Site blog

Page: () 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 ... 34 ()
Picture of Meguid El Nahas
by Meguid El Nahas - Sunday, 20 November 2016, 1:06 PM
Anyone in the world

Prof Arif Khwaja Reporting from Chicago:

Late Breaking Clinical Trials


LEADER study looking at Liraglutatide on renal outcomes in patients with T2DM. This was a huge study with over 8000 patients with T2DM at higher CV risk who were randomised to placebo or Liraglutaide. The primary endpoint were major adverse cardiovascular events (MACE) and in the paper published this year in NEJM liraglutide was associated with a significant reduction in MACE. Today the secondary renal endpoints were presented - a composite of doubling of serum creatinine, ESRD, new onset macroalbuminuria and development of microalbuminuria. There was a significant reduction in the renal composite endpoint with Liraglutide which was completely driven by less new onset macroalbuminuria in CKD3 patients. No difference in any of the other endpoints including eGFR decline. As this was a placebo controlled trial the HbA1c in the the liraglutide group was significantly lower. I am not sure how surprising this is - we were taught at medical school that good glycemic control reduces the risk of nephropathy and increasing albuminuria is often the 1st sign of nephropathy - thus impossible to know if there is a drug specific effect or simply a lowering HBA1C effect.

The next study was the REMAIN study from UK which looked at the effect of early remote ischaemic preconditioning (RIPC) and late remote preconditioning on outcomes in live related transplantation. RIPC was done by 5 minutes inflation of BP cuff on upper arm followed by 5 minutes deflation for 5 cycles done either the day before theatre or on the morning of the transplant - and done prior to anaesthetic agents being given ( in contrast to the negative RIPC studies done before cardiac surgery). Controls underwent the same procedure but the cuff was inflated to only 40mmHg.
The primary endpoint was difference in mGFR at 1 year - and this was negative. The secondary endpoints were death, eGFR and graft survival at 5 years. Strangely in the early RIPC group there was a significant reduction in death and an improvement in eGFR at 5 years. Mortality at 5 years was 3% in the RIPC group and 8% in the control group. The authors recommend that we should start doing RIPC routinely in live transplants on the grounds that it is cheap, safe and easily deliverable. That maybe the case but I would add a word of caution - unsurprisingly the event rate was extremely low - patients with live related transplants do very well and though the percentage reduction in patient survival was statistically significant the absolute effect was probably very small - as a member of the audience pointed out nearly all liver recipients should be alive at 5 years. Secondly the eGFR improvement was seen at 1 year and persisted through to 5 years - yet there was no mGFR difference at 1 year which suggests to me that the eGFR result may not be ‘real’. To me it would have been much more interesting to do the study in deceased donor transplants particularly in this with a prolonged cold ischaemia time.

The 3rd study (HARMONY) from Germany evaluated whether ATG could enable rapid steroid withdrawal in low risks kidney transplant patients. Patients were randomised to 3 groups i) Tac, MMF, pred + Basiliximab ii) Tac MMF, Basiliximab with steroid withdrawal at 1 week iii)ATG, Tac, MMF and pred withdrawal at 1 week. The real purpose of the study was to see if this would reduce the incidence of new onset diabetes after transplantation (NODAT).
The primary endpoint was biopsy proven acute rejection (BPAR) and there was no difference between all three groups. Steroid withdrawal in both the basiliximab and ATG group halved the incidence of NODAT as compared to the steroid group. Astonishingly the NODAT occurred in 40% of the steroid group - which may partially be explained by the fact that tacrolimus levels were kept slightly higher in this study- nevertheless this is an incredibly high rate of NODAT and the rate of NODAT in the steroid free arm in this study (around 20%) is comparable to the rate seen in studies using low dose tac with prednisolone - see ELITE-SYMPHONY study
So the study suggests that in low risk, caucasian transplant patients steroids can be withdrawn after one week with standard basiliximab therapy. This is associated with no excess of rejection and a reduction in NODAT. The study is available online in the Lancet. www.thelancet.com/journals/lancet/articl...(16)32187-0/fulltext

4th study was the AURA-LN study that looked at adding a new CNI (Voclosporin low and high dose) to standard care (MMF+prednisolone) in class 3,4 and 5 Lupus. 24 week data was presented. Complete remission was defined as a composite endpoint of reduction proteinuria (<0.5g/24 hours) stabilisation of eGFR. Secondly endpoints included SLE activity scores such as SLENAI-SLEDAI. Voclospotin therapy was associated statistically significant impact on all primary and secondary endpoints with a phase 3 study being planned. Important to know that this positive outcome was driven completely by reduction in proteinuria with Voclosporin.
My caveats - i) patients had good kidney function - median eGFR was 100mls/min at baseline and so may not represent aggressive lupus ii) proteinuria remains a surrogate in lupus - and using a CNI will reduce proteinuria in any condition (via reduction in renal perfusion or stabilising actin cytoskeleton in the podocyte or both) - so in the absence of a repeat renal biopsy its very difficult to know if this is a genuine disease modifying effect or just improvement of a surrogate. I guess if there was a rebound rise in proteinuria after stopping the voclosporin then that would suggest that the effect is largely haemodynamic rather than disease modifying.
The SOLD study from new zealand looked at the impact of lowering dialyse Na (135mm vs 140mm) on Left ventricular mass index - no impact all at 1 year but further analyses planned. Authors postulate that LV mass is as much determined by uraemia as fluid overload.

