Site blog

Page: () 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 ... 34 ()
Anyone in the world

Dr Shanmuga KUMAR (Sheffield Kidney Institute) wrote: 

A recent paper[1] assessing exercise capacity of patients with chronic kidney disease (CKD) has rekindled some interest in the application of cardiopulmonary exercise testing (CPX) in CKD. The last such work was published a decade ago[2] which showed that exercise capacity, as measured by peak oxygen consumption (peak VO2), is a good predictor of survival in dialysis patients. The recent paper has shown similar results albeit utilising a different CPX parameter, anaerobic threshold (AT) presented as a percentage of peak VO2. However the question remains: What do we measure when we measure exercise capacity in CKD patients? The claim that measures of exercise capacity could serve as a surrogate of cardiac reserve function in CKD needs verification. The claim is based on the premise that VO2 is a product of cardiac output (CO) and arterio-venous difference in oxygen concentration [VO2= CO x C(a-v)O2] and hence VO2 could serve as a surrogate of cardiac output. There are several physiological considerations, commonly described in text books of exercise physiology,[3] which would render this simplified model less applicable in CKD.

Anaemia: Oxygen is primarily transported as oxyhaemoglobin (and a small fraction dissolved in plasma) and it has been estimated that the O2 carrying capacity of the blood falls from 22.5ml/dL to 14.1ml/dL as the haemoglobin concentration drops from 16gm/dL to 10gm/dL.3 Hence, for a given cardiac output, the impaired O2 delivery to exercising skeletal muscles results in reduced peak VO2 and anaerobic threshold (AT).

Chronic metabolic acidosis: Exercising skeletal muscles generate acidic end products and the ventilation must keep in pace with the acid load to maintain normal pH. The presence of metabolic acidosis in CKD would add to the acid load and limit exercise capacity because of higher ventilatory requirements.

Peripheral vascular disease: PVD is a common co-morbidity of CKD. The diseased vasculature with reduced internal diameter impairs blood flow to the exercising skeletal muscles. The relative ischaemia leads to early onset of lactic acid production and reduced AT irrespective of normal cardiac performance.3

Skeletal myopathy: Muscle wasting is not an uncommon finding in ESRD. Reduced skeletal muscle mass limits the utilisation of delivered O2. This coupled with the less studied phenomenon of skeletal myopathy secondary to uraemia would limit exercise capacity in spite of a normal cardiac output.

It has indeed been shown that haemoglobin, serum albumin, co-morbid diabetes mellitus and cardiovascular disease are significant determinants of exercise capacity in dialysis patients.[4] Therefore one wonders whether exercise capacity in CKD is just a composite marker of co-morbidities rather than a true representation of cardiac performance. Better interpretation of conventional CPX parameters in CKD can be achieved by employing techniques that simultaneously measure direct indicators of cardiac performance as well as exercise capacity.[5]



References

[1] Ting S.M. et al. Functional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation. J Am Soc Nephrol 25, 187-95 (2014).

[2] Sietsema K.E. et al. Exercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease. Kidney Int 65, 719-24 (2004).

[3] Wasserman K. et al. Principles of exercise testing and Interpretation. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005.

[4] Sietsema K.E. et al. Clinical and demographic predictors of exercise capacity in end-stage renal disease. Am J Kidney Dis 39, 76-85 (2002).

[5]Cooke G.A. et al. Physiological cardiac reserve: development of a non-invasive method and first estimates in man. Heart 79, 289-94 (1998). 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world
J Am Soc Nephrol. 2013 Dec;24(12):1934-43. doi: 10.1681/ASN.2013060632. Epub 2013 Oct 17.

Evidence-based cardiology in hemodialysis patients.

 This is an interesting review article in JASN December 2014 reviewing major CVD RCTs in CKD patients treated by HD.

Basically, it is a long list of negative trials:
Statins:
AURORA
4D
SHARP
all essentially negative.
 
Anemia correction:
Normal hematocrit Trial (1998): Negative
 
Mineral Metabolism:
DCOR
EVOLVE
NEGATIVE
 
Dialysis Dose and Membranes:
HEMO
MPO
NEGATIVE
 
as well as HDF:
CONTRAST
Turkish OIL-HDF
NEGATIVE
 
ESHOL: positive but unlikely to be a real HDF effect on survival more a case of confoundied by indication
A recent meta-analysis of HDF versus HD showed NO BENEFIT ON SURVIVAL
http://www.ncbi.nlm.nih.gov/pubmed/24434188
 
ACE inhibition:
FOSIDIAL NEGATIVE
 
etc...
 
This may be because we assume that HD patient smortality is directly linked to CAD related CVD and mortality; this may not be the case...
 
