Clinical outcomes of COVID-19 in Palestinian hemodialysis patients: A cross sectional study

Abstract

Background

The coronavirus disease 2019 (COVID-19) is known for its effects on the respiratory system. Two years after the pandemic morbid and mortal consequences, growing evidence is showing that the disease also has adverse outcomes and complications on additional organs including the kidneys. This study aims at investigating the effects of COVID-19 on hemodialysis patients receiving services at Palestine Medical Complex (PMC) kidney dialysis department.

Methods

In April 2022, data was collected using the electronic medical records system for the dialysis department at PMC. The study included all PMC hemodialysis patients that were infected with COVID-19 between January 2020-April 2022. The collected data included patient demographics, clinical features, laboratory tests, dialysis frequency and the disease outcome.

Results

The results showed that the patients outcomes and dialysis frequency were impacted by their blood urea nitrogen (BUN), serum creatinine (SCr) and calcium levels. About one third of the study population died after being infected with COVID 19. The frequency of dialysis was also affected by the presence of comorbidities like hypertension, diabetes mellitus (DM) and myocardial infarction (MI).

Conclusions

This study found that there was a high mortality rate within the dialysis patients infected with COVID-19. Having comorbidities affected the frequency of dialysis following COVID-19 infection. Dialysis patients should be protected from infections such as COVID-19 and their comorbidities should be monitored and kept under control as much as possible.

Background

Coronavirus disease 2019 (COVID-19) is one of the epidemic infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was declared as a global pandemic in 2020 which was followed by its devastating health, social, and economic consequences. Since then, the health impact of COVID-19 has been examined on the general population as well as the more vulnerable patients. In 2021, COVID-19 was the leading cause of death in the West Bank accounting for 25.2% of deaths, followed by cardiovascular diseases and cancer, which were responsible for 23.7% and 12.2% of deaths respectively, the fatality rate of COVID-19 in 2021 in Palestine was 1.25% [1].

COVID-19 is one of the beta-coronavirus group, consisting of a single-stranded positive-sense RNA genome and 4 structural proteins (S, E, M and N). N is for the nucleocapsid protein that covers the genome in addition to another envelope that is associated with membrane protein (M), (S) for Spike protein and E the envelope protein [2]. SARS-CoV-2 mainly enters the human body via the respiratory pathway either directly by respiratory droplets from sneezing and coughing or indirectly by contaminated surfaces. It is very contagious, droplets typically reach about two meters and can stay suspended in the air for three hours. Also, it can spread indirectly via touching contaminated surfaces then to the mucous membranes in the nose, eyes or mouth [3].

Since COVID-19 mainly affects the respiratory tract, its common symptoms including fever, non-productive cough and shortness of breath (SOB), in addition to fatigue, headache, dizziness, nausea and vomiting (N/V), and pain in joints and muscles. The average of COVID-19 incubation period is about 5 days which can vary depending on the patient health status and the virus variant, it can be severe and can have longer duration for patients with other underlying diseases such as respiratory failure, congestive heart failure (CHF), myocardial infarction (MI), arrhythmias, acute or chronic kidney disease (CKD) or liver failure [4, 5].

COVID-19 can also affect other organs. The kidney is one of the affected organs since the virus can bind with angiotensin converting enzyme (ACE) receptors in the lungs and kidneys [6]. CKD is classified into five stages according to kidney disease improving global outcomes (KDIGO) classification that is based on the estimated glomerular filtration rate (GFR), which estimates how much blood passes through the glomeruli per minute [7]. GFR is affected by age, gender, and patient serum creatinine (SCr) levels. After measuring the GFR, stage can be identified as: Stage 1 CKD, mild kidney damage (eGFR more than 90 milliliters per minute); Stage 2, mild damage (eGFR = 60 to 89 milliliters per minute); Stage 3a, moderate damage (eGFR = 45 to 59 milliliters per minute); Stage 3b, moderate damage (eGFR = 30 to 44 milliliters per minute); Stage 4, severe damage (eGFR = 15 to 29 milliliters per minute); and Stage 5, kidney failure (eGFR less than 15). COVID-19 has different intensity and complications which increase depending on the stage, especially in patients at the end stage of renal disease that require replacement therapy including dialysis [8].

There are two types of dialysis, hemodialysis and peritoneal dialysis, they both act as a replacement of kidney functions include filtering waste and excess fluid from the blood. Hemodialysis, the most common type used, uses a machine that takes blood from the body, filters it through a dialyzer and returns the cleaned blood to the body. Hemodialysis is performed for patients with end stage chronic CKD having GFR of less than 15. The process takes approximately 4 hours and commonly takes place at hospitals or at a dialysis center.

