Epidemiology and CHRONIC KIDNEY DISEASE–Specific Disease Mechanisms
CKD dramatically increases the risk of developing cardiovascular disease (CVD; 3-30 times depending on CKD stage and study).97,98,99 Nearly half of all deaths in CKD patients are from cardiovascular events, and CKD patients are more likely to die from CVD than progress to ESRD during their lifetime.100,101
Risk factors for the development of CVD in patients with CKD can be divided into traditional and nontraditional factors. Traditional factors include hyperlipidemia, hypertension, diabetes, and smoking and are important risk factors for CVD also among patients without CKD. These risk factors are also risk factors for CKD, and their prevalence has been reported to be twice as high among CKD patients compared to non-CKD patients.102 Nontraditional risk factors refer to the effects of chronic renal dysfunction on cardiac health. These factors are consequences of CKD and include volume overload, increased sympathetic tone, activation of the RAAS, oxidative stress, uremic toxins, abnormal mineral metabolism (calcium, phosphorous, vitamin D), anemia, and malnutrition. The importance of the nontraditional risk factors is highlighted by the poor performance of the Framingham Risk Criteria in CKD patients.103 Three important mechanisms contribute to CVD progression in CKD: autonomic dysfunction, vascular pathology, and cardiac pathology.
Autonomic function is impaired in CKD patients, with a relative dominance of sympathetic over parasympathetic activity.104,105,106,107 The autonomic nervous system constitutes the efferent arm of the baro- and chemoreceptor reflex arcs. These reflexes are impaired in CKD. The detailed mechanisms through which CKD leads to autonomic dysfunction are unknown, but autonomic dysfunction in CKD is improved after transplantation, nephrectomy, or renal denervation. Hence, local pathological processes within the diseased kidney likely play a role.108,109
Signs of autonomic dysfunction in CKD patients include reduced heart rate variability (a marker of vagal autonomic sensitivity and a poor prognostic sign) and greater low-frequency oscillations of systolic blood pressure variability (a marker of sympathetic tone).110,111,112
Increased sympathetic tone promotes smooth muscle cell and fibroblast proliferation in blood vessels and activates the RAAS pathway.113,114 Hence, autonomic dysfunction contributes to cardiovascular pathological remodeling. Through these mechanisms, autonomic dysfunction also causes worsening of renal function.104
CKD exacerbates atherosclerotic processes.115 CKD patients have more severe arterial hypertrophy and calcification and have stiffer arteries compared to non-CKD patients.116
The mechanisms leading to arterial pathology and endothelial dysfunction in CKD are incompletely understood, but increased oxidative stress, low-grade inflammation, uremic toxins, increased wall stress (associated with arterial hypertension), and impaired calcium/phosphorous homeostasis likely contribute.117,118,119 Sympathetic hyperactivity promotes smooth muscle proliferation via norepinephrine, and indirectly via salt and fluid retention and arterial hypertension.
Left ventricular hypertrophy is present in 40% of CKD patients (mostly of the eccentric type), and the prevalence increases with declining GFR; for ESRD patients on hemodialysis, it is over 75%.120 Left ventricular hypertrophy is likely promoted by chronic hypertension (increased afterload), anemia (reduced oxygen delivery), sympathetic and RAAS hyperactivity (increased cardiac fibrosis), and volume overload. Cardiomyocyte hypertrophy is not accompanied by a similar degree of neovascularization. Hence, the cardiomyocyte-to-capillary ratio increases, leading to relative ischemia of the myocardium. This is believed to explain why some CKD patients present with angina even in the absence of significant CAD.121
Almost 50% of CKD patients have either mitral or aortic calcification, and CKD is a strong predictor for valvular dysfunction (stenosis and/or regurgitation).122 Valvular disorders increase left ventricular afterload (aortic stenosis) and/or preload (aortic regurgitation, mitral regurgitation).
Heart failure is common in CKD, with a prevalence > 50% among ESRD patients. Heart failure with preserved ejection fraction accounts for approximately half of these cases and carries a worse prognosis than heart failure with reduced ejection fraction.123 The etiologies of heart failure in CKD patients include pathological left ventricular remodeling secondary to sympathetic and RAAS overstimulation, left ventricular hypertrophy, valvular heart disease, and ischemic heart disease. Chronic anemia and uremic toxins may also contribute.