In fact, the very high mortality rate of HD patients in US in particular 20%/year with a 5 year survival of 50% only...may be due to non CAD or even CHF reversible or preventable mortality; it is more to do with the fact that more than 60% of HD patient sdie from sudden cardiac death (SCD) and the latter is associated with left ventricular hypertrophy (LVH)_ which is not always easy to reverse within the short windown of 1-3 years from HD onset. Further, we dont quite know how to address LVH and reverse it in HD:
Blood pressure control: NEGATIVE
Anemia control: NEGATIVE
Frequent HD: MAY BE but more likely ultrafiltration improvement and better fluid control. This we may have to target more aggressively and avoid chronic fluid overload in HD patients.
 
Also revisiting promising interventions may be warranted, like:
Beta Blockers: 
Atenolo may be superior to ACE inhibition in HD patients and may impact positively on LVH and mortality:
http://www.ncbi.nlm.nih.gov/pubmed/24398888
 
Anti-oxidants: Vitamin E:
Oxidant stress may be more improtant than lipids in HD patients
SPACE study was positive, may warrant further investigation.
http://www.ncbi.nlm.nih.gov/pubmed/11072938
 
More importantly, a better understanding of the causes and mechanisms of SCD is essential to address them and seek the reversible.
http://www.ncbi.nlm.nih.gov/pubmed/24256575
 
Electrolytes disturbances is a factor amongst others and may explain the higher death rate after long HD interval:
http://www.ncbi.nlm.nih.gov/pubmed/21992122
 
Also, and if SCD is the main cause of deathon HD, then ICD may be the answer in HD patients or even waerable defibrillators.
http://www.ncbi.nlm.nih.gov/pubmed/24252154
 
So clearly, a different and more critical approach to mortality on HD is warranted before more non-CKD look-alike RCTs are implemented to no avail in HD patients.
 
Perhaps, mortality will remain high on HD as by the time ESRD is reached windows of therapeutic opportunities have been shut.
PERHAPS WE ARE TRYING TO CLOSE THE HD (MORTALITY) DOOR AFTER THE HORSE (CVD COMPLICATIONS) HAVE BOLTED (SET IN...); IN THAT CASE A COMPLETELY DIFFERENT APPROACH IS WARRANTED.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Friday, 20 December 2013, 12:37 PM
Anyone in the world
JAMA Intern Med. 2013 Dec 16. doi: 10.1001/jamainternmed.2013.12700. [Epub ahead of print]

Renoprotective Effect of Renin-Angiotensin-Aldosterone System Blockade in Patients With Predialysis Advanced Chronic Kidney Disease, Hypertension, and Anemia.

Abstract

IMPORTANCE The benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients with advanced chronic kidney disease (CKD) remains undetermined. OBJECTIVE To assess the effectiveness and safety of ACEI/ARB use for advanced predialysis CKD in patients with hypertension and anemia. DESIGN Prospective cohort study. SETTING Taiwan. PARTICIPANTS From January 1, 2000, through June 30, 2009, we selected 28 497 hypertensive adult patients with CKD. Serum creatinine levels were greater than 6 mg/dL, hematocrit levels were less than 28%, and patients were treated with erythropoiesis-stimulating agents. INTERVENTIONS Users (n = 14 117) and nonusers (n = 14 380) of ACEIs/ARBs. MAIN OUTCOMES AND MEASURES We used Cox proportional hazards regression models to estimate hazard ratios (HRs) for commencement of long-term dialysis and all-cause mortality for ACRI/ARB users vs nonusers. RESULTS In a median follow-up of 7 months, 20 152 patients (70.7%) required long-term dialysis and 5696 (20.0%) died before progression to end-stage renal disease requiring dialysis. Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, 0.91-0.97]) and the composite outcome of long-term dialysis or death (0.94 [0.92-0.97]). The renal benefit of ACEI/ARB use was consistent across most patient subgroups, as was that of ACEI or ARB monotherapy. Compared with nonusers, the ACEI/ARB users had a higher hyperkalemia-associated hospitalization rate, but the risk of predialysis mortality caused by hyperkalemia was not significantly increased (HR, 1.03 [95% CI, 0.92-1.16]; P = .30). CONCLUSIONS AND RELEVANCE Patients with stable hypertension and advanced CKD who receive therapy with ACEIs/ARBs exhibit an association with lower risk for long-term dialysis or death by 6%. This benefit does not increase the risk of all-cause mortality.

COMMENTS:

Having read this article more than once, I find it somewhat incoherent and also potentially misleading.

