Uremic pericarditis, pericardial effusion, and constrictive pericarditis in end‐stage renal disease: Insights and pathophysiology

Abstract

A rising prevalence of end‐stage renal disease (ESRD) has led to a rise in ESRD‐related pericardial syndromes, calling for a better understanding of its pathophysiology, diagnoses, and management. Uremic pericarditis, the most common manifestation of uremic pericardial disease, is a contemporary problem that calls for intensive hemodialysis, anti‐inflammatories, and often, drainage of large inflammatory pericardial effusions. Likewise, asymptomatic pericardial effusions can become large and impact the hemodynamics of patients on chronic hemodialysis. Constrictive pericarditis is also well documented in this population, ultimately resulting in pericardiectomy for definitive treatment. The management of pericardial diseases in ESRD patients involves internists, cardiologists, and nephrologists. Current guidelines lack clarity with respect to the management of pericardial processes in the ESRD population. Our review aims to describe the etiology, classification, clinical manifestations, diagnostic imaging tools, and treatment options of pericardial diseases in this population.

1. INTRODUCTION

End‐stage renal disease (ESRD) is a common clinical comorbidity given the increasing prevalence of diabetes and hypertension. Even though mortality in ESRD patients has decreased by 30% since 1999, it is still higher than age‐matched individuals in the general population.1 Furthermore, a growing incidence of complications from chronic renal failure and long‐term hemodialysis has been observed, including pericarditis and uremic pericardial effusion, which frequently remain unrecognized in the absence of clinical signs and symptoms.2 Complications of ESRD are responsible for approximately 14 in‐hospital days, with an average of 2 hospitalizations per year, per dialysis patient.3

Herein, we review the structure and function of the pericardium, its etiology, classification, clinical manifestations, and treatment options of pericardial diseases. We also examine ESRD to help clinicians understand the different disease processes and guide them in making informed management decisions for their patients.

2. THE PERICARDIUM

The pericardium is a relatively avascular, fibroserous sac composed of 2 layers, the parietal and visceral pericardium, covering the entire surface of the heart to the proximal portion of the great vessels. Pericardiophrenic arteries, branches of the internal mammary artery, and feeder branches from the aorta supply the pericardium. Phrenic nerves along with vagal fibers from the esophageal plexus innervate it.4 The layers are separated by a space filled with approximately 50 mL of serous fluid.4 This pericardial fluid is derived as an ultrafiltrate of plasma and has a cardioprotective role.4 Excess fluid may accumulate in the pericardial space due to either decreased resorption, as in congestive heart failure, or increased permeability from an inflammatory state.

2.1. Classification

Pericarditis in ESRD patients has been described as 2 entities: uremic and dialysis pericarditis.5 Uremic pericarditis has been traditionally described as the onset of clinical signs and symptoms before the initiation of renal replacement therapy (RRT) or within 8 weeks of its initiation.5 Dialysis pericarditis has been defined as the occurrence of clinical manifestations after being stabilized on RRT for more than 8 weeks.5

Although uremic pericarditis is perceived to occur in patients with advanced untreated chronic kidney disease (CKD), patients already on long‐term dialysis are also at risk of uremic pericarditis. Patients who present with noninfectious pericarditis, having ruled out other etiologies, are likely to be under‐dialyzed due to either the dialysis technique employed or nonadherence to RRT. The idea of providing an 8‐week span of dialysis before declaring a patient as having dialysis pericarditis was based on the understanding that it allows enough time for the clearance of toxins, salt, and excess fluid volume.

