NephMadness 2015: Cardio-Nephrology Region

Andrew House, MD; Andrew Malone, MD; Matthew Sparks, MD


March 02, 2015

Editorial Collaboration

Medscape &

In This Article

Sudden Cardiac Death Acute Coronary Syndrome in ESRD

These are two very important topics that contribute heavily to mortality and morbidity in patients with end-stage renal disease (ESRD). They overlap in their pathophysiology and take from the same playbook (think 4-corners offense and Dean Smith).

Sudden Cardiac Death in ESRD

This is the scourge of nephrology and will be a difficult concept to overtake in NephMadness. It's an alarming statistic that almost 1 in every 4 deaths among hemodialysis and peritoneal dialysis patients is from sudden cardiac death (SCD). Even worse, the risk of SCD increases substantially as kidney function declines (in the absence of ESRD).

We need to understand why this is occurring so we can introduce interventions to help decrease this trend. To put it a different way: the risk of sudden cardiac death in this patient population is actually above and beyond the risk attributable to classic risk factors.

What is the reason behind this? The pathophysiology of SCD has not been clearly established, and this is why SCD represents a formidable foe. In the general population, structural heart disease with reduced left ventricular ejection fraction is responsible for the majority of SCD events. However, this is not the case in CKD and ESRD. Coronary artery disease in the general population consists of lipid-laden intimal atherosclerotic lesions. This pattern is not the case in CKD, where diffuse multivessel arterial stiffening and calcification of the medial layers of the vessels predominates.

In fact, Bleyer et al showed that ischemic cardiomyopathy with reduced ejection fraction was only present in less than 30% of patients on hemodialysis who died from SCD. Patients with CKD predominantly have HFpEF, presumably from left ventricular hypertrophy.

MRI studies of patients on hemodialysis describe a diffuse pattern of myocardial fibrosis underlying left ventricular hypertrophy without a background of ischemic coronary artery disease. Multiple factors could be contributing to this in patients with CKD such as:

microvessel disease and capillary deficit (capillary/myocyte mismatch)

disorders of mineral metabolism and secondary hyperparathyroidism

repetitive myocardial injury from reduction in myocardial perfusion during dialysis

dialysis-induced myocardial "stunning"

These differences in pathophysiology may explain why the traditional risk factors fail at explaining the enhanced risk of SCD in dialysis patients.

What about arrhythmic triggers? This could be another factor besides just structural abnormalities leading to the increased risk of SCD in patients with ESRD. First, SCD occurs most frequently on hemodialysis days, especially on the first hemodialysis day after the long dialysis-free weekend for patients on a three times a week dialysis. This suggests that factors related to the hemodialysis procedure itself can potentially trigger fatal arrhythmias.

What are some of the factors?

both hyperkalemia and hypokalemia (Pun et al)

exposure to low potassium and calcium dialysate (Karnik et al)

rapid ultrafiltration rate (Movilli et al)

Therefore, these findings suggest that shifts with varying amounts of potassium and calcium are critical risk factors for SCD in patients maintained on hemodialysis.

What can be done to prevent SCD in this vulnerable patient population? This is the ultimate question. There is no doubt that fatal ventricular arrhythmias can be prevented in patients with ischemic heart diseases and HFpEF. But what about patients maintained on hemodialysis?

Well, unfortunately all patients with advanced kidney disease were excluded from automatic internal cardiac defibrillator (AICD) trials such as MADIT-2 trial. However, a retrospective analysis of patients with reduced EF and ESRD in Michigan and Ottawa, Canada, did show a mortality benefit with placement of an AICD for both primary and secondary prevention combined.

A definitive randomized controlled trial looking at the primary prevention of SCD with AICD in ESRD has not been performed. A recently published matched cohort study in NDT utilizing data from the National Cardiovascular Data Registry’s ICD Registry did not detect a difference in overall mortality in AICDs as primary prevention for SCD.

What about pharmacologic therapy in preventing SCD? A study by Cice et al in JACC linked beta-blockers to improved survival in patients on hemodialysis with dilated cardiomyopathy. However, a secondary analysis of the HEMO study published in AJKD did not find a difference in SCD in patients taking beta blockers compared with those who were not. In looking at the renin-angiotensin system blockers, multiple studies have failed to show a reduction in cardiovascular mortality in patients on dialysis (albeit they do show a reduction in LV mass).

