Cardiorenal Syndrome in COVID-19 Patients: A Systematic Review

Aims To perform a systematic review assessing the clinical manifestations and outcomes of cardiorenal syndrome or the presence of both cardiac and renal complications in the 2019 coronavirus disease (COVID-19) patients. Methods All relevant studies about cardiorenal syndrome or both cardiac and renal complications in COVID-19 patients were retrieved on PUBMED, MEDLINE, and EMBASE from December 1, 2019 to February 20, 2022. Results Our search identified 15 studies including 637 patients with a diagnosis of cardiorenal syndrome or evidence of both cardiac and renal complications followingSARS-CoV-2 infection. They were male predominant (66.2%, 422/637), with a mean age of 58 years old. Cardiac complications included myocardial injury (13 studies), heart failure (7 studies), arrhythmias (5 studies), or myocarditis and cardiomyopathy (2 studies). Renal complications manifested as acute kidney injury with or without oliguria. Patients with cardiorenal injury were often associated with significantly elevated levels of inflammatory markers (CRP, PCT, IL-6). Patients with a diagnosis of cardiorenal syndrome or evidence of both cardiac and renal complications had more severe disease and poorer prognosis (9 studies). Conclusion The presence of either cardiorenal syndrome or concurrent cardiac and renal complications had a significant impact on the severity of the disease and the mortality rate among patients with COVID-19 infection. Therefore, careful assessment and management of potential cardiac and renal complications in patients with COVID-19 infection are important to improve their outcomes.


INTRODUCTION
The 2019 coronavirus disease  is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current literature indicates that sepsis secondary to COVID-19 infection has typical pathophysiological characteristics, namely early cytokine storms and subsequent immunosuppressive stages (1). Sepsis is frequently associated with cardiovascular complications and acute kidney injury either in isolation or in combination (2).
Angiotensin-converting enzyme 2 (ACE-2) is thought to be the major cell entry receptor for SARS-CoV-2 (3). ACE-2 is also expressed in the heart and kidney, providing a link between coronavirus infection and potential cardiovascular and renal complications (4). A recent epidemiological study (5) demonstrated that acute myocardial injury, cardiac arrhythmias, and shock can occur in 7.2, 18.7, and 8.7% of COVID-19 patients, respectively. Renal involvement is also not uncommon in the course of COVID-19. More than 40% of patients admitted to hospitals with COVID-19 infection had proteinuria (6). Among critically ill patients, acute kidney injury (AKI) is common, affecting ∼20-40% of patients infected with COVID-19 admitted to intensive care units (7).
Although COVID-19 is most commonly associated with COVID pneumonitis, it can also result in several extrapulmonary manifestations, such as thrombotic complications, acute cardiac injury (ACI), acute kidney injury (AKI), gastrointestinal symptoms, and hepatocellular injury (8).
Cardiorenal syndrome can occur in COVID-19 patients, precipitated by arrhythmias, ACI, and AKI (2). Cardiorenal syndrome comprises a spectrum of disorders involving both the heart and kidneys, in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other (9).
Limited data is available when evaluating the outcomes of COVID-19 patients with cardiorenal syndrome. Thus, FIGURE 1 | Flow diagram of the study selection process. the objective of this systematic review is to analyze and summarize the available literature on COVID-19 patients with both cardiac and renal complications, or cardiorenal syndrome, to gain an improved understanding of these issues in COVID-19 patients.

Search Strategy
The literature search was conducted in PUBMED/MEDLINE and EMBASE databases from December 1, 2019 to February 20, 2022 using the following terms: (COVID-19 OR SARS-CoV-2 OR severe acute respiratory syndrome coronavirus 2) AND (acute kidney injury OR acute renal impairment OR acute renal failure OR renal replacement therapy) AND (cardiomyopathy OR CMP OR cardiomyopathies OR myocardiopathy OR cardiac injury OR myocarditis OR heart injury) in the title/abstract. We limited our search to articles written in English. The literature search was conducted independently by three authors (LL, YQC, and DWH). Additionally, all references of selected papers were searched manually. This systematic review followed instructions from the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) statement (10).