2.2. Incidence and prevalence

The earliest studies that describe uremic pericarditis date back to 1836, when Richard Bright reported 8 out of 100 uremic patients with pericarditis in a necropsy study.6 The true incidence of uremic pericarditis is difficult to ascertain from the literature and is dependent upon the diagnostic criteria used, namely clinical symptoms, electrocardiography, echocardiography, or pathologic studies. Recent studies implementing specific diagnostic clinical criteria have reported a prevalence of 2% to 21%,5, 7, 8 which is lower than prior reports from autopsy studies showing 11.1% to 50%.1, 6 Comty et al. reported a decreasing incidence of uremic pericarditis from 13% (1966–1970) to 9% (1972–1976), and dialysis pericarditis from 15.4% (1964–1971) to 12.1% (1972–1976).9

Constrictive pericarditis used to be more common among uremic pericarditis patients before renal replacement therapy (RRT) was available.9 Nowadays, this is mostly seen in dialysis pericarditis patients with 3.7% to 12% progressing to constriction.5, 9

The incidence of uremic pericarditis has temporally decreased with highly efficient dialyzer membranes, which enable better solute clearance, volumetric control, isothermal dialysis, and convective modalities.10 However, an efficient dialysis machine alone cannot ensure adequate dialysis, unless the timing of therapy is adequate.

Recent data have shown a trend in initiating dialysis at higher glomerular filtration rates compared with more than a decade ago.11 Such changes may also just be a reflection of changing practices in initiating chronic dialysis.11

2.3. Etiology and pathophysiology

The risk of coronary artery disease, cardiac arrhythmias, valvulopathy, and cardiomyopathy has been widely associated with renal dysfunction across several studies.12 In fact, the relationship between cardiovascular disease (CVD) and renal dysfunction has been described as reciprocal or bidirectional.13

High albuminuria in CKD is associated with abnormalities in fibrinolysis, inflammation, and dyslipidemia.13 Increased urinary albumin excretion exacerbating endothelial permeability in a low inflammatory state may have a role in the development of pericarditis.14 Dialysis patients have been found to have high levels of free radicals, suggesting uremia is a pro‐oxidant state. However, dialysis is ineffective in correction of oxidative stress.15 The causal relationship between oxidative stress and CVD in ESRD patients has not been firmly established.15 Reduction in CVD events was seen in dialysis patients receiving vitamin E supplements,16 whereas another trial showed similar results with N‐acetylcysteine use in the same population.17 Regardless, the understanding of the pharmacokinetics of antioxidants in ESRD patients is limited.

The accumulation of toxic metabolites, nitrogenous metabolic end products, and changes in water, electrolytes, and acid–base homeostasis have also been attributed to the pathophysiology of uremic pericarditis.8 Hyperparathyroidism, hyperuricemia, deranged calcium levels, infections (particularly cytomegalovirus [CMV], influenza, and coxsackie) have also been implicated; however, comparative studies have not shown statistical difference to calcium, phosphate, parathyroid, or uric acid levels.18

Immunologic perturbations and autoimmune diseases, including systemic lupus erythematosus, scleroderma, or granulomatosis polyangiitis, can manifest as pericarditis.8, 19 Cremer et al. described autoinflammatory and autoimmune pathways in the mechanism of recurrent pericarditis.20 Inflammasomes have been implicated in innate immunity and respond to varied insults and pathogen‐associated molecular patterns by releasing interleukin (IL)‐1, a target of pharmacological interest in autoinflammatory disease.21 It is suggested that damage‐associated molecular patterns, including urea and toxins, trigger coding of inflammasomes and mediate IL‐1–related damage to the pericardium.

It is speculated that dialysis pericarditis occurs from inadequate dialysis in stable patients or relatively inadequate dialysis in patients with higher catabolic activity due to multiple comorbidities. A surge in dialysis pericarditis has been seen in patients with vascular access problems leading to missed or inadequate treatments.22

2.4. Physiological changes on the heart in uremia

People with ESRD have a number of concomitant comorbidities including arterial hypertension, fluid overload, atherosclerosis, anemia, local hormonal disturbances, vitamin deficiencies, and arteriovenous (AV) fistulas, all of which make it difficult to isolate the independent effect of the uremic process.20

