Uremic Pericarditis

Etiology

Patients with ESRD typically have a fluid and electrolyte balance defect leading to an accumulation of toxic metabolites such as nitrogenous wastes. Study results have shown that the combination of toxic metabolite accumulation, uremic toxins, fluid overload, and electrolyte derangement contributes to the pathogenesis of uremic pericarditis.[8] Some study results have also demonstrated that an increase in nitrogen waste products has a proinflammatory effect, leading to pericarditis; other results have concluded that the changes in acid-base homeostasis, hypercalcemia, and hyperuricemia are all implicated in the development of uremic pericarditis.[5] However, most recent studies and the fact that increased dialysis improves most cases support the theory of uremic toxins causing the pericarditis. The levels of blood urea nitrogen and creatine are not definitively linked to the development of uremic pericarditis, so it is likely that an unidentified or a combination of uremic toxins causes this condition.

For patients on dialysis with stable ESRD, missed or insufficient treatments—often due to vascular access issues or increased catabolic burden from acute illness—can cause pericarditis. Factors associated with more severe pericardial effusion in chronic kidney disease and ESRD include hypoalbuminemia and leukocytosis, highlighting the roles of inflammation and malnutrition in the pathogenesis.[3][9][10] Patients with ESRD also have an increased risk of bleeding, and hemopericardium is associated with constrictive pericarditis.[3]

Epidemiology

The actual incidence of uremic pericarditis is difficult to ascertain due to the variability of symptoms and diagnostic criteria. Historically, the prevalence used to range between 3% and 41%. However, recent data confirm a substantial decline. Results from recent studies showed that the prevalence has been less than 5% in recent decades due to improvements in hemodialysis therapy, earlier initiation of renal replacement therapy, and more efficient dialyzers.[1][3][6][11][12]

Pathophysiology

The pathophysiology of uremic pericarditis is primarily related to the accumulation of toxic metabolites and nitrogenous waste in the blood, triggering a systemic and local pro-inflammatory state. Research results indicate that these toxic metabolites affect the pericardium by inducing the release of proinflammatory markers such as interleukin 1, interleukin 6, and tumor necrosis factor. These mediators promote pericardial inflammation, activate fibroblasts, and contribute to fibrosis, ultimately resulting in pericardial damage. In severe cases, effusions can also occur in conjunction with uremic pericarditis, which can be quantified further into serous versus hemorrhagic; the cause of these pericardial effusions is multifactorial and is partially related to platelet dysfunction in renal failure patients.[10][13][14][15][16]

The risk of cardiac abnormalities has been historically associated with renal impairment across several studies. The relationship between renal dysfunction and cardiovascular disease has been defined as reciprocal or bidirectional.[17] High albuminuria in chronic kidney disease is strongly associated with systemic inflammation, fibrinolysis, endothelial dysfunction, and dyslipidemia. Also, albuminuria correlates with elevated inflammatory markers such as C-reactive protein and the neutrophil-to-lymphocyte ratio.[18][19] Excess urinary albumin excretion, aggravating endothelial permeability, may have a role in the pathogenesis of pericarditis.[12] Patients on dialysis have high levels of free radicals, indicating uremia is a pro-oxidant state, but dialysis is not entirely effective in correcting oxidative stress.[13] The causal association between oxidative stress and cardiovascular disease in patients with ESRD has not been firmly established.[13]

Histopathology

Normal pericardium tissue is composed of 3 layers: 1) the serosa, which is made of a surface layer of mesothelial cells associated with a small submesothelial space, 2) the fibrosa, containing collagen and elastin fibrils, and 3) the epicardium, also called the serous or visceral pericardium, is the closest layer to the heart and is comprised of connective tissue containing large collagen bundles joining the pericardiosternal ligament. Uremia causes fibrinous pericardial disease, although studies have shown that it is likely not the blood urea nitrogen and creatinine that cause the pericarditis, but another uremic toxin. A normal amount of pericardial fluid is usually 15 to 50 mL of plasma ultrafiltrate. Pericardial fluid is generally increased in most patients with renal failure; however, this does not cause uremic pericarditis unless fibrinous changes occur.[1][20]

The exudative fibrinous changes have been described as having a "bread and butter" appearance, although this is not specific, as it is common with other forms of exudative pericarditis. The thickening of the pericardium characterizing uremic pericarditis can involve the visceral, serosal, or both layers. Adhesions may also be present between the 2 layers. Multiple adhesions can eliminate the pericardial space, leading to "obliterative pericarditis."[1]

History and Physical

The most common presentation of uremic pericarditis is chest pain in patients with advanced chronic kidney disease or ESRD on dialysis. The chest pain is typically pleuritic in nature, may improve when the patient leans forward, and is often accompanied by dyspnea. Fever and other systemic symptoms are less prominent in uremic pericarditis than in infectious or idiopathic cases. Dyspnea and fatigue are common, especially with moderate or severe pericardial effusion.