Management of Cardiovascular Risk Factors in the Patient with Chronic Kidney Disease
The majority of the pivotal large-scale multicenter trials on which most cardiovascular guidelines are based excluded patients with CKD. Therefore, the management of cardiovascular disease in the CKD patient requires judicious extrapolation of treatment effects in non-CKD patients, supplanted by knowledge derived from observational studies and with consideration of CKD pathophysiology.
Hypertension is prevalent among CKD patients. CKD-associated (nontraditional) risk factors include sodium retention and hypervolemia, increased RAAS activity, autonomic imbalance, and endothelial damage. Furthermore, traditional risk factors for hypertension are prevalent among patients with CKD and hypertension is itself an important risk factor for CKD.
Current guidelines124 recommend a blood pressure goal of 140/90 mm Hg for CKD patients, which is the same as for non-CKD patients. Restriction of sodium intake reduces systolic blood pressure, extracellular fluid volume, and proteinuria compared to patients on a regular diet.125 The National Institutes of Health (NIH)-funded SPRINT study randomized 9361 patients with hypertension, of whom 28% had preexisting CKD, to a systolic blood pressure goal of < 140 mm Hg versus < 120 mm Hg. The trial was stopped prematurely due to a significant 25% reduction in the composite primary end point of myocardial infarction, other ACS, stroke, heart failure, or death from cardiovascular causes and a 27% reduction in total mortality.126 Guidelines are expected to be updated to more aggressive goals.
ACEIs and ARBs are considered first-line medical therapy, especially in cases of concomitant proteinuria or diabetes. These drugs lower blood pressure and slow the decline in renal function in CKD patients.127,128,129,130 ACEI/ARB treatment may result in hyperkalemia. Serum creatinine levels therefore need to be monitored in these patients. An increase in serum creatinine > 25% should prompt further evaluation. Inadequate volume status, too low blood pressure, drugs that may reduce GFR (nonsteroidal anti-inflammatory drugs), or excessive potassium intake should be corrected. If these reversible causes are absent, the ACEI/ARB should be stopped, which should result in the return of kidney function to baseline.131,132 The combination of an ACEI and ARB can further lower blood pressure, but carries a considerable risk of hyperkalemia.133 Dual therapy is, therefore, not recommended.
Calcium channel blockers and/or β-blockers are considered second-line agents.134,135 Diuretics should be considered as second-line agents to be used in cases of volume overload, with loop diuretics being the preferred drugs in later stages of CKD.
Lipid abnormalities are common in nearly all stages of CKD. The most common abnormality is hypertriglyceridemia, as nearly 50% of CKD patients have fasting triglyceride levels above 200 mg/dL,136 the result of impaired removal of triglycerides from blood, secondary to changes in the composition of triglycerides (enrichment in apolipoprotein C3), as well as reductions in hepatic lipoprotein lipase activity. CKD patients also frequently have decreased apo-A1 and high-density lipoprotein (HDL) levels. The typical association with greater low-density lipoprotein (LDL) and greater risk of cardiovascular events is not as robust in this population. In dialysis patients, in particular, those with both the highest and lowest levels of LDL are at greatest risk for CVD, likely related to confounding by malnutrition in those with significantly impaired renal function.137,138 Patients with nephrotic syndrome typically have markedly increased LDL-cholesterol levels related to increased hepatic protein production.
In a post-hoc analysis of the JUPITER (Justification for the Use of Statins in Prevention—An Intervention Trial Evaluating Rosuvastatin)139 primary prevention trial of rosuvastatin 20 mg compared with placebo, among those with moderate CKD (eGFR < 60 mL/min/1.73 m2 at study entry, n = 3267), rosuvastatin was associated with a 44% reduction in all-cause mortality (hazard ratio [HR], 0.56; 95% CI, 0.37–0.85; P = .005) and a 45% reduction in risk of myocardial infarction, stroke, hospital stay for unstable angina, arterial revascularization, or confirmed cardiovascular death (HR, 0.55; 95% CI, 0.38–0.82; P = .002). LDL-cholesterol and high sensitivity C-reactive protein reductions as well as adverse events with rosuvastatin were similar among those with and without CKD.