A study on hemodynamic parameters in uremic patients demonstrated an increase in arterial pressure, cardiac output, plasma volume and total peripheral resistance, and a lower creatinine clearance in those with signs of circulatory congestion.23 Although left ventricular failure is more common in early pericarditis, right ventricular insufficiency is predominant in late pericarditis.24 Cardiac index can be high or remain normal. Increased cardiac index can be attributed to chronic anemia, needing correction to a target hematocrit of at least 30%.23 Isovolumetric correction of anemia can lead to increased total peripheral resistance and arterial blood pressure.23

Moreover, persistent signs of volume overload, absence of arterial hypertension, pericarditis or pericardial effusion, decreased myocardial contractility, ejection fraction, and increased end‐diastolic pressures are indicative of uremic cardiomyopathy.24

Although the mechanism of constrictive pericarditis is poorly understood, it has been seen more often in patients with pericarditis who survived long enough. Uremic patients are at a greater risk of bleeding and coagulopathy due to platelet dysfunction, an altered coagulation cascade, and activation of the fibrinolytic system, in addition to an inflamed pericardium. Repeated bouts of hemopericardium leads to the development of scar tissue and subsequently constrictive pericarditis.24

Difficulty in maintaining systemic blood pressure during dialysis is an important finding for diagnosis of constrictive pericarditis. Development of hypotension, ascites, peripheral edema, distended neck veins, even when on dialysis, are clinical features of possible constrictive pericarditis.24 Echocardiography in constrictive pericarditis shows the presence of small left ventricular dimensions with preserved systolic function, dilated atria, abrupt termination of diastolic filling, and an interventricular septal bounce.25 During early diastole, rapid filling occurs from high systemic venous pressure, which results in elevation and equilibration of diastolic pressures of all 4 chambers.25 Due to the noncompliant pericardium, both intracardiac volumes and diastolic filling are reduced. The amount of fluid removed should be cautiously determined during every dialysis session to prevent a dangerously low blood volume.24

2.5. Signs and symptoms

Chest pain as a result of pericarditis typically occurs in the anterior chest, is worse on inspiration, and can be associated with a pericardial friction rub. Initial evaluation should involve assessing for other causes of chest pain like acute myocardial infarction, unstable angina, and expanding aortic aneurysm, because dialysis patients are at a high risk for a major cardiovascular event.26 Respiratory distress is commonly seen from inflamed pericardium and even the pleura.

3. DIAGNOSIS

Table 1 shows the various diagnostic modalities and management strategies, including electrocardiography, imaging, laboratory investigations, as well as medical, interventional, and surgical management methods in uremic pericarditis.

Table 1.

Diagnostic Modalities and Management Strategies in Uremic Pericarditis

	Diagnostic Modality/ Management Strategy	Contraindications in ESRD	Relevant Findings/Details for Uremic Pericarditis
Imaging investigation	Chest x‐ray	None	Cardiomegaly (pericardial effusion)
			Pleural effusion (pleuro‐pericardial involvement)
	Echocardiography	None	Pericardial effusion
			Evidence of pericardial constriction
	Computed Tomography	–Noncontrast CT: none	Pericardial inflammation and thickening
		–Contrast CT	Loculated pericardial effusion
			Pericardial masses
		May be performed in patients on dialysis if the benefits of the study outweigh the risks	Attenuation values provide information on the nature of pericardial fluid
		Should generally not be performed in patients with ESRD and not yet on dialysis	Simple effusion: 0–20 HU
			Proteinaceous fluid/hemopericardium: >20 HU
			Location and extent of pericardial calcification
	Magnetic Resonance Imaging	–MRI without gadolinium contrast: none	Pericardial thickening
		–MRI with gadolinium contrast should generally be avoided in patients with ESRD, due to risk of nephrogenic systemic fibrosis	Loculated pericardial effusion, pericadial inflammation
			Pericardial masses
			Helps rule out other pathology (ie, chest abnormality)
			Fibrous adhesions of pericardial layers
Management	Medical	Dialysis in appropriate patients with ESRD
		NSAIDs: avoid in patients with ESRD
		Colchicine generally be avoided in patients with advanced renal impairment; colchicine is not cleared by dialysis. Renally adjusted dosing during dialysis; Should only be used for short term treatment.
		Corticosteroids: particularly important in patients with ESRD	Corticosteroids: 0.2‐0.5/mg/kg/d
	Interventional		Pericardiocentesis
	Surgical		Pericardial window, pericardiectomy

Abbreviations: CT, computed tomography; ESRD, end‐stage renal disease; HU, Hounsfield units; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti‐inflammatory drugs.