the final study (DUET study ) compared irbesratan to a combined endothelin receptor antagonist and ARB (Sparsentan). it was an 8 week phase 2 study in a small no of patients so the conclusions are somewhat limited. Unsurprisingly combination therapy was associated with lower BP and proteinuria at 8 weeks.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Monday, 17 October 2016, 4:15 PM
Anyone in the world

BLOG BY PROFESSOR PIERRE DELANAYE:

PPI and CKD: an association… but is it causality?

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease.

JAMA Intern Med. 2016 Feb;176(2):238-46. doi: 10.1001/jamainternmed.2015.7193.

Lazarus B1Chen Y2Wilson FP3Sang Y2Chang AR4Coresh J5Grams ME5.

IMPORTANCE:

Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD).

OBJECTIVE:

To quantify the association between PPI use and incident CKD in a population-based cohort.

DESIGN, SETTING, AND PARTICIPANTS:

In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System.

EXPOSURES:

Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator.

MAIN OUTCOMES AND MEASURES:

Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort.

RESULTS:

Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17-1.55). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01-1.91) and with propensity score-matched nonusers (HR, 1.76; 95% CI, 1.13-2.74). In the Geisinger Health System replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI, 1.20-1.28). Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21).

CONCLUSIONS AND RELEVANCE:

Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.

Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.

J Am Soc Nephrol. 2016 Oct;27(10):3153-3163. Epub 2016 Apr 14.

Xie Y1Bowe B1Li T2Xian H3Balasubramanian S1Al-Aly Z4.

 

The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.

Comments

These two epidemiological studies found a higher significant risk of CKD in patients treated with PPI, notably in comparison with antiH2. It is the merit of the authors to have analyzed large databases of patients with modern, advanced and especially various statistical models. Contrary to other epidemiological studies, the CKD definition is relatively more consistent, especially in the JASN study. Indeed, even if based on eGFR, the authors have also considered CKD as confirmed decreased GFR. Even if the unique threshold at 60 mL/min/1.73 m² can be criticized, it must be underlined that hard endpoints such as 30 or 50% decline of GFR and ESRD have been considered. Also, it is of some interest to see that the risk is very similar between the two studies whereas populations are different.

Having underlined the interest of these studies, we have to discuss the limitations, as well (some of the limitations being discussed by the authors themselves). First, baseline characteristics between patients treated by PPI and antiH2 are very different, and so, adjustment for these different parameters are needed and, as usual, it is always quite difficult to be sure that residual adjustment has not been forgotten. Second, the physiopathological basis to explain this potential higher risk remains actually very speculative. PPI-induced low magnesium level is advanced to explain this risk but hypomagnesemia is actually relatively rare in PPI treated patients. AKI and especially interstitial nephritis is a well, or at least a better, known consequence of PPI therapy, with a probable immune-allergic explanation (such as several other drugs like penicillin etc). For sure these epidemiological results will promote clinical and basic research to explain the risk. Until then, the PPI higher risk remains an epidemiological risk and so, remains hypothetical. As stated by the authors of the JASN paper, the risk remains relatively low especially when hard endpoints and “the number needed to be harm” are considered. Right now, there is still no reason to stop this efficient therapy in CKD when the indication is clear and justified. The fact that PPI is too frequently prescribed beyond indication is a problem in itself.

 

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Friday, 7 October 2016, 2:21 PM
Anyone in the world
J Am Soc Nephrol. 2016 Sep 29. pii: ASN.2016010021. [Epub ahead of print]

Estimating the Risk of Radiocontrast-Associated Nephropathy.

Abstract

Estimates of the incidence of radiocontrast-associated nephropathy vary widely and suffer from misclassification of the cause of AKI and confounding. Using the Nationwide Inpatient Sample, we created multiple estimates of the risk of radiocontrast-associated nephropathy among adult patients hospitalized in the United States in 2009. First, we stratified patients according to the presence or absence of 12 relatively common diagnoses associated with AKI and evaluated the rate of AKI between strata. Next, we created a logistic regression model, controlling for comorbidity and acuity of illness, to estimate the risk of AKI associated with radiocontrast administration within each stratum. Finally, we performed an analysis stratified by the degree of preexisting comorbidity. In general, patients who received radiocontrast did not develop AKI at a clinically significant higher rate. Adjusted only for the complex survey design, patients to whom radiocontrast was and was not administered developed AKI at rates of 5.5% and 5.6%, respectively. After controlling for comorbidity and acuity of illness, radiocontrast administration associated with an odds ratio for AKI of 0.93 (95% confidence interval, 0.88 to 0.97). In conclusion, the risk of radiocontrast-associated nephropathy may be overstated in the literature and overestimated by clinicians. More accurate AKI risk estimates may improve clinical decision-making when attempting to balance the potential benefits of radiocontrast-enhanced imaging and the risk of AKI.

