Nephrology Hypertension

Medical Management of the Dialysis Patient: Cardiovascular Complications

Does this patient have cardiovascular complications related to chronic kidney disease?

Does this dialysis-dependent patient have chronic heart failure or volume overload?

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with chronic kidney disease. (U S Renal Data System, USRDS 2010 Annual Data Report: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2010).The rate of events related to CVD increases exponentially with progressive decrease in glomerular filtration rate (GFR) and/or worsening albuminuria.

Despite recent advances in the managment of chronic kidney disease (CKD) as well as advances in dialysis techniques and dialysis dose delivery, the pathophysiology of CVD in patients with CKD has remained illusive at best. Additionally, the spectrum of CVD in the growing population of CKD as well as dialysis dependent population is quite different than the spectrum of CVD in the general population. Notably, the major burden of CVD in CKD population is the development of chronic heart failure (CHF).

Although the annual mortality rate while on dialysis is nearly 15-20%, 2/3 of these deaths are secondary to underlying and undiagnosed CHF and sudden cardiac death SCD.

Patients with different stages of CKD remain at increased risk for the development of symptomatic CHF. Dhingra et al demonstrated that incidence of CHF and composite end point of CVD death and heart failure increased with progression in CKD; incidence of CHF increased three fold /1000 person-years, such as in patients with estimated glomerular filtration rate (eGFR) >90 ml/min (3.2 / 1000 person-years) vs 8.9 /1000 person-years in patients with eGFR <60 ml/min.

Similarly, the rate of composite end point (CVD death and heart failure) increased from 7.1 to 27.0 /1000 person-years, respectively. Detailed analysis of URDS data demonstrated that nearly 30% of incident dialysis patients have a history of CHFand another 7% will develop heart failure (HF) symptoms during the follow-up on dialysis therapy.

The incidence of de novo coronary artery disease (CAD) is reported in only12% of ESRD patients during the mean follow-up of more than 3 years (hence an annual incidence of <4%). However, the survival (median) decreased by more than 50% in those with HF compared to those dialysis patients who did not have the diagnosis of CHF.

A more recent USRDS database analysis by Stack et al analyzed an incident cohort of dialysis patients (n = 926,298) from 1995 to 2005. Although the prevalence of CHF was significantly higher in women than men and in older than younger patients, overall prevalence of CHF did not change over time either in men (range 28% to 33%) or in women (range 33% to 36%).

Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood. As has been noted in the studies of CHF in the general population, CHF in CKD population could be due to either reduced or preserved left ventricular function, currently designated as systolic heart failure or diastolic heart failure, respectively. Additionally, patients with CKD while on dialysis are at risk of developing high-ouput failure as consequence of arteriovenous fistula or graft.

The diagnosis of CHF in the dialysis population is confounded by the fact that the signs and symptoms of CHF as established by Framingham study overlap with the symptoms and signs of volume overload.

The presence of heart failure could be contributing to increased cardiovascular morbidity and mortality in dialysis patients. It is also possible, as has been demonstrated in the general population with CHF, that the presence of heart failure could be an important underlying morbidity that contributes to an increased rate of SCD in dialysis population.

However, whether a patient is labelled with CHF, pulmonary edema or volume overload, 5-year survival was 12.5, 20.2, and 21.3%, respectively. Recent data analysis supports the notion that inter-dialytic weight gain of >1.99 kg regardless of the diagnosis of heart failure is a risk factor for increased all-cause mortality as well as cardiovascular mortality. The mortality risk increases exponentially with an increasing degree of interdialytic weight gain.

Based on these observational data, it is prudent that dialysis patients who present with new onset dyspnea, or worsening shortness of breath (SOB) , or sudden onset SOB (flash pulmonary edema like picture), or other symptoms and signs of volume overload should be evaluated for the potential diagnosis of acute decompensated heart failure.

What tests to perform?

Value of biomarkers in the work up of chronic heart failure in patients with rchCKD

Lab Testing

The diagnosis of CHF is based on symptoms, signs as well as the evaluation of different biomarkers based on American Heart Association (AHA) recommendations.