3.1. Electrocardiography

The pericardium is electrically inert, and electrocardiography (ECG) changes occur due to injury of the myocardium. Typical ECG changes are found in 60% of patients. Common findings in acute nonuremic pericarditis include new widespread concave ST elevation in most leads (best seen in leads I, II, V5, V6, augmented voltage right arm) and PR depression in the acute phase. Normalization of ST segment and diffuse T‐wave inversion are found in later stages.27 Notably, Q wave changes associated with infarction are absent in pericarditis with resolution of ST elevation before T‐wave inversion occurs.27

3.2. Imaging

Chest x‐ray can help assess cardiac size and the presence of pericardial effusion.26 However, even in the presence of cardiomegaly, there remains a high probability of not attributing the enlarged cardiac silhouette to fluid accumulation.28 A rapid change in heart size, compared with prior chest imaging in the absence of lung changes, is suggestive of pericardial effusion.28

Echocardiography (Figure 1) is the diagnostic procedure of choice if acute pericarditis is suspected.29 It also helps assess myocarditis with alteration in ventricular function, or constriction.29 Other imaging modalities including cardiac magnetic resonance (Figure 2) and computed tomography (CT) (Figure 3) can be employed to diagnose complicated or questionable pericarditis.2, 30 However, gadolinium is avoided in patients with advanced renal disease (estimated glomerular filtration rate < 30 mL/min per 1.73 m²) due to the risk of nephrogenic systemic fibrosis. A high CT attenuation is suggestive of an exudative pericardial effusion and strongly correlates with pericardial fluid albumin, protein, lactate dehydrogenase (LDH), white blood cell (WBC), protein ratio, LDH ratio, and albumin gradient.31 Determining the nature of effusion through imaging will help guide diagnosis earlier, even before pericardial fluid is obtained.

Figure 1.

Transthoracic echocardiogram in a patient with end‐stage renal disease and a chronic moderate circumferential pericardial effusion (asterisk). (A) Parasternal long‐axis view of the left ventricle at end‐diastole showing the measured posterior effusion at 1.6 cm. (B) Apical 4‐chamber view at end‐diastole showing the normal diastolic right atrial contraction without signs of pretamponade physiology. (C, D) Short‐axis view at the base of the left ventricle at the level of the mitral valve (C) and at the midventricular level (papillary muscles) (D) showing the extension of the circumferential pericardial effusion (asterisk)

Figure 2.

MDCT with iodinated contrast and CMR without gadolinium contrast in patients with end‐stage renal disease. (A) Contrast MDCT multiplanar reconstruction of the 4‐chamber view (A), demonstrating the circumferential pericardial effusion (asterisk) in a patient with end‐stage renal disease scheduled for intermittent hemodialysis after the iodine infusion. (B, C) Noncontrast CMR, breath‐held, steady state free‐precession cine, 4‐chamber view (B) and vertical long‐axis (C) views demonstrating the extension of a moderate pericardial effusion in a patient with end‐stage renal disease. Abbreviations: CMR, cardiac magnetic resonance; MDCT, multidetector computer tomography

Figure 3.