Copyright © 2016 by the American Society of Nephrology.

Commentary

Excellent analysis of the incidence of radiocontrast associated nephropathy (RCN). To start with it is NOT a "Nephropathy" instead most often a transient rise in serum creatinine that is transient and by definition reversible...so to call it a nephropathy is a misnomer as serum creatinine values rise transiently after a number of interventions including a cooked meat meal, ingestion of an H2blocker or some antibiotics...these dont become Meat Associated Nephropathy, or Cimetidine Associated Nephropathy etc...although some have attributed a "Nephropathy" to Warfarin....that is as ill conceived !

Back to the RCN, the strength of the current analysis is the adjustment for comorbidities, and the actual impact of comorbidities themselves on changes in serum creatinine rather than the associated interventions; radiocontrast administration in this publication or warfarin overanticoagulation (INR >3) elsewhere.

Secondly, the definitions of these entities often depend on variable cut off points for changes in the measured parameter, serum creatinine, that defines the "Nephropathy"...mostly arbitrarily chosen with no consideration for clinical severity, reversibility or enhanced morbidity/mortality, and/or the underlying CKD stage.

Finally, RCN has been a fertile ground for research and interventions. Mechanistic research that led to a number of interventions, most of which have shown little advantage over a bag of normal (or half normal) saline before and after the administration of RC material... 

Nephrology has to guard itself from embarking on research for the sake of research, rather than prioritise research that has clinical relevance, clinical impact and ultimately research that benefit patients...

If we ask of RCN whether it fulfils the 5 WHATs, it is unlikely to meet any of the 5 Whats criteriae:

1. What is the clinical relevance of RCN: Negligible!

2. What is the validity of the data supporting this entity: As shown by the publication under discussion, Minimal!

3. What is the Usefulness/Utility of identifying RCN: Optimise Hydration

4. Risk versus Benefit of RCN: too much emphasis, too much research, too much investments for little return: a bag of Saline would do...

5. Cost benefit analysis: same as 4!

So can we conclude from this publication and my commentary that RCN is an irrelevance?

Perhaps not, except that more attention needs to be paid to radiological investigations, specially those that are aggressive and invasive, in patients with significant comorbidities as these are at higher risk of acute on chronic kidney disease...regardless of the coadministration of potentially nephrotoxic agents!

 

 

 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Monday, 26 September 2016, 7:25 PM
Anyone in the world
Am J Nephrol. 2016;44(3):179-86. doi: 10.1159/000448341. Epub 2016 Sep 3.

Serum Potassium Levels and Mortality in Hemodialysis Patients: A Retrospective Cohort Study

BACKGROUND:

Hyperkalemia is common in patients receiving maintenance hemodialysis. However, few studies have examined the association between serum potassium level and mortality.

METHODS:

This study used annual cohorts of hemodialysis patients during 2007-2010. To determine hyperkalemia prevalence, monthly hyperkalemia was defined as serum potassium level ≥5.5 mEq/l; prevalence was calculated as a ratio of hyperkalemia episodes to follow-up time, reported separately by long and short interdialytic interval. To determine the impact of hyperkalemia on mortality, patients in the 2010 cohort were followed from first potassium measurement until death or a censoring event; hyperkalemia was defined, sequentially, by potassium levels 5.5-6.0 mEq/l at 0.1 mEq/l intervals. Time-dependent Cox proportional hazards modeling was used to estimate the association between hyperkalemia and mortality.

RESULTS:

The 4 annual cohorts ranged from 28,774 to 36,888 patients. Mean age was approximately 63 years, about 56% were men, 51% were white and 44% had end-stage renal disease caused by diabetes. Hyperkalemia prevalence was consistently estimated at 16.3-16.8 events per 100 patient-months. Prevalence on the day after the long interdialytic interval was 2.0-2.4 times as high as on the day after the short interval. Hyperkalemia, when defined as serum potassium ≥5.7 mEq/l, was associated with all-cause mortality (adjusted hazards ratio (AHR) 1.13, 95% CI 1.01-1.28, p = 0.037, vs. <5.7 mEq/l) after adjustment. AHRs increased progressively as the hyperkalemia threshold increased, reaching 1.37 (95% CI 1.16-1.62, p < 0.0001) for ≥6.0 mEq/l.

CONCLUSIONS:

The long interdialytic interval was associated with increased likelihood of hyperkalemia. Hyperkalemia was associated with all-cause mortality beginning at serum potassium ≥5.7 mEq/l; mortality risk estimates increased ordinally through ≥6.0 mEq/l, suggesting a threshold at which serum potassium becomes substantially more dangerous.

© 2016 S. Karger AG, Basel.