Cardiac biomarkers

The usefulness of different cardiac biomarkers in the diagnosis and management of acute heart failure in the general population is very well established. The recent introduction of the commercial assays for biomarkers such as B-type natriuretic peptide (BNP) and amino-terminal pro-BNP (NT-proBNP) have a significant impact on diagnosis and treatment of acute dyspnea of unknown etiology as well as day to day management of heart failure in the general population.

There is an ongoing debate about the interpretation and significance of different levels of BNP and NT-proBNP in patients with CKD. It remains to be elucidated if increased levels of BNP and/ or NT-proBNP in the presence of CKD could be due to the combination of decreased clearance as well as increased production as a consequence of the almost universal presence of LVH in patients with CKD. If increased levels of BNP and NT-proBNP are in fact related to decreased clearance due to impaired renal function (although controversial), that may not allow these biomarkers to be used for prognostic purposes or to guide therapy of heart failure in the presence of CKD or on dialysis therapy.

However, a recent study by Anwaruddin et al demonstrated that using a cut off value for NT-proBNP (>1200 pg/ml) had a sensitivity (89%) and specificity (72%) for the emergency diagnosis of acute heart failure in patients with CKD ( eGFR <60 ml/min/1.73m2). Additionally, the magnitude of NT-proBNP level at the time of initial presentation in the CKD population correlated with 60-day all-cause mortality. Therefore, these biomarkers remain valid tools for the purposes of diagnosis and treatment in CKD population.

Changes ( particularly a decrease) in the levels of these biomarkers with treatment of acute heart failure predicts all-cause mortality and hospital readmission rates in the general population. For example, a less than 50% drop in admission NT-proBNP was associated with greater risk of death or rehospitalization at 1 year. The predictive value of decreasing levels of biomarkers has not been tested in patients with CKD.

Summary: despite the debate regarding the impact of renal clearance of biomarkers, the strong negative prognostic implications of a high NT-proBNP value in a dyspneic patient holds true even in patients with CKD.

Evaluation of underlying causes

Once the diagnosis of CHF is suspected, such patients should be evaluated for the underlying cause of CHF. Patients with CKD who present with more than an episode of shortness of breath, or pulmonary edema, or need repeated sessions of volume control (ultrafiltration) should be suspected of having acute heart failure or acute decompensated chronic heart failure.

Hospitalization for new onset shortness of breath provides an opportunity for comprehensive assessment, including history and physical examination, an electrocardiogram, cardiac biomarkers, echocardiography with doppler, and other goal-directed advanced testing based on the understanding that treatment of reversible factors for heart failure can be identified, investigated and treated as necessary.

Identify and treat cardiac abnormalities. Patients with CHF may have an underlying cardiac substrate leading to the onset of complex symptoms of heart failure. These substrates can range from obstructive coronary artery disease, viable but dysfunctional myocardium, valvular abnormalities, cardiac dyssynchrony, or pericardial disease.

Dysfunctional myocardium could be due to systolic dysfunction (systolic heart failure) or diastolic dysfunction (diastolic heart failure). Although diastolic dysfunction is the most common etiology of heart failure in patients with CKD, systolic heart failure is important to recognize since it could be due to underlying ischemic heart disease, leading to ischemic dilated cardiomyopathy.

Based on the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; 2009 focused update for the diagnosis and treatment of heart failure in general population.

A complete history and physical examination should be the first step in evaluating the patient with symptoms of heart failure. Specifically it would allow identification of prior and current evidence of acute coronary events or structural heart disease.

The single most useful diagnostic test in the evaluation of patients with CHF is a detailed 2-dimensional echocardiogram in combination with Doppler flow studies to evaluate myocardium, including chamber dilatation, evaluation of heart valves and pericardium. According to ACCF/AHA guidelines, three elements need to be evaluated on echocardiographic examination: a) status of LV ejection fraction (EF): preserved or reduced; b) structure of LV; normal or abnormal; c) presence or absence of structural valvular, right ventricular or pericardial abnormalities.