Before, I go any further, let me declare my serious conflict of interest with this publication...I personally think it is abhorrent to start ACE inhibitors and even to continue them in CKD stage5...and I also published 2 papers to the effect that stopping ACE inhibtiorts in CKD4-5 is BENEFICIAL with renal functional recovery in a majority:

http://www.ncbi.nlm.nih.gov/pubmed/19820248

http://www.ncbi.nlm.nih.gov/pubmed/22135795

Now, that is out of the way...lets look at this publication from China that pretends that RAS inhibiton delays ESRD in CKD5 and improves survival.

1. It isnt clear at all when RAS inhibitors where started or even STOPPED in this publication, other than the fact that patients HAD been on an ACEi and/or ARB: inclusion criteria most unusual and most confusing:

"...patients who had taken any ACEI/ARB within 90 days after the first ESA prescription were defined as ACEI/ ARB users; the remaining patients were defined as ACEI/ARB nonusers...."

whether they took it for a day...or a year...whether they were still on them or not....seems lost in translation...

2. Follow-up period of 7 months, is far to short to ascertain any impact on mortality; regardless of how high the mortality of CKD5 in Taiwan is...

3. Looking at the figures, I strained my eyes to see a difference between the ESRD and composite ESRD + survival lines...although the p value is statistically significant, I very much doubt th eclinical relevance of the number needed to treat (NNT) to prevent a Single death.

4. Is the use of composite endpoint a misleading way/ploy to hide the lack of impact on survival...or to imply a protection by linking it to ESRD delay...??? Statistics...statistics...statistics...and their manipulations to serve researchers and their sponsors objectives...?!

5. The whole paper striking as lacking information about one thing: BLOOD PRESSURE and its control. This is hardly mentioned knowing how poorly BP is controlled in Chinese community. A topic we previously commented upon:

http://www.ncbi.nlm.nih.gov/pubmed/19059042

6. The authors even advocate DUAL BLOCKADE as protective, when the rest of the world deems it contraindicated in view of its increased morbidity and mortality; see ONTARGET and Subsequent publications.

It is disturbing that such poor quality publications find their way to top medical journals.

It is disturbing that reviewers in such journals are incapable of critically appraise a manuscript.

It is disturbing to see that misleading and potentially dangerous message unchallenged by an editorial to moderate its impact.

JAMA has a lot to answer!

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Thursday, 19 December 2013, 11:49 AM
Anyone in the world

THE PASSING OF PROFESSOR ZAKARIAH EL BAZ.

VERY SAD NEWS OF THE LOSS OF PROFESSOR ZAKARIAH EL BAZ.

PROFESSOR EL BAZ WAS A PIONEER OF NEPHROLOGY IN EGYPT AND THE ARAB WORLD.

PROFESSOR EL BAZ WAS ONE OF THE FATHERS OF EGYPTIAN NEPHROLOGY AND A LEADER IN THE FIELD.

HE MADE MAJOR CLINICAL CONTRIBUTIONS TO THE DEVELOPMENT OF DIALYSIS AND TRANSPLANTATION IN EGYPT IN THE 60s and 70S.

HE WAS ALSO VERY INTERESTED IN NUTRITION AND CKD.

PROFESSOR EL BAZ WAS ALWAYS THE CKD PATIENTS ADVOCATE AND FOUNDER OF THE EGYPTIAN KIDNEY PATIENTS ASSOCIATION.

PROFESSOR EL BAZ WAS A GREAT TEACHER AND ALWAYS ATTENDED NEPHROLOGY CONFERNECES WERE HE SAT IN THE FRONT ROW TO LEARN MORE AND SHARE HIS EXPERIENCE. I ALWAYS ASKED HIM A QUESTION AND LEARNED FROM HIS CONTRIBUTIONS.

MORE THAN ANYTHING, PROFESSOR EL BAZ WAS A GREAT MAN AND HUMANIST.

HE WILL BE GREATLY MISSED BY ALL OF US WHO KNEW HIM AND LOVED HIM.

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

A window for novel collagen IV nephropathy therapeutics?

Myrtani Pieri, Charalambos Stefanou and Constantinos Deltas
Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus
December 2013

Alport Syndrome (AS) is inherited as an X-linked (COL4A5) or autosomal recessive disorder (COL4A3/A4) while thin basement membrane nephropathy (TBMN) follows autosomal dominant inheritance (COL4A3/A4). They are collectively known as collagen IV nephropathies and are characterized by phenotypic heterogeneity. AS is a rare disorder with an incidence of about 1/5000 live births, although it varies among ethnic populations. Most patients reach ESRF before the age of 30 years. TBMN is a much more frequent cause for developing ESRF compared to AS, although at later ages, owing to its much higher frequency in the general population (reported as high as 1%) [1, 2].

