenable long-term treatment option for ESRD  in  low-income  countries  since  it  is  both  cheaper and provides a better outcome for patients than other treatment for ESRD”

Dialysis cost is unaffordable in Emerging countries and even in some developed countries where financial austerity and healthcare budget restrictions are a threat. So access to renal transplantation is an imperative but also post-transplant care provisions. Of note this is not even readily available some developed countries?!

The authors state: "The success of transplantation has not been delivered evenly across the world, and  substantial disparities still exist in access to transplantation, we remain troubled by commercialization of living donor transplantation and exploitation of vulnerable populations for profit."  

Commercialisation is unacceptable in healthcare. It is also a very emotive term. Organ exchange with incentives may be more acceptable and commonly practiced. Care has to be taken not to mix Western high ethical standards with the life of those deprived of dialysis and facing death unless they “find” a kidney. Ethics or Death can sometime clash…Most choose Life!

The authors state: "There are solutions available. These include demonstrably successful models of kidney transplant programs in many developing countries; growing availability of less expensive generic immunosuppressive agents; improved clinical training opportunities; governmental and professional guidelines legislating prohibition of commercialisation of transplantation."

Governments and legislation ban of organ exchanges for profit are fully justifiable but will only be effective if and when those Government and legislators offer alternative options for Life for those with ESRD. Until and unless this is made available to those dying from ESRD such legislation will only encourage and foster a growing black market in transplantation with dire consequences due to the worst possible medical practices. Government sponsored and organised organ exchange with incentives may be a viable alternative to ban!?

 

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A review article by McCaughan and Courtney in NDT January 2012 reviews the situation relating to the apparaent increased incidence of PJP recipients of renal allografts. A number of recent reproted outbreaks in renal transplant recipients have raised concern about adequacy of prophylaxis strategies.  In general it is considered that PJP prophylaxis is justified and should be considered if the risk of disease is estimated to exceed 3%. The incidence of PJP infections in moderately immunosuppressed renal transplant recipients is usually <1%. Six renal centres reporting outbraks in Asia and Europe have all adopted the surveillance rather than prophylaxis approach based on the above assumptions. However, it is important toi appreciate that the risk is higher in:

1. High risk patients

2. Higher immunosuppression including use of ATG

3. Frequent rejection episodes

4. CMV infections

Currernt guidelines recommend 3-6 month prophylaxis with septrin (trimethoprim-sulfamethoxazole) from the time of transplantation. These guidelines may warrant review as most recent outbreaks took place more than 6 months after transplantation.

Therefore in higher risk and susceptibe individuals, it would be advisable to continue prophylaxis until the immunosuppression burden can be reduced.

Routine prophylaxis for all may be justifiable.

Prolonged immunosuppression may also be justifiable specially in the days of ever more agressive immunosupressive therapies.

Nephrologists need to inform their decision based on:

What is the justification of the Intervention?

Who is most susceptible to PJP and warrants prophylaxis?

Risk: benefit analysis; Septrin is not without its risks and side effects and PJP can be fatal!

Cost: benefit analysis.

McCaughan JACourtney AEPneumocystis jiroveci pneumonia in renal transplantation: time to review our practice? Nephrol Dial Transplant. 2012 Jan;27(1):13-5. Epub 2011 Aug 3.

 

 

 

 

 

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The answer to this question is usually that ACE inhibitors and ARBs have a protective effect by slowing the progression of CKD.

Yet, in all studeis on inhibition of RAAS and CKD progression diabetic or otherwise, there hasn't been a single study that reported the impact of the intervention on GFR. Instead, all the studies on ACE inhibition and progression since that of Lewis et al in 1993 relied on surrogate markers of progression namely: serum creatinine, creatinine clearance, 1/Cr slopes against time or more recently estimatedGFR. Not a single study published to my knowledge solid data on the hard and relevant endpoint of measured GFR and changes with time???!!!!

Authors have overlooked that changes in serum creatinine and derived formulation can be due to one of 4 factors:

1. Impact on dietary intake of amino acids or creatine

2. Creatine/Creatinine metabolism

3. GFR

4. Tubular secretion

So changes upon ACE inhibition in serum creatinine could be due to any one of these 4 confounders; yet nobody seems to take that into consideration and equate changes in serum creatinine to changes in GFR only....Why I ask myself this oversight????

This, in spite of evidence to suggest that inhibition of the RAAS system impacts on :

1. Efferent arterioles; leading to vasodialtation

2. Increased peritubular capillary circulation secondary to improved efferent arteriolar blood flow

3. Increased tubular secretion of creatinine either indirectly through 1 and 2 or directly through an increase in its organic cationic transporters (OCT1 and 2) that affect creatinine secretion by the proximal tubules (ref 1,2).

