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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.
 
 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Arif Khwaja
by Arif Khwaja - Friday, 4 November 2011, 11:57 AM
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A number of comments about the BEAM study ( Bardoxolone Methyl in Diabetic nephropathy) were posted on OLA a few months ago. Concerns raised by Professor El-Nahas amongst others was that the serum creatinine was used to estimate GFR and there was no formal measurement of GFR. these concerns have been echoed by a number of others in letters to the editor in this weeks New England Journal of Medicine. In particular Rogacev and colleagues point out that "Patients receiving bardoxolone had a significant weight loss of 7.7 to 10.1 kg, as compared with a weight loss of 2.4 kg in the placebo group" which in itself could account for the changes in eGFR. Others raised the possibility of whether Bardoxolone Methyl had an effect on tubular secretion of creatinine. Pergola and colleagues respond to these criticisms by saying that the reductions in urea, phosphate and uric acid cannot be explained by an effect on tubular secretion of creatinine. Furthermore they point out the potential difficulties of using Cystatin C as a measure of GFR but fail to answer the central question about the study... whether they have any evidence to show that Bardoxolone Methyl has any impact on measured GFR

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

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 ]
 
Picture of Arif Khwaja
by Arif Khwaja - Wednesday, 26 October 2011, 10:20 AM
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A number of trials have shown benefit of N-acetylycysteine (NAC) in preventing contrast nephropathy. One of the difficulties in interpreting the data with NAC is that it can promote the tubular secretion of creatinine - i.e. beneficial effect of NAC may simply reflect this rather than be truly nephroprotective. In our institution we use oral NAC and hydration to protect against contrast nephropathy - again Ive always found this confusing given the generally poor oral bioavailability of NAC.
A recent large RCT (published in Circulation) suggests that oral NAC has no beneficial effect beyond simple hydration in the prevention of contrast nephropathy. In this study 2308 patients undergoing an angiography with at least 1 risk factor for contrast-induced acute kidney injury (age >70 years, renal failure, diabetes mellitus, heart failure, or hypotension) were randomised to NAC 1200 mg or placebo. NAC 600mg twice daily orally was given for 2 doses before and 2 doses after the procedure. There was no difference in contrast nephropathy, dialysis or death in the two groups.
These results contrast with a few earlier studies suggesting that NAC was benefcial. Marenzi and colleagues in a previous smaller study of 354 patients had shown there to be a dose-dependent positive effect of NAC in patients undergoing angioplasty on a combined endpoint of death, RRT and need for mechanical ventilation. However in this study intravenous doses of NAC (600mg and 1200 mg ) were given prior to the procedure whilst oral doses were given post-procedure.
An earlier study from Kay and colleagues in Hong Kong in a smaller cohort did show a beneficial effect of oral NAC - but again the primary endpoint was a rise in creatinine and given the effects of NAC on creatinine secretion this data is hard to interpret.
In summary I think this large study shows that there is no beneficial effect of oral NAC on contrast nephropathy. There is data to support the use of IV NAC so for the time being clinicians should probably use either IV NAC with hydration or hydration alone to prevent contrast nephropathy.
 
 
References
 
1. ACT Investigators. Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography: Main Results From the Randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT). Circulation. 2011 Sep 13;124(11):1250-9.
 
2. Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli AL. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006 Jun 29;354(26):2773-82.

3.Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A, Fan K, Lee CH, Lam WF. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA. 2003 Feb 5;289(5):553-8.