Hundreds of different mutations have been identified in the implicated genes that partly explain inheritance patterns and phenotypic heterogeneity [3-5]. Nonetheless, we still have a long way to go before determining the molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus.

It has been shown that most mutation carriers have limited or no expression of the collagen IV chains in the glomerular basement membrane (GBM) and Bowman’s capsule. Interestingly, a recent publication revealed that X-linked AS patients that actually do express the a5(IV) chain in the GBM, exhibit milder clinical manifestations compared to those lacking  GBM expression [6]. Therefore, presence of collagen IV chains in the GBM appears to exert a protective effect on disease course. But does more chains out, also means less chains in the cell? And could increased amount of misfolded protein inside the podocyte be toxic and add to disease progression? As our recent publication in JASN revealed, it does [7].

The focus of our study was the mutational effect on the cell responsible for collagen IV chain expression in the adult glomerulus, the podocyte [7]. For the first time we provided evidence linking collagen chain mislocalization with triggering of the Unfolded Protein Response (UPR), an important cellular pathway [8]. This link, we believe, is a window for testing novel treatments for AS and TBMN.

The glycine missense mutation, COL4A3-G1334E, endemic in the Cypriot population, was expressed in human cell lines and its defective trafficking caused a strong intracellular effect on the podocyte. Interestingly, both overexpression and downregulation of the COL4A3 chain was associated with activation of UPR. This result demonstrates that  collagen IV misfolding does not only result in reduction of all chains in the GBM, but also triggers a cellular pathway that has the potential to drive the cell towards apoptosis should the stress be long lasting [9]. This link was also verified in an in vivo model, the first knock-in mouse model carrying a missense glycine mutation which produced a phenotype consistent with AS. It was also further verified in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation [7]. The variable contribution of this intracellular vs. the extracellular pathological effect for these particular syndromes is something that is yet to be determined.

Interestingly, this link between a collagen IV mutation and the UPR pathway is a very important one, as this particular pathway can be manipulated pharmacologically. Next up, would be to try to treat cells and mutant mice with pharmacological chaperones which can facilitate protein folding and trafficking to examine whether this will increase secretion of the mutant COL4A3 and hopefully decrease hematuria and proteinuria in mutant mice. A similar approach was recently shown for a mutation in the laminin β2 gene (LAMB2) that causes Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects [10].

UPR activation has been observed in many diseases, including cancer, autoimmune conditions, diabetes, liver disorders, obesity and neurodegenerative disorders [9]. UPR in renal pathophysiology is a relatively new area of research [11-14]. Therefore, recognizing its contributory role to the deleterious consequences of collagen IV-trafficking defects would greatly improve AS/TBMN patient prognosis and would pave ways for development of novel, true therapeutics to improve or ameliorate disease.

References

1.              Savige, J., et al., Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol, 2013. 24(3): p. 364-75.

2.              Deltas, C., A. Pierides, and K. Voskarides, Molecular genetics of familial hematuric diseases. Nephrol Dial Transplant, 2013.

3.              Jais, J.P., et al., X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. J Am Soc Nephrol, 2003. 14(10): p. 2603-10.

4.              Jais, J.P., et al., X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol, 2000. 11(4): p. 649-57.

5.              Gross, O., et al., Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol Dial Transplant, 2002. 17(7): p. 1218-27.

6.              Hashimura, Y., et al., Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV alpha5 chain. Kidney Int, 2013.

7.              Pieri, M., et al., Evidence for Activation of the Unfolded Protein Response in Collagen IV Nephropathies. J Am Soc Nephrol, 2013.

8.              Boot-Handford, R.P. and M.D. Briggs, The unfolded protein response and its relevance to connective tissue diseases. Cell Tissue Res, 2010. 339(1): p. 197-211.

9.              Rajpar, M.H., et al., Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet, 2009. 5(10): p. e1000691.

10.           Chen, Y.M., et al., Laminin beta2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J Am Soc Nephrol, 2013. 24(8): p. 1223-33.

11.           Kitamura, M., Endoplasmic reticulum stress in the kidney. Clin Exp Nephrol, 2008. 12(5): p. 317-25.

12.           Inagi, R., Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol, 2010. 10(2): p. 156-65.

13.           Inagi, R., Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol, 2009. 112(1): p. e1-9.

14.           Dickhout, J.G. and J.C. Krepinsky, Endoplasmic reticulum stress and renal disease. Antioxid Redox Signal, 2009. 11(9): p. 2341-52.