Patients with advanced age who are on dialysis already have comorbid conditions such as hypertension, diabetes mellitus (DM), atrial fibrillation, deep vein thrombosis, CHF, chronic obstructive pulmonary disease or asthma. The impact of these diseases is more aggressive on dialysis patients than others. One study found that the GFR was lower after COVID-19 exposure [8].

There are 20 hemodialysis units in Palestine which include 12 units in the West Bank of which 11 are located at ministry of health hospitals that include 255 hemodialysis machines, while the remaining unit belongs to An-Najah National University private hospital which includes 45 hemodialysis units [1]. In 2021, there were 1567 patients that received regular hemodialysis services in the West Bank [1]. The hemodialysis unit at Palestine Medical Complex (PMC) provides services to patients in the Ramallah area. This study aims to examine the effects of COVID-19 on the livelihood and dialysis frequency in PMC hemodialysis patients in Palestine.

Methods

Study design and population

In this study, a cross-sectional design was implemented. Data was collected retrospectively from the dialysis department in PMC in Ramallah during April 2022, the Avicenna medical records program was used to retrieve patients’ data. The study was approved by the research ethics committee at the college of Pharmacy at Birzeit University, approval number BZU-PNH-2135. The informed consent requirement was waived as data was collected from electronic records. The approval of the Palestinian Ministry of Health and PMC was also obtained prior to data collection. Patients who were on dialysis and who have been infected with COVID-19 between January 2020 and April 2022 were included in the study. The effect of COVID-19 on dialysis patients was examined and whether there were any exacerbations of the disease.

The collected data included patient demographics like gender, age, blood group, clinical features such as any comorbidities, COVID-19 symptoms, lab tests such as blood urea nitrogen (BUN), SCr, calcium, potassium and the frequency of dialysis, that is for how long the dialysis was applied and how many times it was repeated per week. All data was obtained from electronic medical records in the hospital.

The study included all hemodialysis patients at PMC who have been infected with COVID 19 since the beginning of the spread of the virus in Palestine till April 2022. 103 patients were included in the study, from different age groups, that were diagnosed with end-stage renal disease requiring dialysis, the patients were receiving chronic maintenance hemodialysis and were diagnosed with acute COVID-19 infection.

Results

Patients demographic and clinical characteristics 

Patients receiving hemodialysis services at PMC kidney dialysis department that were infected with COVID-19 between 2020-2022 were included in this study (n=103), the most common age group within the study sample was the group of 60 and above years old, which represented 42.7% of the sample, with the mean age ± SD (53.378 ± 15.71). 60.2% of patients in the study were males and 39.8% were females. The O blood group accounted for the highest percentage of all blood groups (41.7%). It is important to mention that 68% of patients remained alive at the time of data collection while 32% died, the demographic data of the patients is shown in Table 1. 

Table 1: Demographic and clinical characteristics of the study sample with and without change in their dialysis frequency before and after COVID-19 infection.

 + These patients were already undergoing the maximum number of hemodialysis which is 3 per week according to the PMC kidney unit protocol, after their exposure to COVID-19 the frequency of dialysis did not change and there was no further information that can rule out whether the dialysis did not change because it is at its maximum number or the patients’ situation did not change.

AKI Acute kidney injury, AP Angina pectoris, BUN blood urea nitrogen, CHF Congestive heart Failure, DM Diabetes mellitus, IHD Ischemic heart disease, SCr Serum creatinine. 

As shown in Figure 1, all hemodialysis patients suffered from cough and acute pain during their COVID-19 infection period, with a high percentage of SOB and chest pain, accounting for 30.1% and 29.1% respectively, reported symptoms also included arthritis (28.2%), dermatitis (14.6%), N/V (12.6%), fever (11.7%), headache (8.7%) and diarrhea (4.9%). 

The most common comorbidity in the study sample was DM which was found in 38.8% of patients, followed by acute kidney injury (AKI) (35%), hypertension (17.50%), CHF and ischemic heart disease (IHD) both accounted for a percentage of 16.5% (Figure 2). 

Patients’ outcome 

An important objective of this study is to examine the impact of COVID-19 on the frequency of hemodialysis. Within the study sample, 32 patients have already reached the maximum number of dialysis per week before their COVID infection, which is 3 times per week as per the PMC kidney unit protocol, and their dialysis frequency remained the same after their COVID-19 recovery, there was not enough information in the medical records to conclude whether their need for dialysis was not increased post COVID, or their frequency of dialysis was not changed because it has reached its maximum already before the COVID-19 infection, these patients were sorted out of the further analysis since there was not enough information in their medical records for them to be included in the statistical analysis (Figure 3). As for the rest of the patients, 32 died, and the remaining 39 patients all had an increase in their dialysis frequency, the characteristics and clinical conditions of these 2 subgroups are found in Table 2. 