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Picture of Arif Khwaja
by Arif Khwaja - Wednesday, 26 October 2011, 8:00 AM
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Last year there was much excitement when Kain and colleagues appeared to have made a significant breakthrough in the understanding of the pathogenesis of ANCA associated vasculitis. They reported that over 90% of patients with ANCA disease had lysosomal associated membrane 2 (LAMP2) antibodies and that these antibodies could trigger a crescentic glomerulonephritis when injected into rats. Furthermore LAMP2 antibodies appeared to be triggered by bacterial infections - infection with fimbriated gram negative bacteria such as E-Coli would result in the production of auto-antibodies against LAMP2 due to molecular similarity between the bacterial and LAMP2 epitopes.
In this months JASN, Falk and colleagues attempted to replicate these results in 329 patients with ANCA vasculitis from Chapel Hill and Massachusetts General Hospital. In this cohort anti-LAMP2 reactivity was only present in 21% of patients and administration of anti-LAMP2 antibody to rats did not produce a glomerulonephritis. There was no correlation between anti-LAMP2 titres and disease activity and sera from patients did not cross react with recombinant LAMP2.
Therefore in contrast to the studies from Kain this data suggests that the LAMP2/bacterial infection hypothesis is not relevant in ANCA-associated disease. Whether this is due to methodological differences between the two groups or differences in the population studied will only be clear when data from other groups are published.

References:

1. Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, Davidovits A, Raab I, Jahn R, Ashour O, Spitzauer S, Sunder-Plassmann G, Fukuda M, Klemm P, Rees AJ, Kerjaschki D. Nat Med. 2008 Oct;14(10):1088-96. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.

2. Roth AJ, Brown MC, Smith RN, Badhwar AK, Parente O, Chung HC, Bunch DO, McGregor JG, Hogan SL, Hu Y, Yang JJ, Berg EA, Niles J, Jennette JC, Preston GA, Falk RJ. J Am Soc Nephrol. 2011 Oct 21. Anti-LAMP-2 Antibodies Are Not Prevalent in Patients With Antineutrophil Cytoplasmic Autoantibody Glomerulonephritis.

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by mohammad katout - Thursday, 13 October 2011, 10:19 AM
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Over the last 5 years, the Chronic Kidney Disease in Children (CKiD) prospective cohort study has enrolled close to 600 children ages 1 to 16 years with mild to moderate chronic kidney disease (CKD).

Copelovitch L, Warady BA, Furth SL. Insights from the Chronic Kidney Disease in Children (CKiD) study. Clin J Am Soc Nephrol. 2011 Aug;6(8):2047-53. Epub 2011 Jul 22.

This is the third after two large prospective registries, The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database and the ItalKid Project, to provided important descriptions of the characteristics and comorbidities of children with CKD.  This sort of registry is usually cumbersome and data are limited by variations in measurement, frequently missing longitudinal data and the absence of direct measures of kidney function. The major strength of CKiD is in its systematic measurement and longitudinal follow-up.

CKiD Highlights

1. The authors devised an CKiD equation that Incorporates height, gender, serum creatinine, cystatin C, and blood urea nitrogen. A more precise and accurate estimate of GFR than prior equations as described by authors; but is it practical and applicable?  They also proposed CKiD bedside equation as a clinical useful tool which contains an updated constant of 0.413 to the original Schwartz formula for children with CKD, a fixed constant for all ages!

2. Children who had more longstanding CKD were observed by their parents to have better physical and emotional functioning as compared with children who had CKD for a shorter period of time. Older children self-reported higher physical, emotional, social, and overall quality of life (QoL) compared with their younger peers; however, paradoxically, their parents reported worsening school QoL with age.

3. 48% of those being treated for hypertension remained uncontrolled. Almost 17% of all participants had LVH and 9% had concentric left ventricular remodeling.

4. Lower levels of GFR, nephrotic range proteinuria, and obesity were associated with an increased prevalence of dyslipidemia.

5. Low birth weight (<2500 g), prematurity (<36 wk), small for gestational age (<10th percentile for gestational age), or intensive care unit admission were associated with poor growth outcomes in children with CKD. Interestingly, subanalysis revealed that the negative effect of SGA on weight was significantly worse in those with a glomerular diagnosis compared with those with nonglomerular causes of CKD.