Commentary by Prof Richard Glassock

Hyperkalemia is a common and potentially life-endangering complication of CKD, especially in the very advanced forms of CKD. The risk of an adverse event, including death, arising from hyperkalemia is thought to be related to the magnitude of the increase in serum level of potassium (K+) above the normal ranges, but the exact relationship between the serum level of K+ and mortality is not well known, and probably is influenced be many factors.

Yusuf and co-workers carried out a retrospective cohort study over the period of 2007-2010 in 135,021 prevalent patients receiving hemodialysis for treatment for ESRD, in order to better establish risks of mortality in patients with hyperkalemia of varying severity. About 60% had diabetes and 38% had congestive heart failure. The dialysate potassium was 2-<3mmol/L in 67-77% of the cohorts.  Hyperkalemia was estimated to occur in 16 episodes per 100 patient months, much higher on the day after the longest inter-dialytic interval. The use of sodium polystyrene sulfate was not recorded.

The all-cause mortality (ACM) rate increased incrementally as serum K+ rose above 5.7mmol/L. The fully- adjusted hazard ratio (HR) for ACM for subjects with a serum K+ of >6.0mmol/L was 1.37 compared to that observed in subjects with a serum K of 5.5mmol/L or less. The impact of hypokalemia on ACM was not examined. The fully-adjuster HR for CKD mortality was only increased above a serum K+ of 6.0mmol/L. 

The data used in this study was collected before new K+ binding resins became available (patiromer), so the rate of hyperkalemia and its consequences may not be directly relevant to contemporary treatment of ESRD by hemodialysis,  but the relationship of serum K+ to mortality risk probably still holds true. Interestingly, hyperkalemia was more frequent in Caucasian and younger subjects - the explanation for this finding is uncertain but might relate to dietary factors, concomitant medications or underlying disease. More studies are needed to better define the risks of hyperkalemia and its consequence according to co-morbidities. Most importantly randomized controlled trials using modern oral K+ binding agents with objective hard outcomes are needed to determine be how the adverse effects of hyperkalemia in ESRD can be modified  by such agents and which patients would be ideally suited for such therapy. These findings suggest that short-term (1-2 days) days of therapy during the longest inter-dialytic interval might be a good target.

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Tuesday, 6 September 2016, 10:26 AM
Anyone in the world

BLOG BY PROF PIERRE DELANAYE

Am J Nephrol. 2016;43(4):271-80. doi: 10.1159/000446122. Epub 2016 Apr 29.

Cardiovascular Outcomes in Action to Control Cardiovascular Risk in Diabetes: Impact of Blood Pressure Level and Presence of Kidney Disease.

Papademetriou V1Zaheer MDoumas MLovato LApplegate WBTsioufis CMottle APunthakee ZCushman WCACCORD Study Group.

Abstract

BACKGROUND:

Persons with chronic kidney disease (CKD) represent a population prone to cardiovascular disease (CVD) but vulnerable to adverse medication effects. We assessed the impact of intensive antihypertensive therapy on the cerebrovascular and other CVD outcomes in high-risk patients with type 2 diabetes and baseline CKD.

METHODS:

Using current guideline criteria, 1,726 (36.9%) of 4,678 participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) arm had mild to moderate CKD (CKD1-3B) at baseline. Participants of this study were randomized to intensive (systolic <120 mm Hg) or standard (systolic <140 mm Hg) BP goals. Fatal and non-fatal stroke were pre-specified secondary outcomes of the ACCORD study.

RESULTS:

Total cerebrovascular events were significantly higher in participants with baseline CKD (0.66%/year) compared with participants free of CKD (0.28%/year). A significantly higher rate of events was observed in CKD participants. Intensive antihypertensive therapy in participants without CKD at baseline resulted in a 55% significant reduction of any stroke (hazard ratio 0.447; 95% CI 0.227-0.880) and a 50% reduction of non-fatal stroke (hazard ratio 0.498; 95% CI 0.250-0.993). In participants with CKD at baseline, the occurrence of any stroke was reduced by 38% (hazard ratio 0.623; 95% CI 0.361-1.074) and non-fatal stroke by 36% (hazard ratio 0.642; 95% CI 0.361-1.142). Test for interaction was NS between the 2 groups. Changes in other CVD outcomes did not reach statistical significance.

CONCLUSIONS:

These findings suggest that intensive antihypertensive therapy offers significant cerebrovascular protection in diabetic participants without CKD at baseline, but significant benefit to patients with CKD cannot be excluded.

Globally, this post-haoc analysis confirm the results of SPRINT even if the population here is only diabetic patients.

In a few words, the benefit of intensive antihypertensive therapy in such diabetics is significant for stroke in non-CKD patients...but not in CKD diabetic patients. The authors consider CKD stage 1 to 3b and it could be intresting to know the risk associated with different stagings.

Other results are not very surprising for nephrologists: higher CV risk (all causes) for CKD compared to non CKD (but the risk profile in CKD is also higher). Also, the low BP target (in intensive therapy arm) is obviously more difficult to reach in CKD patients. It is not known if more therapies are required in the CKD arm.

