Prof Pierre Delanaye posted:
FISH OIL or ASPIRIN for AVF maturation: does not wok!
Written by Pierre Delanaye on Monday, 09 January 2017. Posted in OLA BlogJAMA Intern Med. 2017 Jan 3. doi: 10.1001/jamainternmed.2016.8029. [Epub ahead of print]
Effect of Fish Oil Supplementation and Aspirin Use on Arteriovenous Fistula Failure in Patients Requiring Hemodialysis: A Randomized Clinical Trial.
Irish AB1, Viecelli AK2, Hawley CM2, Hooi LS3, Pascoe EM4, Paul-Brent PA4, Badve SV5, Mori TA6, Cass A7, Kerr PG8, Voss D9, Ong LM10, Polkinghorne KR11; Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) Study Collaborative Group.
Vascular access dysfunction is a leading cause of morbidity and mortality in patients requiring hemodialysis. Arteriovenous fistulae are preferred over synthetic grafts and central venous catheters due to superior long-term outcomes and lower health care costs, but increasing their use is limited by early thrombosis and maturation failure. ω-3 Polyunsaturated fatty acids (fish oils) have pleiotropic effects on vascular biology and inflammation and aspirin impairs platelet aggregation, which may reduce access failure.
To determine whether fish oil supplementation (primary objective) or aspirin use (secondary objective) is effective in reducing arteriovenous fistula failure.
DESIGN, SETTING, AND PARTICIPANTS:
The Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) study was a randomized, double-blind, controlled clinical trial that recruited participants with stage 4 or 5 chronic kidney disease from 2008 to 2014 at 35 dialysis centers in Australia, Malaysia, New Zealand, and the United Kingdom. Participants were observed for 12 months after arteriovenous fistula creation.
Participants were randomly allocated to receive fish oil (4 g/d) or matching placebo. A subset (n = 406) was also randomized to receive aspirin (100 mg/d) or matching placebo. Treatment started 1 day prior to surgery and continued for 12 weeks.
MAIN OUTCOMES AND MEASURES:
The primary outcome was fistula failure, a composite of fistula thrombosis and/or abandonment and/or cannulation failure, at 12 months. Secondary outcomes included the individual components of the primary outcome.
Of 1415 eligible participants, 567 were randomized (359 [63%] male, 298 [53%] white, 264 [47%] with diabetes; mean [SD] age, 54.8 [14.3] y). The same proportion of fistula failures occurred in the fish oil and placebo arms (128 of 270 [47%] vs 125 of 266 [47%]; relative risk [RR] adjusted for aspirin use, 1.03; 95% CI, 0.86-1.23; P = .78). Fish oil did not reduce fistula thrombosis (60 [22%] vs 61 [23%]; RR, 0.98; 95% CI, 0.72-1.34; P = .90), abandonment (51 [19%] vs 58 [22%]; RR, 0.87; 95% CI, 0.62-1.22; P = .43), or cannulation failure (108 [40%] vs 104 [39%]; RR, 1.03; 95% CI, 0.83-1.26; P = .81). The risk of fistula failure was similar between the aspirin and placebo arms (87 of 194 [45%] vs 83 of 194 [43%]; RR, 1.05; 95% CI, 0.84-1.31; P = .68).
CONCLUSIONS AND RELEVANCE:
Neither fish oil supplementation nor aspirin use reduced failure of new arteriovenous fistulae within 12 months of surgery.
COMMENTSVery interesting study: prospective RCT, large sample, adequate randomisation, relevant question, clear and practical endpoints and clear conclusions!!Oif fish fir native AVF maturation: costly and useless
Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation: Results of the randomized ELEVATE trial.
In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n=359) or remain on standard calcineurin inhibitor (CNI) therapy (n=356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated GFR from randomization to month 12, was similar for everolimus versus CNI: mean (SE) 0.3(1.5)mL/min/1.732 versus -1.5(1.5)mL/min/1.732 (p=0.116). At month 24, mean (SD) estimated GFR was 62.5(22.4)mL/min/1.73m2 with everolimus and 57.4 (19.9) mL/min/1.73m2 with CNI (p=0.005), and 59.7(20.5)mL/min/1.73m2 and 53.0(18.0)mL/min/1.73m2 , respectively, for the tacrolimus- and cyclosporine-treated CNI subgroups. BPAR at month 12 was more frequent under everolimus versus CNI overall (9.7% versus 4.8%, p=0.014) and versus tacrolimus-treated patients (2.6%, p<0.001) but similar to cyclosporine-treated patients (8.8%, p=0.755). Reporting on de novo donor specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks post-transplant was associated with similar renal function to standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus thaneverolimus. This article is protected by copyright. All rights reserved.