MDCT with iodinated contrast in a patient with constrictive pericarditis and end‐stage renal disease. (A–D) Contrast MDCT multiplanar reconstruction of the 5‐chamber long‐axis view. (A) A 2‐chamber long‐axis view (B), basal short‐axis view (C), as well as a full‐volume rendered reconstruction (D) demonstrating the extensive patchy pericardial calcifications, predominantly around the base of the left and right ventricles, in a patient with long‐standing end‐stage renal disease scheduled for intermittent hemodialysis after the iodine infusion. Abbreviations: MDCT, multidetector computer tomography

3.3. Laboratory investigations

Routine blood work includes inflammatory markers, WBC count with differential count, creatine kinase troponins, and renal and liver function tests.32 Elevated C‐reactive protein and erythrocyte sedimentation rate are common findings.8, 19 Leukocytosis is seen in 40% to 60% of patients with uremic and dialysis pericarditis.8 Cardiac enzymes may be elevated in ESRD, which in patients with normal renal function may indicate myocardial damage. No statistical difference in blood urea nitrogen levels in patients with or without uremic or dialysis pericarditis has been found.29

Pericardial fluid in uremic and dialysis pericarditis is exudative with mononuclear cells on fluid analysis. Pericardial biopsy, though not routinely performed, can reveal necrotizing or non‐necrotizing fibrinous pericarditis to chronic fibrous thickening in constrictive pericarditis, or be normal.33

3.4. Pericardial effusion and cardiac tamponade

The prevalence of asymptomatic pericardial effusion has been reported in up to 70% to 100% of patients with uremic and dialysis pericarditis, which could be from either pericarditis or volume overload alone.29 A study comprised of 150 patients on hemodialysis detected a pericardial effusion in 62% of them, whereas only 7.3% showed ECG or clinical signs of pericarditis.34 It is important to note that persistent or progressive right heart failure, accompanied by hypotension, is suggestive of cardiac tamponade.9

Cardiac tamponade occurs in 20% of patients with dialysis pericarditis.9 Dialysis‐associated hypotension occurs in 60% of patients in tamponade or pretamponade, as opposed to 6% in those without.35

Despite advancements in imaging techniques, cardiac tamponade remains a clinical diagnosis.36 Tamponade can be precipitated by hypovolemia, paroxysmal tachyarrhythmia, and concomitant development of acute pericarditis. Volume resuscitation in hypovolemic patients is essential; however, intravenous hydration in euvolemic and hypervolemic patients can also precipitate tamponade. Patients undergoing dialysis with a higher ultrafiltration rate can also be associated with development of tamponade.36

4. TREATMENT

4.1. Dialysis

The most important and initial management in patients not on dialysis is to begin dialysis as soon as possible, and to intensify dialysis for those who have already been on dialysis (class IIa).32 Intensive dialysis therapy is known to be effective in more than 50% of patients.26 Rutsky et al. reported that 87% of uremic pericarditis patients who underwent dialysis improved within 2 weeks of initiation of treatment, whereas only 53% of dialysis pericarditis patients who received dialysis responded.7 Hemodialysis should be started with caution due to physiological changes that may occur from ultrafiltration and fluid shifts during dialysis. Continuous renal replacement therapy, a steady and gentler approach to removing toxins and metabolites, can be considered, however, with caution if tamponade or a pretamponade physiology is suspected.

Assessing the success of dialysis using any clinical or lab criteria is challenging; however, intensive dialysis should be continued until the disappearance of pericardial friction rub. Systolic blood pressure < 100 mmHg, temperature > 102 F, jugular venous distention, peritoneal dialysis, WBC >15 000 cm³, and the presence of a large pericardial effusion have been associated with a poor response to intensive dialysis, prompting considering alternate forms of medical therapy early.37

4.2. Medications

Current guidelines recommend considering nonsteroidal anti‐inflammatory drugs (NSAIDs) or corticosteroids in patients who do not respond to adequate and intensified dialysis (class IIb), whereas colchicine is contraindicated in severe renal impairment and pericarditis (class IIIc).32

The only double‐blinded, randomized controlled trial on the use of indomethacin in uremic pericarditis, comprising 24 patients on dialysis, 11 of whom received 25 mg indomethacin 4 times a day for 3 weeks, reported shortened duration of fever, with minimal effect on chest pain, friction rub, or pericardial effusion compared with placebo.38 However, it did not decrease the need for an invasive procedure nor did it have an effect on mortality.38 A Cochrane review comparing the use of colchicine and NSAIDs, compared with NSAIDs alone, showed reduction in episodes of pericarditis in patients with recurrent pericarditis (hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.24‐0.58) and reduced recurrence in patients with acute pericarditis recurrence (HR: 0.40, 95% CI: 0.27‐0.61) at an 18‐month follow‐up.39