Because the potential AE with antihypertensive therapies (more frequent in CKD than in non CKD, as well) and the absence of clear benefit, we should be careful with the blood pressure targets in CKD patients.

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world
J Am Soc Nephrol. 2016 Aug 18. pii: ASN.2016030278. [Epub ahead of print]

Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozinconfers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m2 per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m2per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride,canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects.

Copyright © 2016 by the American Society of Nephrology.

COMMENTS:

Spectacular effect of Canaglifozin a SGLT2 inhibitor and effectively a potent diuretic on the progression of T2Diabetic nephropathy.

Effective slowing of the rate of eGFR decline compared to Glimepiride. 

This has led some to beleive that this is a major breakthrough in the management of DN. 

However, a number of limitations, some highlighted by the authors, should be considered:

1. This was NOT a study on DN progression; it was a study powered to ascertain the comparative efficacy of canaglifozin on diabetes control. Therefore, it can only be HYPOTHESIS GENERATING  as it is unsuitable for testing the hypothesis that it is superior or inferior to Glimepiride on the progression of CKD in T2DM.

2. Morevover, SGLT2 inhibitors are potent diuretics, and no diuretic control for the osmotic diuresis induced by the drug was included in this study.

3. As a potent diuretic, canaglifozin did what most diuretics do....lower BP; in fact the reduction of systolic BP was 10-20 fold more significant in patients treated with Canaglifozine compared to Glimepiride... Therefore, is it suprising that DN progression was improved with better BP control. This has been known since the original observations of Mogensen in the 70s: BP control slows the progression of diabetic nephropathy!

Statistical analysis doesnt mitigate that fact.

A more suitable control would have included equal diuresis and equal BP control to determine whether the effect of the SGLT2 inhibitor was specifically renoprotective independently of its anti-hypertensive effect.

3. Progression, as usual these days, was measured by eGFR and NOT MEASURED...?! An agent that interferes with proximal tubular transport and function may interfere with tubular secretion of creatinine and may therefore lower serum creatinine, and eGFR changes, through that mechanism rather than TRUE GFR CHANGES. It seems as if the lessons of Bardoxolone and its effects on eGFR have not been learnt...?!

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bardoxolone%2C+quarterback

So as far as I am concerned, SGLT2 inhibitor are effective oral hypoglycemic agents with a potent glycosuric, osmotic diuretic effect. These agents have been associated with serious side effects including urogenital infections and cancer. http://www.ncbi.nlm.nih.gov/pubmed/27541294

Their renal and cardioprotective effects need to be evaluated by comparison with comparable diuretic and anti-hypertensive agents.

Their reno-protective effecst need to be properly evaluated by measuring GFR rather than the fudge of calculating it...

The jury is out on any specific, BP reduction independent, renal and cardiovascular protective effects of these potentially harmful agents.

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

Clin J Am Soc Nephrol. 2016 Aug 8;11(8):1472-83. doi: 10.2215/CJN.13841215. Epub 2016 May 5.

Climate Change and the Emergent Epidemic of CKD from Heat Stress in Rural Communities: The Case for Heat Stress Nephropathy.

Abstract

Climate change has led to significant rise of 0.8°C-0.9°C in global mean temperature over the last century and has been linked with significant increases in the frequency and severity of heat waves (extreme heat events). Climate change has also been increasingly connected to detrimental human health. One of the consequences of climate-related extreme heat exposure is dehydration and volume loss, leading to acute mortality from exacerbations of pre-existing chronic disease, as well as from outright heat exhaustion and heat stroke. Recent studies have also shown that recurrent heat exposure with physical exertion and inadequate hydration can lead to CKD that is distinct from that caused by diabetes, hypertension, or GN. Epidemics of CKD consistent with heat stress nephropathy are now occurring across the world. Here, we describe this disease, discuss the locations where it appears to be manifesting, link it with increasing temperatures, and discuss ongoing attempts to prevent the disease. Heat stress nephropathy may represent one of the first epidemics due to global warming. Government, industry, and health policy makers in the impacted regions should place greater emphasis on occupational and community interventions.

 Comments

This review published in the August issue of cJASN argues for a Heat Stress Nephropathy (HSN) associated with Global warming...

It would involve a variety of incidences of renal impairment in countries such as El Salvador/Central America (Mesoamerican nephropathy, Sugar cane Nephropathy), Sri Lanka and India.

The review implicates global warming, dehydration, nephrotoxins as well as heavy metal contamination of drinking water, not to mention the ever present hyperuricemia and also hypokalemia as well as fructose toxicity...

The reality is that agriculture workers working unprotected for very long long hours in extreme heat are simply prone to dehydration...

Longterm dehydration leads to longterm activation of the renin angiotensin aldosterone system (RAAS) that leads to renal ischemia and chronic hypokalemia; severe dehydration along with chronic hypokalemia (observed in many of these workers) is enough to cause impaired renal function in anybody...