From this and previous studies, I can see little advantage, and possible disadvantages from CNI to mTOR inhibitors (mTORi) conversion in renal transplantation.
Beside marginally better renal function, that can be ascribed to CNI withdrawal rather than mTORi substitution,https://www.ncbi.nlm.nih.gov/pubmed/25088685
it would seem that mTORi are associated with more biopsy proven acute rejections (BPAR) as also shown in the SOCRATES study: https://www.ncbi.nlm.nih.gov/pubmed/24279685
and possibly more AMR (antibody mediated rejection)... https://www.ncbi.nlm.nih.gov/pubmed/24684741
mTORi are generally poorly tolerated and associated with numerous and often significant side effects. https://www.ncbi.nlm.nih.gov/pubmed/25146383
In the absence of malignancy, I see no place for these agents in renal transplantation.
Prevention of progressive IFTA (Interstitial Fibrosis and Tubular Atrophy) could be managed by CNI dosage optimisation to avoid renal fibrosis whilst minimising AMR.
Combination therapy with mTORi and low dose CNI therapy has also been advocated rather than total discontinuation of CNI as in the ELEVATE study. This may attenuate the risk of DSA and associated chronic AMR: https://www.ncbi.nlm.nih.gov/pubmed/25040585
I invite comments and a discussion.
Prof Richard Glassock wrote:
I went to a session on Onco-Nephrology at the ASN meeting yesterday.
Two randomized controlled trials of high-cut off (HCO) membrane intermittent hemodialysis compared to standard membrane hemodialysis for established AKI secondary to biopsy-proven Myeloma Cast Nephropathy (MCN) were presented (the French MYRE and the New Zealand EuLITETrials).
The primary endpoints were similar (short-term freedom from need for dialysis), but the entry criteria and the basic chemotherapy for Multiple Myeloma administered in conjunction with dialysis were different in the two trials.
Both studies were well powered (n= about 100 cases) but only the MYRE trial had a positive result.
The EuLITE trial failed to show any benefit for HCO dialysis for MCN. Patient survival was not affected in either trial. The differences in the outcomes may well have been due to the trial design characteristics and/or the type of Myeloma chemotherapy utilized. It seems likely that HCO will remain as a controversial therapy for MCN.
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.
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.
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).
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.
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.
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.
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.
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.
Estimating the Risk of Radiocontrast-Associated Nephropathy.
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.
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!
During the plenary session of the first day of the 17th International Pediatric Nephrology A ssociation Congress, September 20-24 in Iguacu, Brazil
Professor Moin A Saleem delivered the keynote talk entitled “Molecular stratification of the nephrotic syndrome”
Being an expert in the field professor Saleem smoothly surfed in the current acumen of exponentially increasing molecular and cell biology updates into the pathogenesis of nephrotic syndrome.
The glomerular podocyte plays a key role in filtration and its loss of function results in loss of protein. Therefore, the recent advances in molecular genetics and cell biology studies in nephrotic syndrome patients not only revealed the molecular mechanisms of podocytes dysfunction responsible for the disease, but equally importantly provide clues to focus on target molecules on the podocyte to figure out potential circulating factors.
Moreover, those molecules can be utilized as both diagnostic and prognostic biomarkers. This paves the way to personalized therapy to patients with nephrotic syndrome tailored to maximize benefit while minimizing side effects caused by drugs as well as the devastating post-transplantation disease recurrence.
It is quite interesting how whole-exome sequencing revolutionized our understanding through identifying several mutations in families with SSNS, which shed light on new mechanisms of podocyte disruption in minimal change nephrotic syndrome. For instance, epithelial membrane protein 2 (EMP2) is known to regulate the amount of caveolin-1, which contributes to endocytosis and the transcytosis of cholesterol and albumin. Lipopolysaccharide (LPS)-induced caveolin-1 phosphorylation was reported to lead to the increase of transcellular permeability [1,2].
Professor Saleem suggested that there is seemingly an evidence of overlap of SSNS and SRNS. He expects, given the preliminary results of the ongoing research as well, that nephrotic syndrome will be reclassified soon based on pathogenic mechanisms that keep evolving. These would hopefully include the mechanisms of how corticosteroid and immunosuppressives have their effect on single gene mutation nephrotic syndrome.
Parton RG, del Pozo MA: Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol. 2013; 14(2): 98–112
Wang N, Zhang D, Sun G, et al.: Lipopolysaccharide-induced caveolin-1 phosphorylation-dependent increase in transcellular permeability precedes the increase in paracellular permeability. Drug Des Devel Ther. 2015; 9: 4965–77
Serum Potassium Levels and Mortality in Hemodialysis Patients: A Retrospective Cohort Study
Hyperkalemia is common in patients receiving maintenance hemodialysis. However, few studies have examined the association between serum potassium level and mortality.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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...?!
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.