Still more focus is needed as to determine and quantify traditional and novel RISK FACTORS for CKD progression and the sequence of associated multisystem comorbidities. This will hopefully lead to targeted intervention strategies designed to prevent or ameliorate the frequently observed adverse outcomes and therefore improving the quality of life of CKD children.

Similar multicenter studies, with strong methodology and longitudinal follow up, are greatly needed in emerging countries as well!!!

 

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

 

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 Denise Smith - Wednesday, 12 October 2011, 9:16 AM
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Is 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!

 

Trimethoprim, Creatinine and Creatinine-Based Equations(Pierre Delanaye and colleagues, Liege, and Ontario; Nephron Clin Pract 2011;119:c187-c194) Trimethoprim (TMP) inhibits tubular creatinine secretion, leading to a rapid but ultimately reversible increase in serum creatinine independent of any changes in GFR. This leads to a falsely low estimated GFR when creatinine-based equations are used. This review focuses on evidence of the differential effects of TMP and sulfamethoxazol (Sfx) on serum creatinine concentrations and GFR and their relevance to clinical practice, with particular attention to kidney transplantation. It reviews the evidence that  the combination of TMP and Sfx can induce AKI, but stresses that it is likely that it is Sfx that is responsible for the vast majority of cases of 'true' AKI occurring with co-trimoxazole therapy and that TMP induces a reversible increase in serum creatinine through inhibition of tubular secretion of creatinine. New GFR biomarkers could be of interest to estimate GFR in subjects treated with TMP. For example, plasma cystatin C is freely filtrated through the glomerulus and is then reabsorbed by renal tubular cells where it is completely metabolized. Thus, TMP should theoretically not influence plasma cystatin C concentrations.

 

Chyluria Associated with Nephrotic-Range Proteinuria: Pathophysiology, Clinical Picture and Therapeutic Options(Giorgio Graziani and colleagues, Rozzano; Nephron Clin Pract 2011;119:c248-c254) This mini-review reminds nephrologists of the diagnostic and therapeutic approaches to patients with milky urine secondary to chyluria. It discusses parasitic, most commonly filariasis, causes of chyluria in the tropics but also more common causes in the West such as lymphangioma, carcinoma, trauma, abscess, tuberculosis, pregnancy and stenoses of the thoracic duct. Many such causes generate lymphourinary communications leading to chyluria. Distinction between nephrotic syndrome and chyluria, both associated with heavy proteinuria, can easily be made by urine analysis; the cloudy/milky aspect, lymphocyturia as well as the positive reaction to Sudan III characterize chyluria. Also, hypocholesterolemia in chyluria contrasts with the hyperlipidemia of nephrotic syndrome. Preferred investigations include MRU and lymphangiography as well as MR lymphography. Clearly, treatment is guided by the underlying cause ranging from antiparasitic antibiotics to sclerosing therapy. The authors also put forward a conservative, dietary, therapeutic approach consisting of a low-fat diet supplemented with medium-chain triglycerides. Such an approach may be worth considering in selected patients before embarking on more invasive approaches. Chyluria remains an uncommon renal manifestation but one that warrants careful investigation to exclude more sinister underlying pathology.

 

Genetic Association Studies: Discovery of the Genetic Basis of Renal Disease(Marion Verduijn and colleagues, Amsterdam, and Reggio Calabria; Nephron Clin Pract 2011;119:c236-c239) In this article, the authors detail genetic association analysis with clinical examples. This is a timely publication in view of the growing number of approaches to link genotypes with phenotypes in Nephrology. For more information about the genetic associations with CKD see the Nephron Special Issue 2011 on Renal Genetics and Clinical Practice edited by J. Sedor, Cleveland, Ohio, and R. Sandford Cambridge

 

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

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Tuesday, 11 October 2011, 7:36 PM
Anyone in the world

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

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Tuesday, 11 October 2011, 3:31 PM
Anyone in the world

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!

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