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Thursday, 12 December 2013, 9:48 AM
Anyone in the world
Kidney Int. 2013 Dec 4. doi: 10.1038/ki.2013.470. [Epub ahead of print]

Subclinical cardiovascular disease is associated with a high glomerular filtration rate in the nondiabetic general population.

Source

1] Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway [2] Section of Nephrology, University Hospital of North Norway, Tromsø, Norway [3] Department of Clinical Research, University Hospital of North Norway, Tromsø, Norway.

Abstract

A reduced glomerular filtration rate (GFR) in chronic kidney disease is a risk factor for cardiovascular disease. However, evidence indicates that a high GFR may also be a cardiovascular risk factor. This issue remains unresolved due to a lack of longitudinal studies of manifest cardiovascular disease with precise GFR measurements. Here, we performed a cross-sectional study of the relationship between high GFR measured as iohexol clearance and subclinical cardiovascular disease in the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6), a representative sample of the middle-aged general population. A total of 1521 persons without cardiovascular disease, chronic kidney disease, diabetes, or micro- or macroalbuminuria were examined with carotid ultrasonography and electrocardiography. The GFR in the highest quartile was associated with an increased odds ratio of having total carotid plaque area greater than the median of non-zero values (odds ratio 1.56, 95% confidence interval 1.02-2.39) or electrocardiographic signs of left ventricular hypertrophy (odds ratio 1.62, 95% confidence interval 1.10-2.38) compared to the lowest quartile. The analyses were adjusted for cardiovascular risk factors, urinary albumin excretion, and fasting serum glucose. Thus, high GFR is associated with carotid atherosclerosis and left ventricular hypertrophy and should be investigated as a possible risk factor for manifest cardiovascular disease in longitudinal studies.Kidney International advance online publication, 4 December 2013; doi:10.1038/ki.2013.470.

 Comments

Interesting study showing an association between high measured GFR (iohexol clearance) and subclinical CVD. It is remarkable as it did MEASURE GFR, but also measured 24h Ambulatory Blood pressure measurements (ABPM) as well as undertook measurements of atherosclerosis (Carotid intima media thickness) and LVH by ECG (would have been better by echocardiography).

Adjustment were also made for obesity and BMI.

But pre-diabetes, metabolic syndrome or insulin resistance cannot be excluded as an underlying cause for both raised GFR and increased atherosclerosis. Multivariate analysis adjusted for fasting blood glucose but not for HbA1c.

http://www.ncbi.nlm.nih.gov/pubmed/21860804

Insulin resistance and suboptimal hyperglycemia may impact on both GFR, LVH as well as ATS by altering autoregulation thus increasing glomerular blood flow and GFR. Insulin resistance is also known to be associated with atherosclerosis and LVH. Additionally, the study being cross-sectional and measured once, ABPM may underestimate the overall rise in BP over a longer period of time in those affected.

The authors also put forward the possibility of sympathetic overactivity.

Having said all that, this is a very interesting observation that ties up nicely with the so-called hyperfiltration of early diabetes mellitus. It associates such early hyperfiltration with sub-clinical CVD. This may in itself also explain the strong link between subclinical CVD and CKD in the community;

http://www.ncbi.nlm.nih.gov/pubmed/18388124

http://www.ncbi.nlm.nih.gov/pubmed/22935481

Perhaps starting with hyperfiltration and progressing to hypofiltration and CKD.

As with many previous publications, this paper highlights the close association between underlying CVD and renal abnormalities, be it hyperfiltration, incident CKD or even progressive CKD.

CKD in the community (cCKD) is a manifestation of underlying subclinical or over CVD and atherosclerosis.

 

 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Tuesday, 26 November 2013, 10:19 PM
Anyone in the world

"Providing guidance in the dark: rare renal diseases and the challenge to improve the quality of evidence." Bolignano and colleagues address the vexed issue of Rare and Orphan Disease and difficulties to obtain good and meaningful data either thought observational studies or through clinical intervention trials due to the small number of those affected. Small sample studies that are underpowered can lead to difficulties in statistical evaluation of the results and interpretation.

They suggest a number of approaches including:

Cross-over trials, performance of repeated measurements and analysis of covariance instead of a single comparison between treatment groups.

They also put considerable emphasis on the importance of registries and networks facilitating data collection, thus generating larger patients group more amenable to observational and cohort studies as well as randomized clinical trials.

This is a point previously elegantly made by Professor N Soliman in a similar review published a few years ago where she highlighted the importance of activism in this area of healthcare through alliance between patients groups such as the one she founded in Egypt, EGORD, and healthcare providers.