By contrast, the German Diabetes and Dialysis Study140 enrolled 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were randomized to receive 20 mg of atorvastatin per day versus placebo. The primary end point was a composite of death from cardiac causes, nonfatal myocardial infarction, and stroke. After a median follow-up of 4 years there was no significant reduction in the primary composite end point. Cardiac events were reduced with an HR of 0.82, while cerebrovascular events were increased twofold. The more recent SHARP (Study of Heart and Renal Protection)141 trial randomized 9270 patients with CKD (3023 on dialysis and 6247 not) without prior myocardial infarction or revascularization to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The primary end point—a composite of first major atherosclerotic event, nonfatal myocardial infarction or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure—was reduced by 17% without an increase in nonvascular mortality. Notably, results were consistent in the dialysis group. Given that there was no ezetimibe-only group in SHARP, it is not clear whether the results were driven by ezetimibe, simvastatin, or both.
Treatment guidelines generally reflect those found in non-CKD patients, with a particular emphasis on statin therapy for patients with moderate renal dysfunction. Indeed, as CKD is a coronary heart disease equivalent in ACC/AHA hyperlipidemia guidelines,142 most CKD patients are candidates for statin therapy. KDIGO guidelines recommend statin or statin/ezetimibe in patients older than 49 years of age, and statin therapy if there are other known risk factors in patients aged 18 to 49 years.143 The KDIGO guidelines recommend against the use of LDL-cholesterol levels as a target of therapy in patients with CKD, focusing instead on treatment of high-risk patients irrespective of LDL-cholesterol levels. For patients with hypertriglyceridemia alone, the most recent KDIGO guidelines only recommend lifestyle modification therapy. Fibrates have only weak evidence of reducing pancreatitis risk or cardiovascular risk in CKD patients with elevated triglycerides, and are thus not recommended.143
Anemia of Chronic Kidney Disease
Anemia is common in CKD and is almost uniformly present at late stages of CKD.144 It is associated with increased risk for heart failure, stroke, and death.145,146,147 CKD-associated anemia is normocytic and normochromic. It is caused by decreased production of erythropoietin by the kidney as well as by reduced red blood cell survival in the uremic environment. It contributes to the symptoms observed in patients with CKD (fatigue, reduced exercise tolerance, dyspnea) and may exacerbate angina symptoms in patients with concomitant ischemic heart disease. Anemia has also been shown to be a causative factor in left ventricular hypertrophy.
Therapeutic options include erythropoiesis-stimulating agents and red blood transfusion, with iron supplementation as appropriate. Alternative causes of anemia should be identified and corrected if possible. These include iron deficiency anemia and anemia of chronic disease, which are relatively common among patients with CKD. The optimal time to start treating CKD-associated anemia is unknown, but a target hemoglobin concentration between 10 and 12 g/dL is associated with improvements in physical activity, less fatigue, and less left ventricular hypertrophy. However, both blood transfusions and erythropoiesis-stimulating agents carry the risk of serious adverse events, including thrombosis and stroke. Therefore, current FDA and KDIGO guidelines emphasize a personalized approach to care.148 No strict recommendations are given in regards to hemoglobin targets, but because three major randomized trials (CHOIR, CREATE, and NHCT) showed an increased mortality at Hb levels above 13 g/dL,149,150,151 KDIGO guidelines recommend an upper limit of 11.5 g/dL (although the guidelines acknowledge that some patients may benefit from higher levels).