Comprehensive echocardiographic evaluation allows definition of cardiac abnormalities, as patients oftentimes may have more than one cardiac abnormality that is responsible for the development of heart failure. Additionally, follow-up echocardiogram offers useful information regarding the changes ( improvement or worsening, or development of new abnormalities) from baseline to assess the prognosis and gauge the response to therapy.

How to evaluate ischemic dilated cardiomyopathy? Systolic dysfunction (LVEF <0.5) should be evaluated for underlying obstructive coronary artery disease for reversible ischemia ( viable myocardium) by myocardial perfusion study (nuclear medicine) or dobutamine echocardiogram.

Noninvasive imaging to detect myocardial ishcemia and myocardial viability is an important step in the evaluation of patients presenting with HF, since such patients can benefit by coronary revascularization. Patients with reversible ischemia shall be referred for coronary angiogram and if necessary for right heart catheterization unless the patient is not eligible for revascularization.

Endomyocardial biopsy

What is the role of endomyocardial biopsy (EMB) in the diagnosis and management of CHF in CKD population? EMB remains controversial and opinion based.

The role of EMB in the diagnosis of CHF in the general population has not been established. A recent guideline paper published by AHA reviewed different clinical scenarios based on the level of evidence about the role of EMB in the diagnosis of heart failure of different etiologies. Unfortunately this position paper did not discuss the epidemic of CHF in the CKD and dialysis population. However, CKD patients with heart failure may be somewhat different than CHF patients in the general population.

Since there is a possibility that uremic milieu in dialysis dependent patients with systolic heart failure (non-ischemic dilated cardiomyopathy) could have irreversible myocardial damage due to uremic toxins as well as repetitive dialysis induced myocardial injury, both will ultimately lead to myocardial fibrosis. Evaluation of endomyocardial biopsy will allow to evalaute the degree and extent of myocardial fibrosis.

Extensive endomyocardial fibrosis in the presence of worsening and treatment refractory heart failure would indicate treatment with either mechanical device or heart transplantation will not be beneficial. More importantly, it will allow to determine if patients with heart failure and significant degree of myocardial fibrosis may not benefit with kidney transplantation alone but will benefit from combined heart and kidney transplantation.

After the diagnosis of CHF in the CKD population, the most important task is to determine the underlying pathophysiology of CHF.

Almost invariably patients with CKD have problems with volume control along with lack of response to diuretic agents. However, the challenge is to determine if the symptoms complex is simply the reflection of underlying heart failure; systolic heart failure, diastolic heart failure, or high output failure, or the combination of these factors.

In patients with systolic heart failure, the most important challenge is to determine if systolic dysfunction is secondary to underlying epicardial coronary artery disease, which could be amenable to treatment with revascularization or due to uremic cardiomyopathy or other types of non-ischemic dilated cardiomyopathy as seen in the general population with heart failure.

Controversies in diagnostic testing for the evaluation of underlying ischemic myocardium (ischemic heart disease)

The optimal screening test ( pharmacologic myocardial perfusion imaging or dobutamine (stress) echocardiogram) for the detection of obstructive coronary artery disease in patients with different degrees of CKD and in dialysis dependent patients is still debatable. However, institutional cardiology expertise is the main determining factor as to the type of modality to be used for the evaluation of the ischemic heart disease.

How should patients with heart failure or volume overload be managed?

Management of heart failure in CKD patients

Management of heart failure in the CKD population is a daunting task. Management of heart failure in the CKD population can be dichotimized based on CKD stage. Dialysis dependent patients with acute heart failure can be managed by aggressive ultrafiltation unless heart failure is associated with hemodynamic instablitiy (MAP < 70 mmHg) or cardiogenic shock.

Such patients should be treated in the intensive care setting and considered for continuous renal replacement therapy (CRRT) based on the local hospital practices. The goal of the therapy is to relieve the symptoms and maintain the hemodynamic stability, and to evaluate the underlying pathophysiology and tailor the treatment for CHF.

