TOPIC DISCUSSION: Diuresis in CHF

An amazing article this month in NEJM discusses Diuretic use in CHF- a must read for Cardiologist and Nephrologists.

Some interesting take home points:

1. Diuretic resistance causes: Non adherence, gut edema, impaired diuretic secretion due to CKD or aging, hypoproteinemia, hypotension, nephrotic syndrome, use of NSAIDS, low renal blood flow, nephron remodeling and neurohormonal activation.

2. Bumetanide and torsemide have higher and more consistent oral bioavailability over furosemide and make oral and IV doses kinetics similar( often under utilized by many)

3. Torsemide has the longest half life of all loop diuretics-- 6 hours.

4. Two forms of adaptations: a) A dose of loop diuretic increases urinary Na loss for few hours but then is followed by a period of very low sodium excretion often called " post diuretic Na retention". When dietary Na intake is high, the post diuretic Na retention effect will offset the initial natriuresis. 
The second is braking phenomenon.  When diuresis happens and fluid volume declines, this activates the SNS and RAS leading to nephron remodeling( distal nephron hypertrophy). This is a helpful thing to put brakes on the severe contraction of the ECF. But when this occurs in a patient that is volume overloaded, it's causing harm.

5. Treatment should aim for daily urine volume of 3-5L till euvolemia.  A stepped wise approach is suggested in bolus of furosemide followed by drip if needed. Metolazone or HCTZ( high dose) can be used as additional agents.

6. Tolvaptan: Data is mixed and can be used in some especially if Na issues are also a concern
7. Dopamine and Nesirtide - no data to support use
8. Aldactone didn't improve outcomes in acute CHF patients that require aggressive diuresis
9. Diuretic Resistance: Failure of diuretics to achieve decongestion, so with max doses you still get a a urine Na<10.
10. Use of amiloride and carbonic anhydrase inhibitors may be beneficial in diuretic resistant patients.
11. UF in CHF appears to be indicated primarily when dialytic therapy is also indicated for worsening cardiorenal syndrome.
12. Hypertonic saline with diuresis might be an interesting option -- robust trials still pending.
13. Skillful use of diuretics is the bottom line on how to succeed in treating CHF with renal dysfunction.

I had hoped the authors had commented on use of lung US in this disease. Diuretic use guided by Lung US findings might be more useful in many cases than later exam findings of edema( personal observation). 

Topic Discussion: Novel anticoagulants in CKD and ESRD

New Oral Anticoagulants(NOACs)	Renal clearance of parent drug	Dosage in ESRD	GFR 15-29ml/min	GFR 30-40ml/min	GFR >-50ml/min	Dialyzable (yes/no)	Reversal agent
Dabigatran( Direct thrombin inhibitor)	80%	Avoid	75mg BID	150mg BID	150mg BID	Yes with 10% rebound rate	Idarucizumab Dialysis
Rivaroxaban(Factor Xa inhibitor)	36%	15mg QD	15mg QD	15mg QD	20mg QD	No	4-factor prothrombin complex concentrate Andexanet Alfa
Apixaban( Factor Xa inhibitor)	27%	5mg BID	2.5mg BID	5mg BID	5mg BID	No	4-factor prothrombin complex concentrate Andexanet Alfa
Edoxaban (Factor Xa inhibitor)	50%	30mg QD	30mg QD	30mg QD	60mg QD	No	4-factor prothrombin complex concentrate Andexanet Alfa

Patients with atrial fibrillations are being treated with NOACs as they are simple to use, no monitoring and excellent safety profile. They are higher in costs and experience still limited. NOAC use in patients with advanced CKD and on dialysis is substantial and increasing, despite AHA, ACC, and HRS and European Heart Rhythm Association guidelines that endorse warfarin as the anticoagulant of choice when CrCl is <30 ml/min. There are few randomized trial data on NOACs among patients with advanced CKD or on dialysis. Most NOACS are dependent on the kidney for elimination. Since most patients with advanced CKD were excluded in clinical trials, this topic is important. 