So rather than calling these conditions fancy names, it suffices that we acknowledge that dehydration is not good for the kidneys...and that adequate hydration is essential for workers of any type in any country working under extreme heat conditions!

Nephrologists love to come up with new "Nephropathies", it gives them a claim to have "discovered" and labelled an entity, even when it is as mundane as dehydration...!

Some recent examples of labelling...

Warfarin nephropathy: Basically raised serum creatinine in sick and multi-comorbidities, over anticoagulated, patients with CVD...causal link with warfarin unproven!

Smoking Nephropathy: Basically CKD in heavy smokers...with multiple comorbidities and underlying CVD...causal link with heavy smoking unproven!

Mesoamerican nephropathy: Dehydration in agricultural workers...link with anything else unproven!

Sugar Cane nephropathy: Dehydration in agricultural workers...(not just sugar cane), affecting those working a low altitude and extreme heat and not the cooler higher altitude farmers...

Fructose nephropathy, Uric Acid Nephropathy, etc...

In the case of "Heat Stess Nephropathy"...it would better be called Dehydration induce kidney failure...its prevention in adequate hydration and better working conditions of those exposed to hot climate...it treatment is re-hydration before long term damage takes place!

Lets keep the simple, simple and make its prevention and management equally simple.

As to Climate Change and Global Warming...thats better left to geographers and politicians...as we, as nephrologists, have no data to compare the incidence of impaired kidney function...before and after global warming...!?

Fianlly, another CKD "Epidemic"... another term to make the problem sound more important, urgent, and global...Dehydration on the other hand, would not have the same linguistic impact, but would be much nearer the truth...as the evidence of a HSN induced epidemic is as shaky as that of the CKD "epidemic" that has been branded around the last 20 years...

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Thursday, 1 September 2016, 11:10 AM
Anyone in the world

http://www.ncbi.nlm.nih.gov/pubmed/?term=glaser%2C+lemer%2C+johnson

A review published in the August issue of cJASN argues for a Heat Stress Nephropathy (HSN) associated with Global warming...

It would involve a variety of incidences of renal impairment in countries such as El Salvador/Central America (Mesoamerican nephropathy, Sugar cane Nephropathy), Sri Lanka and India.

The review implicates global warming, dehydration, nephrotoxins as well as heavy metal contamination of drinking water, not to mention the ever present hyperuricemia and also hypokalemia as well as fructose toxicity...

Comments

The reality is that agriculture workers working unprotected for extremely long hours in extreme heat are simply prone to dehydration...

Longterm dehydration leads to longterm activation of the renin angiotensin aldosterone system (RAAS) that leades to chronic hypokalemia; severe dehydration along with chronic hypokalemia (observed in many of these workers) is enough to cause impaired renal function in anybody...

So rather than calling these conditions fancy names, it suffices that we acknowledge that dehydration is not good for the kidneys...and that adequate hydration is essential for workers of any type in any country working under extreme heat conditions!

Nephrologists love to come up with new "Nephropathies", it gives them a claim to have "discovered" and labelled an entity, even when it is as mundane as dehydration...and hypokalemia!

Some recent examples of labelling...

Warfarin nephropathy: Basically raised serum creatinine in sick and multi-comorbidities, over anticoagulated, patients with CVD...causal link with warfarin unproven!

Smoking Nephropathy: Basically CKD in heavy smokers...with multiple comorbidities and underlying CVD...

Mesoamerican nephropathy: Dehydration in agricultural workers...

Sugar Cane nephropathy: Dehydration in agricultural workers...(not just sugar cane), affecting those working a low altitude and not the cooler higher altitude farmers...

Fructose nephropathy, Uric Acid Nephropathy, etc...

In the case of "Heat Stess Nephropathy"...it would better be called Dehydration induce kidney failure...its prevention in adequate hydration and better working conditions of those exposed to hot climate...it treatment is re-hydration before long term damage takes place!

Lets keep the simple, simple and make its prevention and management equally simple.

As to Global Warming...thats better left to geographers and politicians...

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

In this month KI, Eriksen and colleagues reports on a Norwegian longitudinal study of the general population examining the links between age related decline in GFR and Blood Pressure (at baseline) (BP).

http://www.ncbi.nlm.nih.gov/pubmed/27188503

The study did NOT show any association between baseline BP parameters and the rate of decline of measured GFR (mGFR) in an older general population with exclusion of those known to have cardiovascular disease or DM.

Comments:

The study has a number of advantages and strengths:

1. It is a general population cohort study where over a period of 5.6 years of follow up the GFR was measured by iohexol clearance.

2. Measured GFR (mGFR) showed a decline of aroun 098-0.9ml/min/year consistent with previous observations that GFR is lost at a rate ~1ml/min/year after the age of 50.

