Treatment Options in Cardiorenal Syndrome

interaction between chronic kidney disease (CKD) and cardiovascular disease (CVD), termed the cardiorenal syndrome (CRS), is characterized by enhanced risk of atherosclerosis and uremia-related myocardial disorders (Figure 1). While milder degrees of renal impairment (CKD stages 1–3) are associated with accelerated risk of atherosclerotic events, a uremia-specific cardiomyopathy characterizes the more severe and advanced stages of renal dysfunction and end stage renal disease (ESRD) (stages 4, 5, and ESRD) (Figure 1).

Figure 1.

Cardiorenal syndrome: clinical presentation and therapeutic options

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Abbreviations: RRT, renal replacement therapy; PVD, peripheral vascular disease; ESA, erythropoiesis-stimulating agents

Therapeutic options in CRS depend on the severity of the degree of renal impairment and associated clinical conditions.

In CKD stages 1–3, the goal of therapeutic approaches is directed at controlling atherosclerotic comorbidities, while in CKD 4, 5, and ESRD, the aim of therapy is to improve the general condition of the patient.

Atherosclerosis

To reduce the impact of the cardiorenal syndrome on CVD morbidity and mortality, the following therapeutic strategies are currently recommended:
  • blood pressure (BP) control

  • albuminuria reduction

  • dyslipidemia and statin therapy

  • antiplatelet agents

  • vitamin D–calcium–phosphorus control

Blood pressure control

Long-term cardiorenal protection involves two important concepts: BP control to a much lower target of systolic BP < 130 mmHg and use of an agent that blocks the renin-angiotensin-aldosterone (RAAS) system as base therapy. However, appropriate BP control becomes more difficult as kidney function declines. In addition, patient with CKD also have increased rates of uncontrolled hypertension.

Antihypertensive therapy should be initiated with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). The antihypertensive regimen can be further modified according to BP-lowering efficacy and CVD reduction. Coadministration of diuretics is mandatory: thiazides in early/mild stages and loop diuretics when serum creatinine > 2.5 mg/dL. Potassium-sparing diuretics are contraindicated. Addition of beta blockers affords cardioprotective benefits such as angina reduction, improved left ventricular function, reduced rates of hospitalization and reduced rates of sudden death in patients after myocardial infarction and in those with concurrent heart failure.

The current consensus is to lower SBP to at least 130 mm Hg. However, further reduction may be unsafe, particularly in high risk patients as it has been associated with increased CVD risk.

Albuminuria

Reduction of albuminuria, a treatment target associated with improved cardiovascular and renal outcomes, can be achieved by BP reduction with RAAS blockade.

However, in a substantial number of patients, albuminuria > 1 g/day persists despite SBP < 130 mmHg and continued RAAS blockade. This condition results from secondary increase in aldosterone production and responds to addition of spironolactone or eplerenone on top of RAAS blockade.

Dyslipidemia and statin therapy

Patients with CKD and ESRD exhibit a pattern of mixed dyslipidemia characterized by decreased high density lipoprotein cholesterol (HDL-C), increased triglycerides, and increased low-density lipoprotein cholesterol (LDL-C). The National Kidney Foundation’s (NKF) recommended target goals for treating dyslipidemia in patients with CKD are: total cholesterol < 200 mg/dL, LDL-C <100 mg/dL, HDL-C > 40 mg/dL.

NKF recommends lifestyle changes in accordance with pharmacotherapy. Based on the lipid pattern of dyslipidemia most commonly found in CKD, with elevated triglycerides and low HDL-C, treatment with nicotinic acid and fibrate is indicated. However, fibrate use in patients with ESRD has been linked to rhabdomyolysis, possibly generating additional acute renal failure.

For reduction in LDL-C, statins are first-line agents. These drugs are well tolerated and safe. They have been shown to reduce cardiovascular events and mortality in CKD patients, and to attenuate declines in renal function and increase in albuminuria. Although considered safe for use in CKD, dose reduction is required with the use of lovastatin, rosuvastatin, and simvastatin. The metabolism of statins is altered by certain filtrates, increasing the risk of myopathy when drugs from these two classes are used concurrently.