In conclusion, the oberved effect of RAA system inhibition of the rate of decline of serum creatinine may be simply the reflection of increased tubular secretion of creatinine rather than anything to do with prevention of GFR decline as the latter has never been measured!? Clearly, this is a hypothesis as much as the assumption that inhibition of RAAS slows the decline of true GFR!

Isnt it intriguing that investigators studying the progression of CKD never reported measured changes in GFR....I wonder why????

References

1. Thomas MCTikellis CBurns WCThallas VForbes JMCao ZOsicka TMRusso LMJerums GGhabrial HCooper ME,Kantharidis PReduced tubular cation transport in diabetes: prevented by ACE inhibition.Kidney Int. 2003 Jun;63(6):2152-61.

2. Thomas MCJerums GTsalamandris CMacisaac RPanagiotopoulos SCooper MEMDNSG Study GroupIncreased tubular organic ion clearance following chronic ACE inhibition in patients with type 1 diabetes.Kidney Int. 2005 Jun;67(6):2494-9.
 
 
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by Meguid El Nahas - Wednesday, 15 February 2012, 10:42 PM
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Questions and answers put to Prof Glassock following his talk on the Management of Vasculitis:

 

Prof Salah Naga: Is there a role for CNIs in the management of ANCA associated systemic vasculitis?

Prof Glassock: CNIs do not seem to be very effective in the management of AASV. They certainly dont feature in the recognised effective therapeutic approaches.

Prof Sabry Gohar:  Is there a role for Infliximab in AASV?

Prof Glassock: No role and many reports of significant side effects including a high rate of infectious complications.

Prof Adel Afifi: IN the face of an increase in sCr, when would you rebiopsy?

Prof Glassock: Rebiopsying should be considered in the face of clinical, biochemical (CRP) or immunological (Autoantibodies) signs of disease activity.

Prof Afifi: How do you treat relapses?

Prof Glassock: I treat relapses of AASV with rituximab to avoid the toxicity of repeat courses of cyclophosphamide.

Prof Essam Nooreldin: How do you prevent hemorrhagic cystitis?

Prof Glassock: In more than 30 years of practice, I did not see a single case of hemorrhagic cystitis.

I tend to prescribe the cyclophosphamide to be taken at 9am

along with 4 glasses of water and I encourage th epatient to drink more water at bedtime (another 4 glasses).

Prof El Nahas: Do you think that Plasma exchange is beneficial outdside the indication for lung hemmorhage?

Prof Glassock: Whilst the MEPEX study showed some benfit at 12 months, follow up study over more than 3 years failed to show any advantage of plasma exchange of ESRD or death and was associated with increased toxicity/side effects (Walsh and Jayne, Personal Communication).

 

 

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Tuesday, 14 February 2012, 4:49 AM
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I am attending the Annual meeting of the Egyptian Society of Nephrology and Transplantation (ESNT) in Marsa Alam, Egypt.

 On the 13 and 14 of February and Pre Congress CME meeting is held.

On day 1 of the CME meeting, I attended a lecture by Professor Richard Glassock, USA, in which he discussed arguments related to the timing of the initiation of renal replacement therapy. He showed very elegantly in his lecture how timing of starting dialysis has evolved over the last 30 years from those who in the 70s and 80s advocated early start of RRT at GFR levels of around 15 to 20 ml/min to those morte recent observations arguing that late start of HD may be more beneficial.

A number of reviews and analysis concluded that there was little advantage in starting RRT too early; GFR>15 ml/min.

Professor Glassock referred to his work and that of Rosansky (2010) showing that those starting HD at the highest quartile of eGFR (>15) had the highest mortality. Of interest, this was more specifically evident in those with higher GFR and serum albuminlevels >35g/l. He also referred to the IDEAL study by Cooper et al (2009).

Prof Glassock explained the possible confounder of the interpretation of such observation with emphasis on the value of low serum creatinine as a marker of somatic malnutrition whilst changes in serum albumin are more reflective of visceral malnutrition. Sarcopenia and wasting may therefore explain some of the observations linking poor outcomes to early initiation of HD based on calculated GFR derived from equations such as the MDRD. 

He also stressed the poor performance (imprecision and bias) of the MDRD formula in CKD stage 5. In fact, he showed data that eGFR calculated in CKD5 by such an equation considerably overestimates measured GFR. He suggested that the average of creatinine + Urea clearance may be a more accurate way of measuring GFR at this late stage of CKD.

It is also important to consider that timely referral of CKD4-5 patients to pre-dialysis care clinics and optimal preparation for RRT ar eas important in relation of the overall care of the CKD5 patient than the timing of the initiation of dialysis. Early referral to nephrologists is often not the case with patients presenting late and ill prepared for RRT. The setting up of pre-dialysis/low clearance clinics has been avocated in the UK to optimise the pre-RRT care of CKD patients. Optimal pre-ESRD care leads in many cases to prolong period of stable kidney function between eGFR of 10 and 15ml/min in asymptomatic patients. Many of the symptomas of these patients are alleviated by good anemia control as well as good control of their calcium and phosphorus metabolism as well as attention to their nutritional requirements. Pre dialysis clinics also allow for a better planning of vascular access as well as consideration/investigations for renal transplantation. Finally, good pre dialysis care involves social and psychological counselling for the patient and his family.