Many patients will present similarly to a myocardial infarction patient, so it is essential to rule out an ischemic event.[9][21] Hypertension may be present related to renal disease and volume overload, in contrast to the usual hypotension observed with other pericarditis etiologies. One study of hemodynamic parameters results showed that patients with uremic pericarditis had higher blood pressure, cardiac output, total peripheral resistance, and plasma volume compared to those with signs of cardiac congestion.[6] Hypervolemia and hypotension despite adequate dialysis may also indicate constrictive pericarditis, although this is rare.[3]

Physical examination often reveals a pericardial friction rub, which is typically scratchy and squeaky, and is best appreciated on the left sternal border when the patient leans forward and holds their breath. According to results from several studies, pericardial friction rub is the most consistent physical finding in uremic pericarditis; however, it can sometimes be transient.[22] The rub has 3 components:

• Atrial systole
• Ventricular systole
• Rapid ventricular filling during diastole

Patients may also have other signs and symptoms of uremia, including the following:

• Neurologic: Encephalopathy, confusion, fatigue, memory deficiency, seizure, weakness, myoclonic jerks, muscle cramps, or asterixis
• Pulmonary: Cough, dyspnea, shortness of breath, decreased breath sounds at the bases, rales
• Gastrointestinal: Anorexia, nausea, vomiting
• Urinary: Urinary hesitation, decreased urination
• Hematologic: Easy bruising, petechiae, pallor
• Dermatologic: Uremic frost, dry skin, hair/nail changes [23]

Evaluation

An electrocardiogram (ECG) is one of the most important diagnostic tools to evaluate a patient with suspected uremic pericarditis. The most characteristic ECG findings in acute pericarditis are widespread concave ST-segment elevation and PR-segment depression. Compared to an ST-segment elevation myocardial infarction, the ST and T-wave findings in pericarditis are typically diffuse and not localized to a coronary artery territory. Normalization of the ECG findings may be observed in the later stage of the disease course. Notably, fewer than 60% of patients will present with the classic ECG findings, and some patients may show no changes on ECG.[21][24][25] See Image. Acute Pericarditis Findings, Electrocardiograph. Further, cardiac biomarkers may also be elevated, ie, troponins, but are not necessary to diagnose. This can be complicated by the fact that tropins are often mildly elevated with advanced renal failure.[9]

A chest x-ray can reveal cardiomegaly, blunting of the costophrenic angle, and decreased retrocardial space on the lateral image.[20] See Image. Uremic Effusion, Radiograph. Other imaging options include cardiac magnetic resonance imaging and computed tomography (CT), which can be used to diagnose pericarditis.[26] However, gadolinium should be avoided in patients with advanced renal disease due to the risk of nephrogenic systemic fibrosis. A high CT attenuation indicates an exudative pericardial effusion and correlates with the pericardial fluid's protein, albumin, white blood cell (WBC) count, lactate dehydrogenase, protein-to-albumin ratio, and albumin gradient.[27]

An echocardiogram plays a key role in confirming or further evaluating the severity of uremic pericarditis. Typical findings include a pericardial effusion, often with evidence of atrial and ventricular restriction. Although laboratory tests and imaging studies provide supportive information, the diagnosis of pericarditis remains primarily clinical. These diagnostic tools may aid in assessment, but are not always required to establish the diagnosis.[6]

Routine blood work includes WBC count with differential count, inflammatory markers, renal and liver function tests, and cardiac enzymes.[28] Elevated erythrocyte sedimentation rate and C-reactive protein levels are commonly observed in patients with pericarditis.[29] One review found leukocytosis present in 40% to 60% of patients with uremic pericarditis.[20] A pericardial biopsy is not routinely performed; however, when indicated, the biopsy may reveal non-necrotizing or necrotizing fibrinous pericarditis in cases of constrictive pericarditis, or it may demonstrate normal histologic findings.[30] If fluid is retrieved from the pericardial effusion, it is exudative with high protein and mononuclear cells.[7][22]