Altogether, we still have much to learn about SCD in ESRD. It is clear that it will take different strategies to curtail SCD. Lastly, it will also be important to start including patients with CKD and ESRD in clinical trials so we can start to achieve a degree of evidence when seeing patients with what we think are risk factors for SCD.

Acute Coronary Syndrome in ESRD

This matchup couldn’t be more similar—definitely a knock down drag out. ACS, just as SCD, is just a completely different phenomenon in patients with diminished kidney function (CKD and ESRD) than in the general population.

To be fair, the discrete ruptured plaque in an isolated stenotic vessel still occurs in this population, but this is far less common than in the general population. The pathophysiology and thus the clinical presentation differ, not to mention the risk of restenosis, bleeding, or the obligatory AKI event after contrast exposure in CKD. Acute coronary syndrome might need a name change to acute coronary syndromeCKD.

First, let's tackle the clinical presentation of ACS. Patients with diminished kidney function present differently than what is typically seen. ACS represents a spectrum of syndromes from unstable angina (UA) to non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation myocardial infarction (STEMI). So, how are they different?

First, patients with CKD are less likely to have:

typical angina symptoms

EKG changes (ST elevation or depression), Q waves, LBBB

Secondly, patients with CKD are more likely to have:

Hospital admissions with alternate diagnoses

HF symptoms

The diagnosis of ACS becomes even more confusing when you factor in alterations seen in serum troponin levels. Troponin levels have become ubiquitous in the diagnosis of ACS. Troponin issues in CKD was a recent topic of #NephJC. Case in point: the mere presence of a slightly elevated serum troponin level portends to worse cardiovascular outcomes in patients with advanced CKD or ESRD. The delta change (from baseline level) in troponin is more sensitive for AMI than the absolute level.

What is different in patients with CKD? Why this different presentation and accelerated phenotype?

Several theories have emerged. Patients with CKD tend to have a higher burden of multivessel disease with complicated anatomy (longer and more tapered stenoses). The diseased vessels typically have more medial calcification (instead of intimal fibroatheromatous plaque). The traditional risk factors like LDL cholesterol, tobacco use, and family history are weaker associations in CKD despite the higher burden.

Postulated pathophysiological reasons are:

chronic inflammation

less nitric oxide availability

chronic oxidative stress

phosphate retention

secondary hyperparathyroidism

elevated FGF-23

intravascular calcium phosphate crystallization

uremia-related metabolic exposures

Even after the diagnosis is made, the treatment of ACS in CKD remains a poorly studied area. Even worse are studies that show that patients with CKD receive suboptimal care compared with patients who have normal kidney function (however, evidence from clinical trials are lacking to truly say these are "evidence based," as CKD is a typical exclusion criteria).

Studies have shown that patients with CKD are less likely to receive:

reperfusion therapy in NSTEMI

coronary angiography in ACS

beta-blockers, ACEi, statins in AMI

Just as with AICD trials for primary prevention of SCD, ACS treatment trials typically excluded patients with advanced kidney failure. For instance, the NORDISTEMI trial (looking at percutaneous intervention [PCI] after thrombolysis) excluded patients with creatinine > 2.8, and the TACTIC-TIMI-18 Trial (looking at PCI in NSTEMI) excluded patients with a creatinine > 2.5. What are we to do? A systematic review published in 2009 reported that patients receiving an early invasive strategy for UA/NSTEMI fared better in CKD.

What about coronary artery bypass grafting (CABG) in CKD/ESRD? Only observational studies looking at PCI vs CABG have been performed in patients with advanced CKD or ESRD. A meta-analysis published in European Journal of Internal Medicine in 2013 looking at 28 retrospective studies showed that patients with CKD fared better with CABG compared with PCI. However, this sort of analysis is fraught with problems. It is conceivable that only the "healthier" patients were referred for CABG, thus leading to bias in these studies.

Where do we go from here? We need to start including patients with kidney failure in clinical trials, for one. We need to start advocating that patients with diminished kidney function receive the same attention as any other patient. We also need to widen our differential diagnosis when seeing patients present with fatigue, shortness of breath, and consider ACS.

ACS vs SCD will be a tough matchup. Both are serious contenders to go far in NephMadness. However, we still have a lot to learn about each of them.


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