3. The study Renal Iohexol Clearance Survey in Tromso 6 (RENIS-T6) also compared mGFR with eGFRCr and eGFRCys and find thme wanting as their values, compared to mGFR, in the general population with near normal renal function were confounded by non-renal variables such as inflammation:

http://www.ncbi.nlm.nih.gov/pubmed/26668020

4. mGFR was repeated over the 5.6 years observation period.

5. BP was measured in day and night time as well as ambulatory (ABPM) in this study: http://www.ncbi.nlm.nih.gov/pubmed/22278141

The study failed to show an association between baseline BP values and the subsequent rate of mGFR decline with time.

This observation agrees with older ones showing the impact of BP on the decline in GFR was primarily linked to bouts of accelerated hypertension jeopardising GFR in a stepwise fashion, whilst a steadily elevated BP was not associated with a faster rate of GFR decline. In fact, a meta-analysis of 10 RCTs back in 2002 failed to show a strong association between BP and incident CKD: http://www.ncbi.nlm.nih.gov/pubmed/11981255

This was supported by observations that non-accelerated, mild to moderate, hypertension was not associated with nephrosclerosis in the general population: http://www.ncbi.nlm.nih.gov/pubmed/?term=freedman+appel%2C+1995

A limitation of the current study is the emphasis on Baseline BP and subsequent mGFR decline.

More emphasis on changes in BP control with time would have been more informative; in fact, their unadjusted data suggest that those whose BP (MAP) increased with time had slower mGFR decline...

whilst those treated for hypertension had faster rate of decline (raising the possibility that antihyeprtensive agents, including RAAS inhibitors may have detrimental effects on GFR decline with time)...

In spite of its limitations this observation, with accurate GFR measurements and thorough BP recordings, draw attention to the fact that the links between mild to moderate BP elevation and age-related decline in GFR do not show a linear association.

Confounders, may impact on that association including genetic factors (APOL1 genotype), obesity and environmental factors such as smoking as well as susceptibility to hypertension induced atherosclerosis and its impact on renal perfusion and function.

The conclusion of this observation has to be:

There is more to the link between hypertension and CKD decline than elevated Blood Pressure; other confounders and comorbid factors have to be taken into consideration. This notion may lead to a more targeted and individualised approach to the management of hypertension in older people based on the presence or absence of other comorbid confounders. This has been emphasised by the JNC8 recommendations:

http://www.aafp.org/afp/2014/1001/p503.html

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Tuesday, 14 June 2016, 11:06 AM
Anyone in the world

FGF23: A novel role in systemic immunosuppression:

FGF23 an osteoblast produced key stimulator of renal phosphate excretion has previously been known to be associated with CKD-MBD, hypertension, CVD

http://www.ncbi.nlm.nih.gov/pubmed/24677555

and now with an immunosuppressive effect through an inhibition of neutrophil recruitment and anti-bacterial activities.

http://www.ncbi.nlm.nih.gov/pubmed/26878171

New therapies aimed at neutralising FGF23 may prove to be effective at many levels.

Comments:

However, like with all Cytokines, the story is never that simple as experimental data based on neutralisation of FGF23 and/or its receptor Klotho have not proved universally successful. 

http://www.ncbi.nlm.nih.gov/pubmed/22396168

Nephropathic cystinosis: Conclusions from a KDIGO Controversies Conference

This conference held in 2015 involving Prof Neveen Soliman reviewed diagnostic and management approaches to nephropathic cystinosis. Amongst other issues it highlight the discrepancy between access to care in developed and devloping countries. Research questions were discussed including WBC and gene testing for the disease, access to treatment but also issues related to children and adolescent non-compliance. The conference also put a lot of emphasis on the recognition of the systemic nature of cystinosis thus stressing the importance of early diagnosis and initiation of therapy  with cysteamine. Beside the kidneys, bones, eyes, the neurological system, the endocrine system (diabetes, hypothyroidism, GH deficiency) and fertility can all be affected.

Comments:

A major challenge resides in how the medical community can address the issue of limited access to healthcare for cystinosis sufferers in non-western world countries and disadvantaged population. Cost of treatment is often unaffordable in these communities. It is high time the Pharmaceutical Industry show more social and global responsibility towards those millions denied care!

Mining the human urine proteome for monitoring renal transplant injury. Sidgel et al.

This study shows the result on searching for urine proteins that could enhance teh diagnosis, prognosis and management of renal allograft recipients.

Out of over 900 proteins identified in the urine of those tested, 11 showed interest in relation to acute rejection, 12 for chronic allograft nephropathy and 12 for BK virus nephropathy.

Comments:

This obssession with urinary proteomic in renal transplantation goes back over 20 years and so far has yielded no clinical useful results. One is entitled to ask, whether any of the putative proteins identified in this study are superior in predictive value to; raised serum creatinine (for acute rejection), proteinuria and declining function as well as renal biopsy (for CAN) and to urinary and serum PCR for BKV nephropathy specially when associated with a rising serum creatinine. Also cost-effectiveness of these techniques and the time lag between sampling and obtaining results are likely to be of little value in acute rejection when a prompt diagnosis and treatment is required, as to the other conditions...well there is usually plenty of time to confirm their diagnosis by conventional means without requiring the sophistication and unreliability of urine proteomic analysis. I guess it keeps some scientists interested and giving lectures...many such tests have been validated more than 10-15 years ago and never made it to the bedside...?!

http://www.ncbi.nlm.nih.gov/pubmed/11750404

http://www.ncbi.nlm.nih.gov/pubmed/12777869

http://www.ncbi.nlm.nih.gov/pubmed/20526237

Endostatin and Transglutaminase 2 are involved in fibrosis ageing. Lin et al.