Acute Coronary Syndrome in the Patient with Chronic Kidney Disease
CKD is an important risk factor for CAD, including ACS.152 The difficulty in diagnosing ACS in CKD patients tends to delay treatment, and prognosis after ACS is worse for CKD patients than for non-CKD patients.153 As is the case in other areas of cardiology, the majority of the pivotal multicenter randomized trials on which guidelines for ACS treatment are based have excluded CKD patients.154
CKD patients with ACS are less likely to present with chest pain (at least partly due to autonomic dysfunction). CKD patients are also more likely to have preexisting ST-segment depressions and/or Q waves on resting electrocardiogram (ECG; caused by cardiac hypertrophy and/or previous ischemic injury), which considerably decrease the specificity of the ECG for diagnosing ongoing ACS. Furthermore, plasma biomarkers of cardiac damage, including creatine kinase (CK) and troponins, are often elevated at baseline due to reduced clearance, low-grade inflammation and silent myocardial injury due to small vessel disease. This reduces the specificity of these tests.155,156 The ACS diagnosis is therefore more likely to be missed in CKD patients than non-CKD patients.155 It is recommended to focus on temporal trends in troponin levels and ST-segment depressions and on angina-equivalent symptoms such as worsening dyspnea.157
In the absence of dedicated trials for patients with CKD, ACS treatment guidelines are similar to those for patients without CKD. However, current guidelines recommend a judicious use of antithrombotic agents in patients with CKD (who have an increased bleeding risk) with consideration of CKD as well as other risk factors before initiating particularly potent antithrombotic therapy (eg, triple therapy).158 Importantly, drugs that are cleared from the body predominantly through the kidneys need to be dose-adjusted (Table 105–5).
TABLE 105–5.Cardiovascular Drugs That Need Special Attention in Renal Patients ||Download (.pdf) TABLE 105–5. Cardiovascular Drugs That Need Special Attention in Renal Patients
|Medications ||Precaution |
|Warfarin ||Requires close monitoring of INR and other OTC medications. |
|P2Y12 antagonist and aspirin ||Combination in dialysis patient increases risk of bleeding.238 |
|Low-molecular-weight heparins ||Dose adjustment and monitoring of anti-factor Xa.239 |
|ACEIs and ARBs ||Risk of acute worsening of renal function when used with aggressive diuretic regimen.240 |
| ||Risk for hyperkalemia increases when used with potassium-sparing diuretics.241 |
| ||All ACEIs except fosinopril need dose adjustment for renal impairment.242 |
| ||ARBs do not need dose adjustment in CKD.207 |
|Spironolactone and eplerenone ||Use along with ACEI/ARB and β-blockers increases risk for hyperkalemia.241 |
|α-Adrenergic blockers ||Methyldopa, doxazosin, prazosin, and reserpine active metabolite can accumulate in CKD.243 |
|β-Blockers ||Acebutolol, nadolol, and sotalol need dose reduction in CKD.243 |
|Calcium channel blockers ||No need for dose reduction in CKD.243 |
| ||Verapamil, diltiazem, amlodipine, and nicardipine may significantly increase cyclosporine and tacrolimus levels in transplant recipients. |
|Nitroprusside ||Risk of thiocyanate toxicity in CKD, limit exposure. |
|Hydralazine ||Need dose reduction for eGFR less than 50 mL/min. |
|Lipid-lowering drugs ||Statins when used in combination with cyclosporine may increase risk of rhabdomyolysis. |
|Antiarrhythmics ||Bretylium, digoxin, flecainide, and procainamide need dose adjustments in CKD.243 |
There are a paucity of high-quality data regarding the relative benefits of medical therapy (a conservative strategy) and revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) for patients with CKD and ACS. Retrospective analyses imply that revascularization is favorable compared to a conservative approach.159,160,161 CABG is associated with particularly high risks of stroke and death for patients with CKD, but appears to offer a better long-term prognosis compared to PCI for patients with multi-vessel disease.162,163,164 Hence, guideline recommendations relating to reperfusion strategies are similar for patients with and without CKD, including the importance of individualized decisions based on risk scores (eg, surgical risk, ability to tolerate dual antiplatelet therapy) as well as patient preference165 and use of a heart team approach.
Cardiovascular Drug Pharmacokinetics in the Patient with Chronic Kidney Disease
Many cardiovascular drugs are eliminated from the body by the kidneys. Dose adjustments of some of these drugs are necessary in CKD. Unfortunately, failure to dose-adjust is a common cause of drug toxicity in CKD patients.