The above table summarizes what the current data exists on this topic for use of NOACs in CKD patients with Atrial Fibrillation for prevention of stroke.  Bleeding risk is important in patients with CKD and ESRD due to uremic dysfunction of platelets and use of heparin in HD.  Unfortunately, no patients with CKD Stage V or ESRD were not allowed in any of the NOAC trials. Apixaban was the most commonly used NOAC in a recent analysis in advanced CKD patients. Apixaban and Rivaroxaban have renal eliminations around 30% hence most safe in late stage CKD with lower dosing. Dabigatran and Edoxaban ar 80% and 50% renal elimination respectively and should technically avoided in late CKD patients.  Dabigatran is the only NOAC removed by dialysis based on studies thus far.

This review in JACC summarizes the latest uptodate information on use of these agents in CKD and ESRD patients. – A must read!

IN THE NEWS: Contrast Nephropathy

Preventing contrast nephropathy has always been a research topic. From anti oxidants to hydration to dialysis all have been suggested. Hydration likely to be the only winner thus far.
Two recent studies need to be highlighted that have come out in the cardiology literature.

1.  Tamai et al from Japan studied a moderate size subgroup of patients with significantly high doses of bircarbonate infusion( close to 800meq/L) compared to standard bicarbonate infusions(160meq/L) pre cardiac cath at a rate of 3ml/kg/h for one hour. As expected urine pH was higher in the first group but statistical significant rate of decline of contrast induced nephrolopathy as well in that group. Potassium values didn't change much. 48 Hour GFR change was much more in the standard bicarbonate group. Interestingly, baseline renal function was around 1.3-1.4mg/dl with some difference in both groups making this study weaker. Also, while initial Na concentrations were similar, wonder what 24 hour Na levels were in these cases. Interesting study to bring back alkalization as a potential prevention for contrast nephropathy.

2. Marenzi et al show that fluids with match diuresis might prevent contrast induced nephropathy compared to standard fluid therapy The MYTHOS study looked at 250ml Normal Saline bolus followed by furosemide to keep urine output >300cc/h and then do the cardiac procedure versus a standard fluid infusion model. Contrast induced nephropathy rates were much lower in the case where urine output was high. Another interesting concept and study to look at this problem

Both studies: single centers, small studies, many limitations. Have a look but they might catch on in the cardiology world and we might be seeing some of this happening at our centers.

IN THE NEWS: Nephrology NEJM showcase

Latest offerings in NEJM highlight nephrology articles:

One of them is comparing ultrafiltration to diuretic use in cardio renal syndrome(CARRESS-HF).
Interestingly, ultrafiltration performed inferiorly compared to a catered diuretic regimen in a randomized controlled trial. Does it end the role of UF? Or is SCUF still a consideration. An editorial attached still says slow and steady might be preferred.

ADPKD and treatment with aquretic treatment is the next major article. The TEMPO trial showed this using tolvaptan. Can this drug show promise in protecting renal function in ADPKD.

EVOLVE trial looked at cinacalcet in ESRD patients in a randomized trial and evaluated cardiac endpoints and found shockingly negative results.

ALTITUDE trial evaluated adding aliskiren to other renin angi inhibitors in DMII for cardio renal end points and found harm and no significant benefit.

3 negative trials
1 positive trial

Evidence based medicine keeps knocking off physiology based medicine in Nephrology.

eAJKD: Cardiac biomarkers in CKD

Troponin T and N-terminal pro brain natriuretic peptide are potential markers of cardiac injury that are often measured in the inpatient setting. Can these markers be used in the outpatient setting to predict risk of developing ESRD in patients with diabetic kidney disease? Check it out in an exclusive interview on eAJKD. 
Ref:
http://ajkdblog.org/2011/11/29/cardiac-biomarkers-in-ckd-and-esrd-what-to-make-of-them/

In the News: ESA dose responsiveness? Some thoughts

A Japanese study just recently published in AJKD looked at dose responsiveness to ESA and effect on mortality. They defined 6 categories of ESA responsiveness based on a combination of ESA dosage.  They studied the relationship between hemoglobin level, ESA responsiveness and outcomes among hemodialysis patients. The authors found that mortality in patients on hemodialysis may be affected by ESA responsiveness and by the interaction of hemoglobin and ESA dose. Low hemoglobin level and high ESA dose were strongly associated with an increased risk of mortality. 