Antiplatelet agents

The use of aspirin at 81 mg/day in renal patients is safe and is associated with cardiovascular protection. In patients intolerant to aspirin, clopidogrel is generally recommended. Although it inhibits platelet aggregation, clopidogrel lacks the benefit of cardiovascular protection in CKD patients.

Vitamin D—calcium—phosphorus metabolism

Normalizing the concentration of the precursor molecule 25(OH)D3 if less than 30 mg/mL with active vitamin D drugs (Cholecalciferol) is recommended, as is normalizing serum phosphate by oral phosphate binders or intestinal phosphate transport.

Cardiomyopathy

Chronic heart failure (CHF) occurs in about 25 percent of patients with ESRD and accounts for 50 percent of cardiovascular disease (CVD) mortality. In ESRD, CHF results from a uremia-specific type of cardiomyopathy. Its prevalence increases with further deterioration of renal function and may progress to an ominous state of acute decompensated heart failure (ADHF).

The heterogeneous and complex pathophysiology of cardiorenal dysfunction in these patients makes management an intricate clinical challenge. To date, there is no single therapeutic approach guaranteed to succeed, because of the unique risk profile and combination of co-morbidities in each patient.

General measures

The patient needs continuous hemodynamic monitoring, especially if BP is low and the filling pressure uncertain. Body weight, the single most important indicator, should be recorded frequently.

It is advisable to restrict intake of free water to less than 1000 mL per 24 h if the patient is hyponatremic. In some patients with low BP and low filling pressure, volume expansion may be required.

Diuretic therapy and resistance

Diuretics remain the mainstay of the management of fluid overloaded patients with heart failure and ADHF.

Loop, thiazide and potassium-sparing diuretics provide diuresis and natriuresis within 20–30 minutes of administration. When administered orally or parenterally these drugs must be secreted actively, and not passively filtered into the renal tubules to exert their desired effects of blocking sodium reabsorption in the renal tubules. In patients with renal insufficiency, higher doses of loop diuretics are needed to achieve the same level of natriuresis. In contrast, the use of thiazide diuretics as monotherapy is markedly reduced in states of renal dysfunction with GFR under 30 mL/min/1.73m2.

Diuretics provide effective short-term symptomatic relief. However diuretic use exacerbates neurohormonal activity, which often leads to postdiuresis sodium retention and further renal dysfunction, limiting their effectiveness (diuretic resistance). In ADHF, this resistance can be managed by continuous intravenous infusions, rather than bolus doses, of furosemide starting at 5 mg/h to 10 mg/h following an intravenous thiazide diuretic (often primed with 250–500 mg intravenous chlorothiazide). To avoid the risk of ototoxicity, the high doses of furosemide should be administered slowly over 30 to 60 min.

If the patient is resistant to furosemide, the efficacy can be improved by the addition of salt-poor albumin to the infusion. The resulting furosemide-albumin complex is believed to deliver more diuretic to the kidney, primarily by remaining in the vascular space. Adding salt-poor albumin has been shown to substantially increase sodium excretion.

Vasodilator therapy

Intravenous nitroglycerin or nesiritide have been used to alleviate pulmonary congestion in patients with ADHF. These drugs are effective in reducing myocardial oxygen demand by reducing central venous and ventricular filling pressures, and improving cardiac output by reducing systemic vascular resistance.

Of particular importance is nesiritide, a vasodilator with mild diuretic effects. There has been much debate on benefits and risks of nesiritide. Recent studies, however, indicate that at low doses, nesiritide causes no risk to kidney function and in some cases, it may be renoprotective. When used in doses of 0.005–0.01 µg/kg/mL, nesiritide poses no additional risks to renal function and, even may afford cardiorenal protection when administered in doses of 0.0025–0.005 µg/kg/mL without an initial bolus.