* See Review by Mustafa Arici in the OLA Libray on Timing of Start of RRT.

Library->CKD

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Semin Dial. 2012 Jan;25(1):9-14. doi: 10.1111/j.1525-139X.2011.01003.x. Epub 2011 Dec 6.

 

An Obituary for GFR as the Main Marker for Kidney Function?

 
This editorial review in NDT challenges the use of serum creatinine and derived eGFR to estimate kidney function in terms of glomerular filtration.
We forget all too often that serum creatinine is the result of creatinine homeostasis based on:
1. Intake, amino acids and creatine
2.Cr Metabolism  from creatine to creatinine; relying on muscle mass and related enzymes
3. Glomerular filtration
4. Secretion; renal tubular and intestinal
 
So any intervention that seemingly lowers serum creatinine or slow its rise may be the result of any of the above or a combination of some of them. Cionsequently, interventions pertaining to slow teh progression of CKD based on a slower rise in serum creatinine compared to control may be due to:
1. Decrease intake, metabolism and secretion as with Low protein Diet
2. Secretion as with ACE inhibitors and ARBs as they improve in CKD peritubular circulation and enhance the transport and secretion of Creatinine. This raise teh question as to whether the whole literature on ACE (RAAS) inhibition and CKD is a tubular secretion paraphenomenon of these agent... Not a single study bothered measuring or reporting GFR.
 
It is high time nephrologists go back to basics and remember how Creatinine is handling and stop equating changes in serum creatinine to changes in glomerular filtration alone... this is wrong and misleading!
 
 
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by Meguid El Nahas - Saturday, 28 January 2012, 11:00 AM
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De Vriese and colleagues in Belgium argue in teh january issue of KI that all patients on RRT should be screened for coronary artery disease (CAD). This implies that symptomatic but also asymptomatic patients should be screened.

Their argument is based on the fact that a very high prevalence of CAD in chronic dialysis patients including up to 53% in asymptomatic patients and 83% in those with diabetes. Also higher prevalence in older dialysis patients. Consequently, the majority of dialysis patients with angiographically documented CAD are asymptomatic (Ohtake et al).

They show data confirming the good predictive value of a positive Myocardial Perfusion Scintigraphy (MPS) for CAD. Adenosine, dipyridamole or dobutamine stresss MPS  have all been shown to have high predictive values for CAD;  the presence of reversible ischemia upon stress MPS closely correlating with the gold standard of coronary angiography (Rabbat et al, 2003).

The question that comes to mnd is why screen asymptomatic patients as data in non CKD patients shows that survival in such patients is not affected by intervention and therefore investigations not recommended. Furthermore, there is a good body of evidence that medical therapy? The authors argue that dialysis patients are at much higher risk of CAD and related mortality thus justifying screening and intervention. The published data, albeit limited, suggest that in dialysis patients with CAPD treated with PCI or CABG have a survival advantage compared to those on medication only. 

The authors advocate screening all those on dialysis listed for transplantation arguing the high prevalence of asymptomatic patients justify such an approach rather than current guidelines recommending screening only in those with a histroy of revascularisation, a signficant reduction in LV function, or symptoms suggestive of CAD/CHF. Guidelines also recommend screening selected high risk patients which woukld automatically, in my view, include diabetic patients.

The authors advocate a large RCT that examines the incremental benefit of revascularisation in addition to medical therapy in asymptomatic dialysis patients.

I remain unconvinced on a cost/benefit analysis basis that all dialysis patients should be screened as their editorial review suggests a risk of asymptomatic CAD predmoninatly driven by diabetic patients on HD. It would therefore be more cost-effective to screen as currently recommended by international guidelines those at high risk: diabetics, history of CAD, those with an abnormal echocardiogram, etc...

It would be desirable to have a cheap and non invasive test/biomarkers that predicts the presence of subclinical CAD. Cartiac Troponins may prove to be such a test. Recent high sensitivity assays showed a considerable higher circulating levels in asymptoamtic CAD ESRD patients (Jacobs et al).  

References:

De Vriese et al. Should we screen for CAD in asymptomatic chronic dialysis patients. Kidney Int. 2012;81:143-151.

Ohtake et al. High prevalence of occult CAD in patients with CKD at th einitiation of renal replacement therapy. JASN 2005;16:1141-1148.

Rabbat et al. Prognostic value of myocardial perfusion studies in ESRD patients: a meta-analysis. JASN 2003; 14:431-439.