The majority of data on the use of NSAIDs and steroids in this setting come from older studies; however, as discussed above, dialyzers today are more efficient in clearing metabolites. Current medical treatment involves aspirin (750–1000 mg every 8 h for 1–2 weeks) or indomethacin (600 mg every 8 h for 1–2 weeks) as first‐line agents.32 The choice of NSAIDs is made based on the side‐effect profile, efficacy, and patient history. We should also realize that NSAIDs can cause bleeding in uremic patients who are already at high risk.

Corticosteroids have been used with varying benefit.40 Low‐dose corticosteroids (prednisone 0.2–0.5 mg/kg/d) can be considered in patients unable to take NSAIDs due to adverse effects, contraindications, or NSAID failure.40

Although colchicine is contraindicated for ESRD patients in the recent guidelines, it is clinically used in small doses for a short duration up to 3 months.32 Current guidelines lack clarity on dosage and duration of treatment with these agents. Nonetheless, renal replacement therapy remains the mainstay of treatment.

4.3. Pericardiocentesis, pericardial window, and pericardiectomy

The 2015 European Society of Cardiology guidelines on pericardial disease have a class 1c recommendation for pericardiocentesis and pericardial window, with limited data on preference of 1 over the other, for recurrent effusion.32 Pericardiocentesis is indicated for a hemodynamically significant pericardial effusion, congestive heart failure, prevent clotting of the arteriovenous shunt, and to improve renal function.41 Predictive factors for drainage requirement include a low albumin <31 g/L, heparin use during dialysis, dialysis pericarditis, leukocytosis, tachypnea >20 breaths/min, fever >39°C, and low voltage on ECG.41

However, a pericardial window can be a viable option, as it provides the added advantage of being able to obtain a pericardial biopsy to exclude any other infectious or autoimmune process. Moreover, a major indication for a pericardial window is the immediate relief of tamponade, when pericardiocentesis is not effective. However, it does not prevent recurrence of pericardial effusion without addressing the uremic state through concomitant dialysis.42 Patients with a large pericardial effusion, cardiac tamponade, or a pretamponade physiology may not be suitable candidates for urgent dialysis as the first line of treatment. A pericardial window, if not pericardiocentesis, is a useful temporary measure before solute clearance and ultrafiltration can be performed.

Pericardiectomy is the definitive approach for the treatment of constrictive pericarditis, with a success rate of over 97%, a recurrence rate of less than 1%, and surgical mortality of under 1%.43 Sagristà‐Sauleda et al., in an early study, recommended pericardiectomy for the recurrence of large pericardial effusions after repeated pericardial drainage.43

5. CONCLUSION

The management of chronic pericardial effusions, acute pericarditis, and constrictive pericarditis in patients with ESRD involves internists, cardiologists, and nephrologists. With improvement in dialysis techniques and mandatory monitoring of solute clearance, earlier initiation of hemodialysis, and efficient identification of advanced CKD patients, the incidence of uremic pericarditis and dialysis pericarditis has been reduced. Hence, when uremic pericarditis is diagnosed, the dialysis regimen for the patient should be revisited. Optimization of water and electrolyte imbalance, acid–base homeostasis through dialysis, remains the mainstay of treatment and prevention of this subset of pericarditis.

Conflicts of interest

The authors declare no potential conflicts of interest.

Supporting information

Figure S1 SUPPORTING INFORMATION

Rehman KA, Betancor J, Xu B et al. Uremic pericarditis, pericardial effusion, and constrictive pericarditis in end‐stage renal disease: Insights and pathophysiology. Clin Cardiol. 2017;40:839–846. 10.1002/clc.22770