Renal clearance of drugs depends on GFR as well as tubular function (reabsorption and/or secretion) and the relative contributions of these mechanisms vary according to drug. Through alterations in body fluid composition and acid–base balance, CKD also affects drug absorption, distribution volume, protein binding, and affinity for drug target molecules.166 Drug clearance in dialysis patients depend on water solubility, distribution volume, protein binding, and diffusion across the dialysis membrane. It can, therefore, be difficult to accurately predict plasma concentrations and therapeutic effect in patients with CKD. Target doses of cardiovascular drugs defined in current guidelines may be difficult to achieve. A general principle is to “start low and go slow” and consider the highest tolerable dose as the optimal dose.
Table 105–5 lists common cardiovascular drugs that need particular attention for patients with CKD. It is recommended to consult specific drug manufacturers’ dose adjustment recommendations when administering drugs to patients with CKD.
Heart Disease in Patients on Dialysis
More than 80% of dialysis patients have concomitant CVD, and CVD is the leading cause of death for dialysis patients (including heart failure, myocardial infarction, and sudden cardiac death [SCD]).167,168,169,170 Three major mechanisms contribute to worsening CVD in patients with ESRD: volume overload, pressure overload, and nonhemodynamic factors such as atherosclerosis, vascular calcification, oxidative stress, inflammation, and stimulation of profibrotic factors.169,171 Managing a patient’s cardiovascular risk profile is, therefore, important in dialysis patients.
The New York Heart Association (NYHA) functional classification for heart failure assessment is less useful in dialysis patients because dyspnea can be related to factors other than heart failure. More importantly, the severity of heart failure–related symptoms changes considerably in relation to the timing of fluid removal. Alternative classification systems have been proposed that take into account the renal component (Fig. 105–2).170
Classification system for heart failure in dialysis patients. Heart failure classification in dialysis patients need to consider that the severity of heart failure symptoms will vary with volume status. ADQI, acute dialysis quality initiative; ESRD, end-stage renal disease; NYHA, New York Heart Association; RRT, renal replacement therapy; UF, ultrafiltration. Reproduced with permission from Chawla LS, Herzog CA, Costanzo MR, et al. Proposal for a functional classification system of heart failure in patients with end-stage renal disease: proceedings of the acute dialysis quality initiative (ADQI) XI workgroup. J Am Coll Cardiol. 2014 Apr 8;63(13):1246-1252.
Important Cardiac Complications in the Patient with Chronic Kidney Disease
Patients with CKD can develop pericarditis secondary to uremia or as a complication of dialysis.172 Rarely, these patients develop chronic constrictive pericarditis. The incidence of uremic pericarditis has declined considerably in the dialysis era, but it still occurs in 5% to 20% of uremic patients. Its exact cause is unknown, but appears related to the accumulation of uremic toxins.172 Uremic pericarditis is less responsive to anti-inflammatory therapy and should be treated by intensive hemodialysis (daily for at least 1 week). Dialysis-related pericarditis typically occurs after several months of dialysis therapy. Whether the etiology is different is debated, but dialysis-related pericarditis is less responsive to intensified dialysis.173 Pericardiostomy and pericardiectomy may be necessary, with the latter the primary treatment for constrictive pericarditis.172 Pericardial effusions are common (volume overload is likely a contributing factor), but tamponade is rare.
Importantly, the differential workup must consider that patients with CKD can also develop viral, fungal, or bacterial pericarditis (particularly if on dialysis), drug-induced pericarditis, and pericarditis due to other underlying disease states.
Patients undergoing hemodialysis have an age-adjusted incidence of infective endocarditis (IE) almost 20 times higher than the general population.174 Patients who are dialyzed through tunneled catheters are at particularly high risk.175 The most common pathogen is Staphylococcus aureus (~ 50%) followed by coagulase-negative staphylococci, enterococci, and Streptococcus viridans.175 The mitral valve is the most commonly involved valve, but ~ 20% of patients have involvement of more than one valve. Dialysis patients with IE have considerably higher mortality (30%-50%) than nondialysis patients with IE.175 Mitral valve involvement and septic embolization are poor prognostic factors.176
IE should be suspected in all hemodialysis patients with fever and/or bacteremia. Classical symptoms and signs include a new regurgitrant murmur, focal neurological deficits, or heart failure symptoms. Transesophageal echocardiography (sensitivity > 90%) is considerably superior to transthoracic echocardiography (sensitivity ~ 50%) at establishing the diagnosis.177,178,179
As a general rule, current pathogen-specific treatment guidelines for IE apply to both dialysis and nondialysis patients with a required minimum of 4 to 6 weeks of parenteral therapy.180,181,182 Antimicrobial therapy is typically delivered after the dialysis session due to the difficulty in maintaining long-term peripheral venous access in dialysis patients. Coordination between nephrologists and infectious disease staff to select optimal antibiotic agent and dosing schedule is recommended. Indications for surgery for dialysis patients with IE are similar to those for nondialysis patients, but operative mortality is considerably higher for dialysis patients.175,180,181,182 Whether dialysis patients who undergo valve replacement should receive mechanical (increased risk of valve thrombosis, requires anticoagulation) or bioprosthetic (accelerated degeneration and calcification in the dialysis patient) valves has not been sufficiently studied.183 A case-to-case decision based on individual risk factors, suitability for long-term anticoagulant therapy, and life expectancy is recommended.