"Orphan Kidney Diseases"

This, in turn, addressed the more urgent issue of drug provisions for Orphan and Rare Kidney Disease (ORKD) as treatment of a single patient with ORKD can cost anything between $100,000-400,000/per year!. With the ongoing economic downturn Western and high economies are finding such cost increasingly unaffordable. In emerging countries, the price of orphan therapies was never affordable. This is another reason why networks and lobbying as well as activism on behalf of patients suffering from ORKD take a more emphasis by putting pressure on the Pharmaceutical industry to address their cost issues. There is little doubt that the Pharma Industry needs a much more responsible approach to ORKD. It is up to healthcare professionals along with patients groups to keep the pressure up not only to improve research facilities but also to generate affordable therapies for these rare but often devastating diseases. 

The Global Kidney Academy (ORKD initiative launched in January 2013 has one more month to run. It had little impact beyond raising awareness and education of these conditions. But perhaps as the Bolignano and Soliman reviews did, education is the first step to awareness which in turn is the first step to  stimulating and facilitating research initiatives but also lobbying on behalf of ORKD sufferers.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 20 November 2013, 10:22 PM
Anyone in the world

TEXT of the MEDSCAPE VIDEO BLOG by Jeff Berns, MD

Hello. This is Jeffrey Berns, Editor-in-Chief of Medscape Nephrology. The American College of Physicians (ACP) recently released a clinical practice guideline[1] on the screening, monitoring, and treatment of stage 1-3 chronic kidney disease (CKD). Four recommendations were provided, some generating a fair amount of disagreement with the American Society of Nephrology (ASN), the National Kidney Foundation (NKF), and the Renal Physicians Association (RPA). First, the ACP document affirms the asymptomatic nature of stage 1-3 CKD, and that having CKD has health implications, including mortality, cardiovascular disease, fractures, bone loss, cognitive dysfunction, infection, and frailty. They also comment on the common co-occurrence of hypertension, cardiovascular disease, and diabetes. Furthermore, they state that the diagnosis of CKD, regardless of stage, requires laboratory testing.

Before getting to the ACP recommendations, I find it extremely difficult to understand the rationale for lumping together stages 1, 2, 3A, and 3B CKD without specific reference to the prevailing level of albuminuria. This is a rather disparate group of patients to consider under a single guideline, and I'm not sure that I would have set out to lump all of these diverse patient groups together.

 Let's look at the ACP recommendations. First there was a weak recommendation based on low-quality evidence against screening for CKD in asymptomatic adults without risk factors for CKD. The text of the article in the Annals of Internal Medicine [1] cites as risk factors diabetes, hypertension, older age, obesity, and family history of CKD in African American, Native American, and Hispanic patients. That seems to include a huge proportion of the US adult population. Very few people are left potentially unscreened.

Another weak recommendation based on low-quality evidence was that patients who are already on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) for hypertension do not need to be tested for proteinuria. It's not specified whether this recommendation applies to patients with known CKD. I cannot imagine that many in the nephrology community don't routinely use some measure of proteinuria or albuminuria to guide ACE inhibitor or ARB treatment of patients with CKD, and I suspect that few, if any, will change their practice on the basis of these guidelines.

Two guidelines address treatment, and both are strong recommendations. One recommendation is to use an ACE inhibitor or an ARB as treatment for hypertension in patients with stage 1-3 CKD, and the other is to use statins to treat high low-density lipoprotein (LDL) levels in these patients. This confuses me a little bit. We should use these treatments in patients with CKD stage 1-3 because they improve patient outcomes, but don't look for patients who might benefit from such therapies? I must be missing something.

An ASN press release urges screening for CKD regardless of risk factors and otherwise pretty much disagrees with the ACP guidelines. The NKF and the RPA are screening for early CKD in patients with risk factors but not in the general population without risk conditions -- again, seemingly a pretty small slice of adults living in this country.

Why look for CKD? You will find poorly controlled hypertension, poorly controlled diabetes, poorly controlled lipid disorders, people who need changes in medications, those who need to avoid certain medications, and people who should be referred for early transplant evaluation. You will find opportunities to educate patients about sodium restriction and weight loss. Our testing tools for estimating glomerular filtration rate (GFR) aren't perfect. They just estimate GFR, but using imperfect tests wisely is probably better than not using them at all.

Finally, let's be clear that screening (which is not really defined in the ACP guideline) is not the same as testing for the presence and severity of CKD in the scope of a patient encounter for general health assessment or management of diabetes, hypertension, and so forth.

Nephrologists shouldn't tell the primary care physicians that they work with to stop looking for CKD. It is still an important health measure, and finding it creates the opportunity to improve patient health.