Jacobs et al. Hemodilayusis patients longitudinally assessed  by highly sensitive  cardiac troponin T and commercial cardiac Troponin T and I assays. Ann Clin Biochem 2009;46:283-290.

 

 

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Wednesday, 28 December 2011, 9:25 AM
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A recent publications by Tonelli and his colleagues in Edmonton, Canada in KI December 2011,  highlights the risks associated with a high estimated GFR (eGFR). Using data from a population data base of 1,526,437 patients, they conclude that a high eGFR is associated with an increased risk of all cause mortality. They estimated that those with an eGFR of 60-74.9ml/min had the lowest risk compared to higher hazard ratio of 3.7 and 1.8 in those with eGFR>105 and 90-104.9ml/min respectively. Such risk is enhanced in those with dipstick positive proteinuria.

In their discussion they offer a number of possible explanations.

I have reservations about a number of  points related to that publication:

1. It relied on a ESTIMATED GFR based on the MDRD equation known to be inaccurate at a measured GFR >60ml/min; in fact many biochemistry laboratories estimate the inaccuracies and imprecision of MDRD formula at eGFR>90 so significant that they do not give a quantitative value above that level of calculation >90ml/min. So to differentiate with a single Cr estimation and an inaccurate formula measured GFRs of  74.9 to 104.9 to >105 is effectively a misleading waste of time...!? The authors somewhat validated their findings with the CKD EPI equation although I an uncertain about that equation adequacy in those with mGFRs between 75-105ml/min?

2. ESTIMATED GFR is not MEASURED GFR; whils this seeems obvious they have become increasingly interchangeable in recent nephrology literature..?  Even clinical trials interchange eGFR with mGFR....like the recently published BEAM stduy where the lowering of sCR by the trial agent was automatically assumed to reflect an improvement in kidney function rather than tubular damage and increased urinary leakage of creatinine...?

As we all know, eGFR is a reflection of serum creatinine levels that can be affected by a number of factors including wasting, sarcopenia and overal body muscle mass. The eGFR formula corrects and adjusts for body surface area but not body muscle mass. Patients with low eGFR may have lower serum creatinine and lower muscle mass due to a number of factors independently of their  true GFR.

In fact, it is well known that low serum and urinary creatinine measurements as well as low muscle mass are associated with increased mortality risk. Whilst the authors acknowledge that wasting associated with underlying illness/comorbidity may explain their findings, this is not the thrust of their discussion.

A better title for this publication would have been: "Low serum creatinine may be associated with increased risk of adverse outcomes..."

It is high time that we go back to basics and remember the ESTIMATED GFR is what it is...an estimate based on serum creatinine levels and NOT a automatic reflection of TRUE GFR; above a GFR of 60-75ml/min it is not even an ESTIMATE but more likely to be a GUESTIMATE....!!!!

Let's not put too much emphasis on guestimates and pay more attention to underlying co-morbidities that explain wasting, low serum creatinine and high risk of mortality in some members of our communities.

 

 

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On Tuesday of this week, the ALTITUDE study investigating the effect of Aliskerin (a renin antagonist) on Diabetic Nephropathy has been stopped for lack of efficacy.

Is that another nail in the coffin of RAAS inhibition in CKD and Diabetic Nephropathy or is it a misunderstanding of the nature of modern day diabetic kidney disease?

Increasingly the patients with diabetes and CKD we see at the Sheffield Kidney Institute are older T2DM patients with longstanding hypertension, often predating the diagnosis of DM, atherosclerosis and minimal (<1g/24h) proteinuria; those are likely to have renal atherosclerosis and ischemic nephropathy. These are unlikely to respond to RAAS inhibition and may in fact be harmed by these agents and their combination (see data from ONTARGET).

The RAAS inhibition story in DN started in 1984 in experimental animals (Zatz et al/Brenner et al.) of T1DM. They were apparently confirmed in the Lewis study published in NEJM in 1993 , but when you read carefully this publication you realised the patients selection bias; those with heavy proteinuria at baseline were in the placebo group, those with milder proteinuria in the captopril group...so selection bias from onset not to mention the fact that BP systolic and diastolic was lower in the captopril group!  Consequently, if beneficial at all these agents would be best used in young, T1DM with heavy proteinuria reflecting severe microvascular disease...not older T2DM with ATS and renal ischemia...

So perhaps, it is high time for nephrologists worldwide to:

1. Distinguish diabetic nephropathy (T1DM) and diabetic nephropathy (T2DM)

2. Get off the RAAS inhibition bandwagon as this approach can do more harm than good if patients selection is not carefully considered.

In fact, we published preliminary data suggesting that STOPPING  these agents in T2DM may lead to IMPROVEMENT in the kidney function of some patients with T2DM and advanced CKD (Ahmed et al, 2011)!

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