SCD is estimated to account for almost 25% of all deaths among dialysis patients.101 Causes include ventricular tachycardia, Torsades de pointes, and ventricular fibrillation, as well as pronounced bradycardia. Ischemic heart disease, heart failure, vascular calcification, electrolyte and acid–base disturbances, and dialysis-induced electrolyte shifts are believed to contribute to the risk of ventricular arrhythmias in dialysis patients.184,185
Predictors for SCD include atrioventricular or intraventricular conduction delays, left ventricular hypertrophy, QRS or QT-interval prolongation, decreased heart rate variability, documented episodes of nonsustained ventricular tachycardia, exercise-induced arrhythmia, multi-vessel CAD, and hypo- or hyperkalemia.186
Primary and secondary prevention with β-blockers and ACEIs/ARBs is recommended for dialysis patients. Implantable cardioverter-defibrillators (ICDs) trials have systematically excluded patients on dialysis, and the majority of dialysis patients who experienced SCD did not fulfill current criteria for ICD implantation.187 For those dialysis patients with ICDs implanted for ventricular fibrillation/SCD, however, observational data suggest that the benefit in terms of risk reduction is similar to patients without CKD, with a 42% risk reduction,188 suggesting that this potentially lifesaving therapy is underutilized. However, long-term prognosis is still poor for dialysis patients irrespective of ICD implantation.189,190
Cardiovascular Risk Stratification Prior to Renal Transplantation
CVD remains the most common cause of death for patients with CKD, even if they receive a kidney transplant.191 Cardiovascular events are common within the first 3 months following transplantation, but are thereafter less common compared to patients who remain on dialysis.192 Risk factors for posttransplant ischemic cardiac events include presence of CAD, heart failure, diabetes, male gender, age, an abnormal resting ECG, and smoking. Observational data suggest that asymptomatic patients with obstructive CAD benefit from revascularization before transplantation, but randomized trials are lacking.
Screening for CAD is considered warranted before transplantation, but the optimal risk stratification algorithm remains to be established. Whether noninvasive tests (pharmacologic stress echocardiography or nuclear imaging) should be preferred for initial screening, and coronary angiography reserved for patients who have objective evidence of ischemia or who are symptomatic, is debatable. Apart from screening for CAD, the pretransplant cardiac evaluation should seek to identify cardiovascular risk factors amenable to modification (eg, diabetes, hypertension, heart failure) and to identify patients who are unlikely to benefit from transplantation due to poor prognosis related to an extra-renal condition.193
Worsening Renal Function in Patients with Chronic Heart Failure
Worsening renal function in chronic heart failure is associated with adverse outcomes and prolonged hospitalization. The prevalence of CKD among patients with chronic heart failure is at least 25%, and even relatively small reductions in GFR (> 9 mL/min) increase the risk of dying.
Cardiorenal Syndrome Type 2
The term “cardiorenal syndrome” (CRS) has been coined to describe the entity in which concomitant cardiac and renal dysfunction is present in the same patient. CRS is subdivided according to the temporal pattern of cardiac and renal disease (Table 105–6). Herein we focus on the most common CRS type 2 (CRS-2), in which chronic heart failure leads to CKD.