Thanks for listening. This is Jeff Berns, Editor-in-Chief of Medscape Nephrology, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

Comments

Jeff Berns voices the confusion many physicians and nephrologists have faced since the release by the ACP of its clinical practice guidelines relating to CKD screening and management and the subsequent contradictory statements made by representatives of the ASN and NKF.

A number of issues warrant clarification:

1. Are all CKD the same?

CKD has become and all encompassing term covering a very heterogeneous group of people and patients, hence the confusion when physicians are faced with guidelines and recommendations for CKD.

A distinction has to be made between CKD in the community (cCKD) and those seen by physicians and nephrologists who are referred (rCKD) because they suffer from an intrinsic kidney disease such as glomerulonephritis, vasculitis or polycystic kidney disease.

cCKD is mostly a reflection of age-related decline in kidney function, with otherwise healthy older individuals mislabeled as suffering from a disease (CKD), when in reality they merely have a lower GFR commensurate with their age and possibly underlying age-related cardiovascular disease; hypertension and diabetes, mostly type2.

2. To Screen or Not to Screen?

Community screening of asymptomatic individuals for cCKD is not warranted and is not cost effective. Testing for abnormal kidney function in individuals with known disease predisposing to CKD such as hypertension and diabetes is good medical practice. Therefore, in cCKD there is little justification for screening asymptomatic individuals but there is full indication of testing for CKD those with known predisposing conditions such as hypertension and diabetes; both poorly detected, treated and controlled in the US. It is these two conditions that warrant screening for; thus effecting early detection and management.

Screening for rCKD is seldom an issue as these patients often present acutely with a glomerulonephritis, vasculitis, pyelonephritis or other clinical manifestation of intrinsic kidney disease; proteinuria or hematuria. Those with ADPKD often have a family history that justifies the screening.

3. To Treat or Not to Treat?

There’s another legitimate confusion; treat with RAS inhibitors and statins but don't screen? Well, the distinction between cCKD and rCKD should shed some light on such apparent contradiction. Asymptomatic cCKD, older individuals within the community, should be left alone neither screened nor treated, as there is no evidence for benefit from neither; screening or primary prevention.

By contrast, those in the community with cCKD accompanied byas hypertension and/ot diabetes, should be treated appropriately and according to established guidelines that recommend renin-angiotensin system (RAS) inhibition or other drugs to lower blood pressure and reduce the magnitude of overt proteinuria (>1+ by dipstick) inhibition and statin therapy if dys-lipidemia is present. Such treatments should impact favorably on the complications of these conditions including secondary CKD.

Finally, all would agree that rCKD often suffer from hypertension and overt proteinuria justifying treatment with RAS inhibition as recommended by most management guidelines.

I hope that this clarification and distinction between cCKD and rCKD makes some sense of the disparate recommendations and conflicting arguments made by bodies that overlook the heterogeneity of CKD and consequently fail to make coherent recommendations.

 

 

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 20 November 2013, 6:14 PM
Anyone in the world

Professor Pierre Delanaye wrote in OLA French referring to the CORAL study recently published in the NEJM and not showing a therapeutic or functional advantage of renal artery stenting (PCI) over conventional medical therapy:

 

Résultat d'une étude très intéressante et attendue dans le NEJM de cette semaine.
La question posée est la suivante: PTCA et Stenting de l'artère rénale font ils mieux que traitement médical chez le sujet âgé?
947 sujets randomisés avec une sténose d'artère rénale (sévère mais pas complète, 80%) et soit une HTA systolique malgré 2 traitements ou plus soit une insuffisance rénale (IR). Les critères d'exclusion étaient: dysplasie fibromusculaire, IR d'autre cause, créatinine supérieure à 4 mg/dL, rein de moins de 7 cm, stenting impossible. Tous les patients devaient être traités pour leur diabète, leur dyslipémie et par antiplaquettaire. Les patients recevaient préférentiellement du candersartan avec ou sans thiazide et/ou l'association amlodipine/atorvastatine. Le contrôle tensionnelle est considéré à 140/90 et 130/80 si diabète ou IR. Le stenting était réalisé avec un systéme anti-embol chez la majorité des sujets.

Le critère de jugement principal était composite: mort CV ou de causes réanles, stroke, infarctus, hospitalisation pour décompensation cardiaque, IR progressive (GFR estimée qui diminue de plus de 30% et sur au moins 60 jours) ou la nécessité d'une dialyse. La randomisation est réussie. Les patients ont en moyenne 69 ans (50% d'hommes), 93% de caucasiens (étude américaine), 50% ont GFR inférieure à 60 ml/min/1.73 m², 33% de diabète, 90% de dyslipémique, sténose à 65-70%. 15 à 22% de sténose bilatérale ou sur rein unique. N=459 dans groupe stenting et n=472 dans groupe non stenting. 94% des patients ont eu un stent avec un résultat satisfaisant (11 dissections, pas de dialyse dans les 30 jours).