Treatment / Management

Initial treatment for uremic pericarditis is to start hemodialysis in patients who are not on renal replacement therapy or intensify dialysis for patients already on dialysis. Hemodialysis removes uremic toxins faster than peritoneal dialysis. Recent literature supports this approach, which emphasizes that uremic pericarditis is a direct indication for urgent hemodialysis. The American College of Cardiology and the American Heart Association also recognize pericarditis as a formal indication for urgent dialysis initiation in advanced azotemia.[31][32][33] One regimen for intensified hemodialysis is to perform 4 hours of hemodialysis for 4 hours 6 to 7 times per week for 7 to 14 days. Monitoring progress through echocardiography and clinical symptoms can help guide the dialysis prescription.[7](A1)

The guidelines recommend anti-inflammatory agents and steroids for patients who fail to respond adequately to hemodialysis, but colchicine is often avoided in severe renal impairment.[28] Anti-inflammatories such as indomethacin may provide some relief for pain but are not successful in eliminating uremic pericarditis. The use of steroids has been controversial, as they can decrease inflammation. Still, they can also increase the risk of recurrence along with potential adverse effects such as hyperglycemia, the risk of osteoporosis, and neurologic effects in older adults.

Low-dose corticosteroids can be used in patients who cannot take nonsteroidal anti-inflammatories.[34] Intrapericardial steroid injections have also been studied, but this approach is rarely used due to the risk of hemothorax, infection, pneumothorax, cardiac arrhythmia, and pneumopericardium. A recent clinical trial demonstrated the effectiveness of interleukin-1 blockers (anakinra, rilonacept) in treating colchicine-resistant or corticosteroid-dependent recurrent pericarditis.[35] If dialysis treatment fails, pericardiocentesis is recommended within 7 to 14 days in patients with uremic pericarditis with effusion. In patients with severe uremic pericarditis and effusion leading to cardiac tamponade, emergent pericardiocentesis is recommended.(B2)

Pericardiectomy is typically not the first-line management option and is only used for recurrent pericarditis with pericardial effusions. The recommendation is to undergo an echocardiogram every 3 to 5 days during the acute event to monitor the resolution of pericarditis and effusion.[36] Rarely, a pericardial window is needed for recurrent effusions, but this is increasingly uncommon in areas with adequate access to dialysis.

Differential Diagnosis

The differential diagnosis for uremic pericarditis is broad. Pericarditis has multiple etiologies, which must be ruled out before a diagnosis can be made. Although uremic pericarditis is the most common form of pericarditis in end-stage renal disease and dialysis patients, others causes must be considered.

Other causes include the following:

• Infectious (viral, bacterial, fungal)
• Inflammatory (systemic lupus erythematosus, scleroderma, vasculitis)
• Metabolic (hypothyroidism)
• Neoplastic (primary or metastatic)
• Trauma (blunt or penetrating)
• Cardiac (postpericardiotomy syndrome, myocardial infarction, aortic dissection)
• Medication-induced (ie, hydralazine, methyldopa, procainamide, minoxidil) [3]

Prognosis

Overall, the resolution of uremic pericarditis is excellent. Recent literature confirms that uremic pericarditis is not that common due to widespread dialysis, but when it occurs, the prognosis is generally favorable with appropriate management. Resolution of the disease is achieved in the majority of cases with a success rate approaching 100% following intensified dialysis and, when indicated, pericardial drainage for large or symptomatic effusions. Even with advanced treatment, mortality and morbidity are not negligible. Recent data showed that one-year survival in uremic pericarditis is approximately 86% especially in patients with advanced kidney disease and other comorbidities. Deaths are primarily related to underlying renal or cardiovascular disease rather than pericarditis itself.[37]

Complications

The major life-threatening complication of uremic pericarditis is the development of cardiac tamponade. If a rapid pericardial effusion accompanies uremic pericarditis, this has the potential to prevent the heart from functioning in pumping blood to the rest of the body. A typical presentation of cardiac tamponade includes hypotension, increased jugular venous distension, pulsus paradoxus, and distant heart sounds. An electrocardiogram may show electrical alternans, a voltage discrepancy caused by the heart floating within the pericardium due to the effusion. The treatment for this is emergent pericardiocentesis.[4][7][4][36]