TABLE 105–6.Cardiorenal Syndromes ||Download (.pdf) TABLE 105–6. Cardiorenal Syndromes
|CRS type 1 ||Acute worsening of cardiac function leading to kidney injury and/or dysfunction |
|CRS type 2 ||Chronic abnormalities in cardiac function leads to kidney injury and/or dysfunction |
|CRS type 3 ||Acute worsening of kidney function leads to cardiac injury and/or dysfunction |
|CRS type 4 ||Chronic kidney disease leads to heart injury and/or dysfunction |
|CRS type 5 ||Systemic extrarenal and extracardiac condition leading to simultaneous injury and/or dysfunction of both the heart and kidney |
The pathophysiology behind the development of renal dysfunction in CRS-2 is incompletely understood. There does not appear to be a strong correlation between left ventricular ejection fraction and estimated GFR among patients with chronic heart failure.194 Proposed mechanisms underlying the development of kidney dysfunction in chronic heart failure are outlined in Fig. 105–3.
Proposed mechanisms of renal injury and damage in patients with congestive heart failure. Reduced cardiac function in chronic heart failure leads to a low-output state with renal hypoperfusion and congestion of the venous system (which is effectively transmitted retrograde from the great veins to the renal veins). This results in relative hypoxia of the renal parenchyma. Reduced effective circulatory (low-output heart failure) volume also leads to renin-angiotensin-aldosterone system (RAAS) activation and release of vasoconstrictors (angiotensin, adrenaline, noradrenaline), which increases renal vascular resistance and further reduces renal perfusion. Chronic heart failure is associated with subclinical inflammation and impaired endothelial function, which interfere with the kidneys’ autoregulatory mechanisms. Low-output heart failure also increases the risk of embolization of thrombotic material from the heart or central arteries. Microembolization may further aggravate renal hypoxia. Lastly, most risk factors for cardiovascular disease and heart failure are also risk factors for kidney disease. Accelerated atherosclerosis of the renal vessels and progression of kidney disease due to genetic or acquired risk factors likely also play a role. CKD, chronic kidney disease; LVH, left ventricular hypertrophy. Reproduced with permission from Ronco C, Haapio M, House AA, et al: Cardiorenal syndrome. J Am Coll Cardiol. 2008 Nov 4;52(19):1527-1539.
Regardless of its exact mechanisms, declining renal function in the chronic heart failure patient has important therapeutic implications. Patients with chronic heart failure typically take a considerable number of medications. Many of these are cleared by the kidneys and need to be dose-adjusted when renal function declines.195,196 Although most heart failure therapies are beneficial for patients with CKD, careful monitoring of renal function is necessary and changes in drug regimen may be appropriate.
An important principle in the treatment of CRS-2 is to optimize cardiac function in order to slow or reverse the pathophysiology outlined in Fig. 105–3. Cardiac resynchronization therapy, when indicated, appears to improve both ejection fraction and GFR in patients with CRS-2.197 β-Blockers also appear to be beneficial.198 Antagonism of the RAAS is an important component in both heart failure and CKD therapy. Both ACEIs/ARBs and aldosterone antagonists attenuate excessive RAAS activation and thereby prevent renal vasoconstriction and fibrosis. However, although ACEI/ARBs are beneficial in CRS-2, there is a risk of hyperkalemia as well as of inducing arterial hypotension resulting in worsening renal function. The risk of these complications is higher for patients with CKD than in patients without renal disease.199,200 Hence, caution, frequent monitoring of electrolyte status, and involvement of a nephrologist is recommended.199
Management of volume status is particularly challenging in patients with CRS-2. Restricting sodium intake is important. Diuretic therapy is recommended, but is complicated by the development of diuretic resistance (DR), which carries a poor prognosis.201
The definition of DR is not straightforward and no consensus exists. One approach is to define diuretic efficacy as the change in weight, net fluid balance, or urine output per a defined diuretic dose (eg, 40 mg of intravenous furosemide-equivalent dose). Patients with DR typically have lower GFR than patients without DR, and DR is a predictor of worse outcomes independent of GFR.202 Although intimately intertwined, DR and GFR probably represent different aspects of renal function. Whereas GFR is reflective of the clearance of metabolites (renal ultrafiltration), DR may be a better index of volume and electrolyte homeostasis (tubular function). Even at a severely depressed GFR of 20 mL/min, almost 30 L of fluid (~ 4000 mEq of sodium) is filtered through the glomeruli each day. Volume overload and organ congestion are the main drivers of readmissions and adverse outcomes in CHF.203 This provides a pathophysiological rationale for the strong independent association between DR and poor outcome.