Dr Steven Fishbane and Azzour Hazzan wrote an editorial to the article in nature nephrology. 

Dr Hazzan puts his thoughts as a post here as well:

Recently there have an intense interest in anemia in patients with CKD and how best to manage it. In the early years of dialysis, anemia was found to be more common in patients with CKD and associated with higher mortality. This has been proven through many studies albeit not of a good quality-RCTs. However; recently we have found that our approach to normalize the hemoglobin level may have been  counterproductive. The reason being; increase stroke risks and probably higher cardiovascular mortality as well. Of the more definitive studies- the TREAT- looked at about 4000 patients with diabetic  CKD-Non dialysis. The treatment arm was darbepoetin to achieve levels of 13 versus using darbepoetin to keep HGb from falling under 9. The investigators found that patients with hemoglobin artificially driven towards normal,  had double fatal and non-fatal strokes risks. The question is why?

There are many stipulations. One possibility is the ESA dose effect? and patient's response to ESA. 

The above mentioned study by Fukuma et al. has investigated the relationship between hemoglobin level, erythropoietin responsiveness and outcomes among Japanese hemodialysis patients. The authors found that mortality in patients on hemodialysis may be affected by ESA responsiveness and by the interaction of hemoglobin and ESA dose. Our editorial piece looks into that and other studies. Basically it would be hard with this kind of studies to make any definitive conclusions to answer this question. Is it the EAS dose or is it  the fact that more severe anemia signify sicker patients and therefore higher mortality? In other words; acute and chronic illness, severity of illness, inflammation and co-morbidity are all highly intertwined with hemoglobin level and ESA dose, making analysis vulnerable to severe confounding variables.

In summary, we should exercise caution in treating anemia and use the lowest dose possible. 

Post by Dr. Azzour Hazzan

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21890255

http://www.ncbi.nlm.nih.gov/pubmed/22009249

Many guidelines equal no guildelines for cardiac evaluation before renal tranplantation

The degree of cardiac testing for potential transplant recipients is highly variable and depends on the practices of the particular transplant center. Multiple guidelines have been proposed by experts in the field however there is a huge variability between each guideline. At the two ends of the spectrum are the KDOQI guidelines which suggest universal testing for CAD at regular intervals depending on risk, and the ACC/ AHA who recommend testing only for symptomatic patients or patients who can not achieve 4 mets of activity. A recent article in cJASN by Friedman et al. demonstrates this beautifully(1). The authors had performed cardiac testing in 87% of their patients then retrospectively applied the KDOQI, AST, Lisbon and ACC/AHA criteria to thier patients to assess how many would have been tested. Turns out that 100%, 92%, 68% and 20% would have been screened respectively. The authors discovered ischemic disease in 17 (10%) of their patients and 10 of them underwent revascularization (7 had single vessel PCI). KDOQI and AST guidelines would have picked up all of the cases, Lisbon criteria would have picked up 16 patients and ACC/AHA would have picked up 4 of the patients with ischemia. The problem is that it is not clear whether identifying ischemia or performing revascularization in such patients is of any benefit in reducing cardiovascular event rates! In fact there are well designed studies that show pre-surgical revascularization in all patients with ischemic heart disease does not reduce cardiovascular morbidity and mortality in patients undergoing major vascular surgery(2) - but of course these studies were not in dialysis patients...

What we need is a large multicenter randomized controlled trial to evaluate the potential benefit in pre-transplant cardiac testing +/- revascularization in reducing cardiac morbidity and mortality in patients undergoing renal transplantation - to settle the question once and for all.

Reference:
1. Friedman et al. A Call to Action: Variability in Guidelines for Cardiac Evaluation before Renal Transplantation. cJASN 2011;6:1185
2. McFalls et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004;351: 2795
2804, 2004