Those patients with advanced CKD but not on dialysis can be treated with intensive diuretic therapy, but response to diuretics may not be optimal. Such patients are also at risk of developing acute kidney injury (AKI) due to cardio-renal phenomenon which may further confound treatment with diuretic therapy.

Medical therapy

According to AHA practice guidelines in the general population with heart failure: the following step-wise approach is based on the strong evidence accumulated by randomized controlled trials (RCTs) in the general population with heart failure. However, expert opinion calls for the treatment of HF in CKD and dialysis population with conventional therapies mostly based on the data extrapolated from the studies performed in the general population with heart failure.

There is a plethora of information indicating that HF in CKD and dialysis population may have different pathophysiological bases, and patients with CKD have a distinct spectrum of drug metabolism with impaired renal clearance or different pharmacokinetics while on maintenance hemodialysis.

Step A

Evidence based studies support the initiation and dose-titration of ACE-I.

There is a lack of data regarding the efficacy and safety of ACE-I in patients with heart failure and concomitant CKD or dialysis therapy. Only a randomized study with the use of angiotensin-receptor blocker (telmisartan vs placebo) by Cice et al in a small number of dialysis patients with systolic heart failure showed that add on telmisartan on the background use of ACE-I, beta-blockers and digitalis resulted in more than 50% reduction in all-cause mortality in the treatment group.

Also, there was significant reduction in other primary end-points such as cardiovascular death, and HF length of stay with telmisartan therapy. The rates of hypotension and drug discontinuation due to other adverse events was not significantly higher with the use of telmisartan therapy despite forced telmisartan dose titration compared to the placebo group.

On the contrary, two large-scale, randomized studies with two different ARBs (Valsartan Heart Failure Trial and Candersartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) failed to show beneficial effect on all-cause mortality in the general population with heart failure. The results of telemisartan vs placebo in dialysis patients with heart failure are very encouraging, but need to be carefully applied in day-to-day practice. Post-hoc analysis of the Valsartan study (Val-HeFT) in the CKD population (eGFR <60) demonstrated persistence of benefit with valsartan in patients with mild CKD with heart failure.

Step B

Treatment with beta-blocker ( particularly with carvedilol) decreases all-cause mortality as well as cardiovascular mortality in the general population with systolic heart failure. Only one study so far has demonstrated that carvedilol has a similar efficacy when used in dialysis patients with systolic heart failure even within the limitations of this study. These limitations include small sample size, single center study and a homogeneous Italian population. Data analysis of USRDS registry showed that the use of beta-blockers in dialysis popuation with heart-failure had an adverse effect on all-cause mortality.

Thus the use of beta-blockers in the dialysis population should be individualized with careful monitoring of the dose titration and adverse outcomes that may not be inconsequential due to lack of data.

Treatment with carvedilol in patients with early CKD and systolic heart failure is associated with decreased mortality and heart failure hospitalizations. However, the safety and efficacy of carvedilol in heart failure patients with advanced CKD (stage 3b and above) could not be established.

Recent analysis and systematic review of all published studies with different types of beta-blockers in heart failure patients concluded that the use of these agents in CKD with heart failure reduced all-cause mortality with the caveat that there was a lack of people with CKD stage 3b and above in this data analysis.

Summary: the use of carvedilol or other beta-blockers in CKD and systolic heart failure is not supported by RCT but is simply being extrapolated from the data from the general population. In the absence of proven evidence, such therapy should be used judiciously and with carefull monitoring.

Step C

Individualized need for digitalis therapy

AHA recommends that after optimizing the dose of beta blockers, ACE-I and diuretics, to further control the symptoms of HF, digitalis therapy may be initiated. The Digitalis Intervention Group established the efficacy of digitalis treatment in the general population with heart failure. Since digitalis is dependent on renal clearance, careful dose monitoring in patients with CKD is required. Secondary analysis of former study participants was stratified based on different stages of CKD and indicated that beneficial effects of digitalis persist in those with mild to moderate CKD. There is a paucity of data about the benefits of digitalis therapy in dialysis patients with systolic heart failure.