Renal replacement therapy (RRT)/ultrafiltration

Given the multiple difficulties and frequent failure with diuretics in the management of heart failure, alternative strategies for the treatment of fluid overload have been explored, including the use of mechanical means. The most notable development in this respect has been veno-venous ultrafiltration. In contrast to diuretics that produce hypotonic urine and intravascular volume contraction, leading to further sodium and water retention, ultrafiltration results in the removal of isotonic fluid without causing neurohormonal activation or disturbances in serum electrolytes (Figure 2). In the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) study, ultrafiltration achieved greater fluid and weight loss than intravenous diuretics, reduced 90-day rehospitalization and unscheduled visits, and appeared to be an effective alternative therapy. The effect of ultrafiltration on mortality, however, remains to be established.

Figure 2.

Modalities of therapy in congestive heart failure in chronic kidney disease

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Renin Angiotensin Aldosterone (RAAS) blockade

Owing to extensive and multiple detrimental effects of chronic RAAS activation, RAAS inhibition has emerged as a mainstay of treatment for patients with heart failure. Angiotensin converting enzyme (ACE) inhibitors improve symptoms of heart failure and reduce morbidity and mortality. Despite a mild reduction in GFR due to blunting of angiotensin II-induced vasoconstriction of the efferent arterioles, ACE inhibitors preserve renal function long-term. However ACE inhibitors should be used cautiously, starting with small doses, in patients with renal insufficiency in order to prevent marked deterioration in renal function.

An alternative mechanism of blocking the effects of angiotensin II is with ARBs, either in place of or in addition to ACE inhibitors. Both of these strategies have been reported to benefit patients with heart failure.

Although both ACE inhibitors and ARBs reduce aldosterone production, further aldosterone inhibition with specific aldosterone antagonists provides additional benefits. They block renal sodium and water reabsorption, reduce fibrosis in the kidney and in the heart helping to preserve cardiorenal function, and reduce significantly mortality in advanced heart failure. However, they should be used cautiously in patients with significant renal dysfunction to prevent hyperkalemia.

Aliskiren, a direct renin inhibitor, has been shown to reduce BNP levels. Urinary aldosterone in heart failure patients already on ARB and ACE inhibitors (Aliskiren Observation of Heart Failure Treatment [ALOFT]) may be considered a therapeutic option in such patients.

Inotropes

A trial of inotropic therapy using dopamine or milrinone may be considered in renal impaired patients with low cardiac output. However, the use of inotropes in these patients has not been associated with improved survival.

Vasopressin (antidiuretic hormone [ADH]) antagonists

In heart failure, low BP and contracted effective arterial blood volume enhance vasopressin (ADH) secretion which, by acting on selective renal V2 receptors, promotes increased water reabsorption and hyponatremia.

Studies have shown that vasopressin antagonists, known as vaptans (such as Tolvaptan), are beneficial in the short term by inducing greater reduction in body weight, increased urine output and increased serum sodium, but with no proven efficacy in the long term. Thus, the use of vasopressin antagonists may be recommended in the acute setting, but will probably not influence disease attenuation and recovery.

Beta blockers

Prescription of beta blockers is recommended to patients with CKD and heart failure. These drugs retard the progression of left ventricular disease and reduce recurrent myocardial infarction and sudden death.

Administration of Carvidelol in dialysis patients with dilated cardiomyopathy was associated with impressive results characterized by decreased left ventricular size, improved ejection fraction, and reduced rates of hospitalization and sudden death.

Erythropoiesis-stimulating agents (ESA)

Several recent studies indicate that treatment of anemia in pre-and postdialysis patients is associated with fewer admissions for heart failure and lower rates of death. However because of the well documented increase in mortality with high hemoglobin (Hb) levels, it is recommended that ESA therapy be initiated when Hb levels fall below 10 g/dL and that dose should be titrated so as not to exceed Hb levels of 12 g/dL.

Notes

[1] Adel Berbari, MD, is with the American University of Beirut Medical Center in Beirut, Lebanon.