Endostatin (EST) a pletropic anti-angiogenic factor and transglutaminase 2 (TG2) its molecular partner may be implicated in renal fibrosis; through the dual mechanism of vascular rarefication and the association interstitlal fibrosis that underly renal fibrosis and scarring. In this study, the injection of EST and/or TG2 to young mice led to an accelerated renal ageing process.

Comments:

We, Tim Johnson and myself, were the first to draw attention in the 90s to the putative role of TG2 in experimental renal fibrosis through the observation of an increased levels in scarred SNx rat kidney sassociated with renal fibrosis

and subsequently through the design of specific TG2 inhibitors that attenuated experimental renal fibrosis.

http://www.ncbi.nlm.nih.gov/pubmed/10505691

http://www.ncbi.nlm.nih.gov/pubmed/12874459

http://www.ncbi.nlm.nih.gov/pubmed/18003782

The authors of this paper chose to overlook the bulk of our pioneer experiments as it is often the case with medical publications. They should be informed that clinical experimentation is already under discussion aimed at manipulating TG2 in human nephropathies. 

It is a sad fact of medical research publications for authors to wish to appear to have discovered facts and mechanisms that are already well established and validated by others, years before, that they chose to ignore. It does them little credit...

Association of short sleep duration and rapid decline in renal function. McMullan et al.

This paper follows a prospective cohort of 4238 middle aged women participants of the Nurse's Health Study and shows that over an observation period of 11 years those who sleep on average <5h per night are at significantly higher risk of a faster decline in renal function, eGFR.

Sleep disturbances can be associated with hypertension, metabolic syndrome/diabetes and CVD; the authors however adjusted for incident hypertension, DM and CVD and found that it did not impact on the relative increased risk associated with short sleep duration.

Comments

Whilst this observation is of interest, and worthy to be pursued, such analysis is always difficult to validate and interpret as:

1. It could be counfounded by underlying co-morbidity; those who dont sleep well may have illnesses that distrub their sleep and also predispose them to declining kidney function.

2. Sleep apnea cannot be discared as a cause of distrubed sleep; sleep apnea has been associated with impaired kidney function.

http://www.ncbi.nlm.nih.gov/pubmed/27152260

2. Hypertension in cohort studies is difficult to validate  as causal and occasional measurement of BP is seldom good enough to exclude underlying or incident hypertension. Also sleep disturbance may be associated with nocturnal hypertension, known to impact of CKD and its progression.

3. Serum creatinine/eGFR occasional (twice in 11 years) measurements may also mislead and give false positive results of decline, in the absence of a truly negative slope of eGFR decline ;non-linear decline may confound the interpretation of the renal functional data in this study.

http://www.ncbi.nlm.nih.gov/pubmed/22284441

4. Sleep disturbance may also be associated with medication, to alleviate the underlying cause or the associated symptoms including headaches, analgesics and others, that could in turn be instrumental in impacting negatively on renal function.

In conclusion, the association of sleep disturbances with CKD progressionmay be difficult to untangle by just counting sleep hours through a self reported questionaire.

CKD, Hypertension and diabets in the adult population of Morocco. Gharbi et al.

This is the publicationof the MAREMAR study that showed the prevalence of NCD and CKD in samples of the Moroccan adult population. CKD prevalence was around 5%. The study showed the importance of re-testing for proteinuria and eGFR in population screening studeis as the prevalence falls significantly upon validation of the initial positive testing...It also showed the important finding of underdiagnosis of CKD in the younger population and overdiagnosis in the older population when relying on one size fit all eGFR cut off of 60 ml/min comapred to teh more age-senstive cut-off of below the third age adjusted percentile.

Comments:

This is an example of how epidemiological studies on CKD detection and prevalence should be conducted.

It also shows the serious limitations of eGF <60 ml/min to define CKD in all age groups.

Underestimation, in younger patients whereby a 25 year old with a GFR of 70 ml/min would be considered as no suffering from CKD in the absence of proteinuira/hematuria, in spite of a significant reduction in kidney function...

Overestimation, by using an inappropriate and age-insensitiev cut off of 60 ml/min for a 75 year odl when 45 ml/min would be much more appropriate.

http://www.ncbi.nlm.nih.gov/pubmed/27057075

http://www.ncbi.nlm.nih.gov/pubmed/26932693

It is time for a rethink of the KDOQI/KDIGO CKD classification with a single defining cut off of 60 ml/min for all ages!

 

[ 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 ()