Step C

AHA recommends that blockade of aldosterone receptors either with the use of spironolactone or eplerenone, in addition to standard therapy, significantly reduces the risk of both morbidity and mortality among general population with severe heart failure. The safety and efficacy of aldosterone receptor blockers have not been demonstrated in patients with different degrees of CKD.

Isolated Ultrafiltration

Another consideration is the early use of isolated ultrafitration when the patient continues to show symptoms of heart failure, very high levels of BNP, and/or NT-proBNP despite use of optimal pharmacological therapy. A recently completed randomized study (UNLOAD study) compared the short and long-term safety and efficacy of an advanced form of ultrafiltration therapy (Aquapheresis) versus conventional diuretic drug therapy in heart failure patients. This study demonstrated that 48 hours of aquapheresis resulted in significant reduction in weight loss (>30%) and net fluid loss( >28%) with a corresponding decreased rates ( more than 50%) for rehospitalization and decreased length of stay during the rehospitalization.

Another study called "The CARdiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF Study), is a NIH funded multicenter study to test the hypothesis that Aquapheresis therapy in hospitalized heart failure patients would result in better control of symptoms of heart failure and improvement in CKD compared to Stepped up pharmacologic therapy. (NCT00608491) It is not clear if aquapheresis therapy offers an added advantage in those heart failure patients who are already on three times per week maintenance hemodialysis therapy. Recent pulblication (2012) of this data suggested that use of ultrafiltration was not associated with added benefit but was associated with increased rate of adverse events. Hence the use of add-on ultrafiltration should be carefully considered.

Use of inotropes or nesiritide has not been studied in the CKD population and their use is being discouraged in the general population with heart failure.

Cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) therapy in a select group of heart failure patients (dilated cardiomyopathy either ischemic or non-ischemic, LVEF =or<35 and a QRS duration of = or>120 ms, sinus rhythm, and NYHA functional class III or IV) despite optimization of medical therapy improves symptoms, morbidity and mortality in CHF patients. Data indicate that CKD patients with heart failure have impaired inctracardiac conduction as well as increased incidence of LV asynchrony. Cleland et al showed that presence of LV asynchrony was an independent risk factor for worsening HF as well as all-cause mortality.

Therefore, one would expect that patients with CKD and CHF will have more than expected benefit from CRT therapy. Clearly there is a paucity of date about the safety and efficacy of CRT therapy in the CKD population. Notwithstanding, the results of post hoc analysis of the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study demonstrated that HF patients with CKD (eGFR <60 ml/min) at the time of implantation of CRT therapy showed that the CKD population responded favorably to CRT intervention.

However, two other small retrospective studies showed that CKD patients failed to respond to CRT therapy (defined as more than 15% decrease in LV systolic volume at 6-months). Those who responded to CRT therapy, also demonstrated improvement in renal function. One would however argue whether this data analysis was in those patients who in fact had AKI due to cardiorenal syndrome.The value of CRT therapy in dialysis patients with HF has not been established. Case reports have indicated that since dialysis patients are at risk of bacteremia, the CRT itself may become infected, requiring removal of the CRT unit.

Mechanical device, heart transplantation, or palliative therapy

AHA states that if CHF patients who continue to remain symptomatic after optimization of medical therapy, or need inotropic support should be considered for mechanical device or heart transplantation.

A ventricular assist device (VAD) can be used for those with failure of response to medical therapy and who are hospitalized with end-stage systolic heart failure. It can be used as a bridge-to-transplant or as a destination therapy for providing a long-term support in patients who are not candidates for heart transplant.

Without this device, there is a greater risk of death during the wait for a transplant. When used as a bridge-to-transplant or as destination therapy, the VAD provides effective hemodynamic support, maintains or improves other organ function, improves exercise performance and enables participation in cardiac rehabilitation.