Criteria for Inclusion
We included human studies meeting the following criteria: (1) Patients with COVID-19 were confirmed through positive results for SARS-CoV-2 nucleic acid testing of nasopharyngeal or throat swab specimens; (2) Patients 18 years or older; (3) Patients diagnosed with cardiorenal syndrome or evidence of both cardiac and renal complications. The exclusion criteria applied to the studies were: (1) Pregnant or lactating women; (2) Study type: review, conference abstract, letter to the editor.

Data Extraction
The following variables were extracted from all included studies: first author, the country where the research was conducted, type of study, number of patients, mean age, gender, underlying comorbidities, cardiac and kidney clinical events (such as cardiac arrhythmia, cardiac injury defined as elevated troponin levels, heart failure defined as EF ≤ 40%, elevated BNP, or echocardiographic evidence of heart failure, myocarditis, oliguria, anuric, proteinuria, acute kidney injury defined as elevated serum creatinine level, tubular injury), laboratory findings, use of Angiotensin-Converting Enzyme Inhibitors (ACEI) or Angiotensin Receptor Blockers (ARB), and clinical outcomes. Three authors (LL, YQC, and DWH) independently performed data extraction. Any disagreements were discussed and resolved with the senior authors (AYW and WJQ).

RESULTS
The search identified 15 studies and 637 patients with a diagnosis of cardiorenal syndrome or evidence of both cardiac and renal complications after SARS-CoV-2 infection. They were male predominant (66.2%, 422/637), with a mean age of 58 years old (Figure 1; Table 1).
The studies were either retrospective (7 studies) or case reports (8 studies). Most patients had multiple comorbidities including hypertension, chronic heart failure, and chronic kidney disease before SARS-CoV-2 infection, but specific data were not provided ( Table 2).
Cardiac complications manifested as myocardial injury (13 studies), heart failure (7 studies), arrhythmia (5 studies), or myocarditis and cardiomyopathy (2 studies) ( Table 2). Five studies demonstrated a reduction in left ventricular ejection fraction. Elevated troponin and brain natriuretic peptides were  seen in 9 studies. Renal complications manifested as AKI with or without oliguria. However, severe AKI requiring dialysis therapy was not common (5 studies) ( Table 3). Patients with cardiorenal injury were often associated with significantly elevated levels of inflammatory markers (CRP, PCT, IL-6) ( Table 4). Use of ACEI/ARB occurred in 2 studies. Patients with a diagnosis of cardiorenal syndrome or evidence of both cardiac and renal complications had more severe disease and poorer prognosis (9 studies).