Le suivi médian fut de 43 mois. Il n'y a pas de différence en terme du jugement primaire, ni dans les critères secondaires (=les critéres dans le critère composite pris individuellement + mortalité globale). On retrouve un avantage modeste (-2.3 mm Hg) (cliniquement peu relevant) en terme de controle de la TA systolique (p=0.03). Le nombre de médicament anti-HTA augmente avec le temps dans les deux groupes mais n'est pas différent entre les groupes (3.3 +/-1.5). En terme de critère primaire on ne trouve pas de résultats meilleurs pour le stenting dans les sous groupes suivants: créatinine >ou < à 1.6 mg/dL, GFR estimée > ou < à 45 ml:min/1.73 m², diabète ou non, femme et homme, atteinte bilatérale ou pas, Noir ou blanc, TA systolique de base > ou <160 mmHG, Âge de > ou <70 ans, sténose > ou < 80%.

Donc après les études suggérant une absence de bénéfice en terme de contrôle tensionnel et en terme de fonction rénale, une étude encore plus ambitieuse démontre l'absence d'intérêt en terme d'événements cliniques.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Arif Khwaja
by Arif Khwaja - Tuesday, 19 November 2013, 5:03 PM
Anyone in the world

The management of FSGS particularly post -transplantation remains difficult with no clear evidence base on how to optimally manage recurrent disease. The search for a permeability factor continues and recent work suggested that serum-soluble urokinase-type plasminogen activator receptor (SuPAR) may have an important role in FSGS by modulating integrin signalling within podocytes promoting foot process effacement and proteinuria. As yet there is significant variablility in SuPAR levels (and no standardised assay) in differing FSGS cohorts so its utility as a biomarker is far from certain.

In last weeks NEJM there was some very elegant and preliminary translational work by  Yu and colleagues from Harvard looking at the role of costimulation blockade in FSGS. B7-1 is normally expressed on antigen presenting cells and provides a costimulatory signal necessary for T cell activation by interacting with 2 ligands on the T Cell - CD28 and Cytotoxic T Lymphocyte Antigen 4 (CTLA4). There are a number of costimulation blockers such as abatacept (licensed for rheumatoid arthritis) and belatacept (licensed in psoriasis and renal transplantation).
 
The group observed that B7-1 (CD80) is not expressed in normal kidney podocytes but was expressed in podocytes in biopsy specimens in a number of proteinuric kidney diseases (13 out of 21 biopsies from patients with proteinuric kidney disease were B7-1 positive). Furthermore the observation that B7-1 staining was seen in biopsies from patients with recurrent FSGS suggested that B7-1 expression had been induced during the disease process. The group go on to demonstrate in in vitro podocyte migration studies that overexpression of B7-1 leads to increased podocyte migration. Furthermore this migration is inhibited by abatacept suggesting that costimulation plays an important role in podocyte migration (which is taken as an in vitro 'surrogate' of podocyte effacement and proteinuria). B7-1 overexpression in podocytes caused a loss of beta1-integrin activation which again was reversed by abatacept. i.e. B7-1 promotes podocyte migration  (and therefore proteinuria) through inactivation of beta1-integrin signalling and this is blocked by abatacept. The putative mechanism of action of abatacept is that it binds to B7-1 thereby preventing B7-1 binding to and inactivating beta1-integrin.
 
The group then go on to present data on 5 patients with FSGS who had positive staining for B7-1 on renal biopsy and were refractory to treatment with immunosuppression including steroids and rituximab and plasmapharesis. 4 cases were post transplant and 1 was FSGS in a native kidney. In all cases there was an impressive reduction in proteinuria. In the methodology session the authors state that the treatment was in line with the 'institutional policies' of  Massachusetts General Hospital although its clear what this actually means in practice. The mechanism by which B7-1 becomes expressed in the podocyte is not clear.
 
So does this mean we should be using abatacept for patients with "B7-1 positive" FSGS? One certainly cant justify this on the basis of the a small case series and its important to note that significant numbers of proteinuric patients were B7-1 negative. However this is a promising avenue of future research and is perhaps an example of  'personalised' therapeutics that maybe increasingly seen in the future as the molecular mechanisms underlying glomerular diseases are more clearly delineated. Clearly an important next step is to see whether B7-1 positivity is seen in larger cohorts from different centres and define the mechanisms by which B7-1 expression can be induced.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Page: () 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 ... 34 ()