Given the benefits of VAD therapy in the population with CHF, there is a limited experience with the use of VAD in patients with heart failure and different stages of CKD or dialysis therapy. Some studies have suggested that renal failure of any degree is a major contraindication for treatment with VAD. Nonetheless, a small retrospective study in patients with heart failure, cardiogenic shock and advanced renal failure demosntrated reversal of AKI when treated with LVAD.

Challenges of treatment in dialysis patients with CHF

Dialysis patients with systolic heart failure pose a complex problem in dialysis units due to; a) baseline hypotension as well as increased risk of developing intradialytic hypotension, b) difficulty in controlling the weight due to inadequate UF, c) frequent hospitalizations due to symptoms of heart failure, d) serial decrease in LVEF due to perhaps ongoing myocardial damage. This group of dialysis patients pose different types of challenges for the providers as well as the dialysis unit staff.

Can such patients be treated with peritoneal dialysis therapy?

Peritoneal dialysis (PD)

Advocates of PD have suggested that PD therapy could prevent hemodynamic fluctations and prevent IDH. However, observational studies, as well as a recently reported prospective study with a follow-up of nearly 4 years demonstrated that mortality is in fact higher in patients with systolic heart failure on PD. In view of this evidence, dialysis patients with systolic heart failure may not benefit by PD or switching from IHD to PD therapy.

Short daily hemodialysis (SDHD)

This modality consists of 1.5 -2.5 hours of daily dialysis for 5-6 days per week. SDHD has the advantage of regulating the volume control on a daily basis with effective reduction in ECF volume excess and without need for forced UF to achieve volume control. It definitely abrogates IDH. Hence, SDHD should be a preferred modality of dialysis in patients with systolic heart failure and recurrent symptoms of heart failure. Furthermore, SDHD reduces the left ventricular mass index (LVMI).

Nocturnal home hemodialysis (NHD)

Nocturnal hemodialysis patients are trained to provide treatments in their home 6 or 7 nights per week for 3 to 8 hours per treatment. The most important advantage of NHD therapy has been associated with cardiovascular benefit, among the post important CV benefit is the regression of LVMI as has been demonstrated by observational study as well as by randomized study. Additionally, NHD has also been demonstrated to lead to an increase in LVEF in patients with systolic heart failure.

Kidney transplantation: Should dialysis patients with systolic heart failure with reduced LVEF be considered for kidney transplantation?

More often than not dialysis providers believe that dialysis patients with chronic heart failure and reduced LVEF are poor candidates for kidney transplantation. Also, it is often arguedthat such patients should be considered for the combination of kidney and heart transplants.

Evidence suggests that systolic heart failure and reduced LVEF can reverse to normal LVEF with resolution of symptoms of heart failure after successful kidney transplantation. These studies support the hypothesis that most of the dialysis patients with heart failure and reduced LVEF could have uremic cardiomyopathy.

Kidney transplantation during the early phases of the onset of cardiomyopathy could be reversible following kidney transplantation. Delaying the transplant process could be adversely associated with the recovery of LVEF, thus supporting the idea that exposure to dialysis for prolonged period could lead to myocardial fibrosis and hence irreversible heart failure.

Dialysis patients with chronic heart failure and reduced LVEF with frequent symptoms of heart failure should be evaluated for the presence of irreversible myocardial scarring (fibrosis) by endomyocardial biopsy, as has been demonstrated by Aoki et al. Patients with extensive fibrosis on myocardial biopsy could be the candidates for combination of heart and kidney transplantation.

What happens to patients with cardiovascular complications?

N/A

How to utilize team care?

Specialty consultations: Dialysis patients with symptoms of shortness of breath that persists after achieving approximate dry weight should be screened for signs of heart failure. A two dimensional echocardiogram should be obtained.

Nurses Dialysis nurses should offer patients with chronic heart failure dietary guidance including low salt diet with adequate protein intake based on their nuitritional status.

Dietician: Chronic heart failure often leads to poor protein intake due to poor appetite leading to cardiac cachexia. These patients benefit from intensive dietary interventions.

Therapists (physical, occupational, speech, other): Dialysis patients with chronic heart failure will benefit from a cardiac rehabilitation program.

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