DISCUSSION
Patients who developed AKI were more likely to have a cardiac event suggesting a probable role of cardiorenal interaction in the renal dysfunction that occurs in COVID-19. AKI may result in volume overload and cardiac dysfunction, and vice versa since cardiomyopathy may lead to hypotension, renal hypoperfusion, and renal congestion resulting in renal dysfunction (26), and culminating in acute respiratory distress syndrome (ARDS). The cardiorenal syndrome is associated with increased morbidity and mortality in COVID-19 patients, as well as healthcare costs. COVID-19 may affect the heart and kidney through several mechanisms (Figure 2). Firstly, new evidence suggests that SARS-CoV-2 may have direct cytopathic effects on the heart and kidney. ACE-2 is the receptor for SARS-CoV-2 to enter human cells, which is highly expressed in extrapulmonary tissues including the heart and kidney (27). Secondly, excessive release of cytokines due to viral infection, known as cytokine release syndrome or cytokine storm, is the mechanism leading to multiorgan damage in COVID-19. The presence of cytokine storms and pneumonia-related hypoxia can contribute to myocardial and renal ischemia due to changes between oxygen supply and demand. Furthermore, Li et al. (28) has reported that the kinetic changes of cytokines correlate with the prognosis of patients with severe COVID-19. Thirdly, thrombotic microangiopathy seen in COVID-19 may also lead to ACI and AKI. Systemic coagulation dysfunction appears to promote thrombosis with the observation of arterial events in patients with COVID-19, such as renal artery thrombosis or acute coronary syndrome.
Up to a fifth of COVID-19 patients have an acute myocardial injury (12-17% of cases) (29,30). In patients with SARS-CoV-2 infection, the most common features of myocardial injury were ECG changes and elevated troponin. Echocardiography showed subclinical left ventricular diastolic dysfunction and even decreased ejection fraction (EF) in severe cases (5). As previously seen during coronavirus outbreaks, patients with a low EF are more likely to require mechanical ventilation (31). This is clinically important for hospitalized patients, as expert consensus recommends an early assessment and continuous cardiac monitoring to identify patients with cardiac injury and help predict further COVID-19 complications (32). Highsensitivity troponin is a useful cardiac monitoring tool in COVID-19. Zhou et al. (30) observed a gradual increase in highsensitivity cardiac troponin I (hs-cTnI) levels in non-survivors (reaching the reference limit on day 11), while hs-cTnI levels in survivors remained low. Piccioni et al. (33) also identified that in patients with COVID-19, high-sensitivity troponin was a negative prognostic indicator. Increased cTnI levels may be associated with endotoxin production, which may be secondary to sepsis, an overall pro-inflammatory state, or direct myocardial infarction through ACE2 receptors in cardiac tissue (34). The increase of IL-6 was parallel to that of hs-cTnI, which increased the possibility of reflecting viral myocarditis. Existing data from China show that one-quarter to one-third of COVID-19 patients have severe heart failure. Zhou et al. (30) reported 23% of heart failure in their series of 191 patients with SARS-CoV-2, while Chen et al. (35) reported 27.5% (33/120) of increased N-terminal pro-B type natriuretic peptide (NT-proBNP).
Although early reports showed a low incidence of AKI (3-9%) among COVID-19 patients in a Chinese population (5), recent data has shown a higher incidence of renal abnormalities. The most prominent findings are proteinuria or hematuria. The most significant findings were albuminuria or hematuria, which was found by test paper evaluation in nearly one-third of patients on the first day of admission, and elevated serum creatinine and blood urea nitrogen in 15.5 and 14.1% of patients (6). Importantly, an elevation  (38,40). AKI may also be the result or complication of COVID-19 treatment. Antiviral drugs can lead to tubulointerstitial diseases (41,42), and biopsy confirmed oxalate nephropathy associated with vitamin C has been reported (43). Certain antibiotics/antibacterial agents have also been implicated in AKI in COVID-19 patients (44). ACE-2 is the main entry point of most coronaviruses, and its binding domain has a high affinity with SARS-CoV-2. The coronavirus binds to the extracellular domain of ACE-2 on the host cell surface through its spike protein (S protein), and then invades the cells, resulting in the down-regulation of ACE-2 expression on the cell surface (3). After entering cells, viruses  replicate and induce cytotoxicity, which may lead to organ failure. ACE-2 is widely expressed throughout the body, with the highest expression in the gastrointestinal tract and oral epithelium, and is highly expressed in the lung, kidney, and heart (45)(46)(47). As mentioned, ACE-2 is highly expressed in the proximal tubule of the kidney (3), which may allow for direct viral cell damage resulting in tissue injury and renal failure (2). On a cellular level, ACE-2 is widely expressed in cardiac fibroblasts, myocardial cells, and coronary artery endothelial cells (48). The use of an ACEI or ARB for antihypertensive treatment in a rat model has been shown to increase ACE-2 gene expression, protein levels, and activity in hearts (49)(50)(51), which may increase the chance of SARS-CoV-2 infection or the severity of COVID-19. Whether these drugs can increase the expression and activity of ACE-2 protein in humans remains controversial. In the absence of convincing clinical data, most professional organizations suggest that ACEI or ARB treatment should be continued for patients with heart failure who have or have the risk of SARS-CoV-2 infection.

CONCLUSIONS
Patients with cardiorenal syndrome or both cardiac and renal complications had a significant impact on the severity of the disease and mortality rate among patients with COVID-19. Therefore, emphasis should be placed on the risk factors for the development of cardiorenal syndrome, its pathophysiologic mechanisms, racial predilection, optimal therapy, and prevention in the COVID-19 patient population. However, there are limited data evaluating outcomes of COVID-19 patients with cardiorenal syndrome. Thus, further research in this area is needed.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

AUTHOR CONTRIBUTIONS
LL, AY, AW, and WQ designed the study. LL, YC, and DH performed the search, study selection, and data synthesis. LL wrote the first draft of the manuscript. AY, AW, and WQ revised the article. All authors contributed to the paper and approved the submitted version.