Pharmacokinetic and Pharmacodynamic Considerations
Loop diuretics inhibit the sodium-potassium-chloride cotransporter in the luminal surface of tubular cells in the thick ascending loop of Henle and are typically first-line diuretics used in chronic heart failure.204 Several characteristics of the loop diuretics, which are not related to tubular damage and/or dysfunction, may explain diuretic resistance. Orally administered loop diuretic absorption may be reduced in congestive heart failure due to gut edema and poor intestinal perfusion. In the plasma, > 90% of the loop diuretics will be bound to plasma protein and are therefore not filtered across the glomerulus. In order to reach the tubular lumen they must be secreted by anion transporters in the proximal tubules. Organic anions (eg, urate) compete with the loop diuretics and their transport is inhibited by acidosis. Significant proteinuria increases protein-binding of loop diuretics in the tubular lumen and prevents their pharmacological action.201,205,206,207,208 All these mechanisms lead to a shift to the right in the dose–response curve for loop diuretics. Lastly, sufficient Na+ must be present in the tubule for loop diuretics to work. If proximal tubular Na+ reabsorption is sufficiently increased (for example, due to poor renal perfusion and increased neurohormonal activity), too little NaCl may be delivered to the distal nephron for loop diuretics to work efficiently. Hence a multitude of factors can cause diuretic resistance.204
Managing Diuretic Resistance
After verifying compliance with therapy, the next step in the management of patients with apparent DR is to establish whether intravascular volume overload is present. When intravascular volume overload is not present, volume reduction by diuretics will not unload the heart, but may instead worsen neurohormonal activation. Clinical signs and symptoms (eg, orthopnea, jugular venous distension, rales, hepatomegaly, and edema) are helpful, but lack sufficient sensitivity. Body weight (unless an accurate estimate of “dry weight”) and natriuretic peptides (which track better with wall stress than volume overload per se) are also helpful, but imperfect, means of assessing volume status. Hence, establishing whether a lack of response to diuretics is due to diuretic resistance or relative intravascular depletion remains to some extent an art of medicine.
In the absence of high-quality data from randomized clinical trials, treatment approaches in diuretic resistance are based on knowledge of heart failure pathophysiology and pharmacology (Fig. 105–4). First, the treatment should aim to optimize renal perfusion. This includes optimizing cardiac function, which may include use of inotropes and mechanical assist devices.209 Second, addition of non-loop diuretics should be tried. Thiazide-type diuretics are the most commonly used diuretics in patients who develop resistance to loop diuretics. Thiazide diuretics are a good choice because they act on the distal tubule NaCl symporter, which largely mediates the intrinsic renal adaptations to loop diuretics called the “braking phenomenon.” In other words, with prolonged loop diuretic use, the kidney adapts by upregulating thiazide-sensitive NaCl reabsorption. Mineralocorticoid receptor antagonists and acetazolamide may also be considered, the latter being particularly useful in the setting of diuretic-induced alkalosis. Ultrafiltration may also be effective in DR, but unfortunately the only large-scale randomized controlled trial was terminated early.204,210,211
Proposed approach to treatment in heart failure patients with diuretic resistance. BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; LVAD, left ventricular assist device; MAP, mean arterial blood pressure; MRA, mineralocorticoid receptor antagonists; QD, once daily. Reproduced with permission from Verbrugge FH, Mullens W, Tang WH: Management of Cardio-Renal Syndrome and Diuretic Resistance. Curr Treat Options Cardiovasc Med. 2016 Feb;18(2):11.
Decreased diuretic absorption due to gut edema is particularly common in the patient with right-sided congestion (increased central venous pressure, a surrogate of which can be detected at the bedside by examining for jugular venous distention). Torsemide has been shown to have better oral bioavailability than furosemide and may be useful in the patient with DR due to poor absorption.