Table 2: The characteristics and outcomes on hemodialysis for patients that remained alive and had changes in the frequency of dialysis or died after their COVID-19 infection.

* Results were considered significant when p<0.05 according to chi-square test.

AKI Acute kidney injury, BUN blood urea nitrogen, CHF Congestive heart Failure, DM Diabetes mellitus, IHD Ischemic heart disease, MI Myocardial infarction, SCr Serum creatinine.  

As demonstrated in Table 2, there was a significant association between the frequency of dialysis and blood group (p=0.006), more people with the A blood group were likely to be affected and have an increase on their frequency of dialysis (78.6%).

Looking at the electrolyte levels analysis after COVID, the BUN, SCr and calcium had significant associations with the frequency of dialysis. For BUN and SCr (p<0.001) and (p=0.037) respectively, hence COVID-19 contributes to increasing the BUN and SCr levels leading to more dialysis treatment (Table 2). BUN and SCr were also high in the patients that were excluded from statistical analysis and whose dialysis frequency did not change as it was at its maximum before COVID (Table 1). For the 46.2% of patients that had a decrease in calcium level there was an increase in dialysis treatments per week (p=0.014), as for the potassium levels, there was no association with the frequency of dialysis (p=0.498) (Table 2).

Regarding comorbidities, there was a significant association between the frequency of dialysis and hypertension (p=0.014), for all patients that had hypertension within the study sample and got infected with COVID-19 the frequency of dialysis was increased. Also, DM and MI had a significant association with the frequency of dialysis with p-values of 0.031 and 0.019, respectively. For the 30 patients that had DM, 12 had an increase in dialysis frequency and 18 have died. While for the 8 patients that had MI 7 have died and one had an increase in dialysis frequency. There was no significant association with other comorbidities such as AKI, IHD and CHF (Table 2). 

Discussion

This study examined the clinical course and outcome of COVID-19 infection in hemodialysis patients in PMC. It included all patients infected with COVID from PMC kidney dialysis unit. Data was collected for 103 patients undergoing hemodialysis with laboratory-confirmed COVID-19 diagnosis from the beginning of the pandemic until the end date for data collection, between January 2020 - April 2022.

The findings of this study showed that COVID-19 adversely impacted hemodialysis patients, the study population was divided into 3 groups, a group that died after COVID-19 accounting for 31% of the patients, a group that survived after the infection but their frequency of dialysis has increased (36.4%), and the third group (33.6%) was already at the maximum number of weekly dialysis before COVID-19, and remained on the same number of dialysis post COVID-19 infection, this group was excluded from the statistical analysis, as it could not be ruled out whether the number of dialysis remained the same as it was at its maximum per the hospital protocol, or because there was no need for the increase.

In our study 32 patient died after their infection with COVID-19 with a percentage of 31%, a study in HD units in Madrid, Spain reported that dialysis constituted the highest risk of death for COVID-19 patient during the first month of diagnosis, similarly in our study the patients died immediately after they got the infection [9]. Other studies also found that the morbidity and mortality following COVID-19 infection was a lot higher in hemodialysis patients than in the general population [10–13].

Symptoms of COVID-19 in this study sample included acute pain in different body parts in addition to cough in all patients, other symptoms occured at varying percentages such as SOB, chest pain, headache, arthritis, dermatitis, fever and diarrhea (Fig. 1). Even though these are the general symptoms that also exist in non-dialysis patients, hemodialysis patients have worse symptoms of COVID-19 because they tend to be elderly and to have multiple comorbid conditions, like hypertension, DM, coronary artery disease, CKD, heart failure and suppressed immune systems [14]. In our study, the recorded symptoms were mild to moderate and drugs have been used to alleviate these symptoms including antibiotics like azithromycin, clindamycin, ceftazidime, cefuroxime, etc., as well as pain management, antipyretic and anti-inflammatory medications including paracetamol, aspirin, hydrocortisone, and various vitamins and mineral supplements (Data not shown).

For the patients included in statistical analysis, the A blood group was the most common and they were significantly affected with an increase in the frequency of dialysis after having the COVID − 19 infection. Previous studies that were performed in many countries such as China and Canada have shown a significant association between blood group A and the complications after COVID-19 infection [15]. Another comprehensive review also found that the A blood type was associated with more COVID infection susceptibility while the O blood type was more protective [16].

The proposed mechanism behind this is that the patients with group A blood type higher levels of ACE 1 and ACE 2, which increases the affinity of SARS-COV-2 to theses receptors resulting in more severe infection, while the O group produces anti-A antibodies that bind with A-like antigen, which is created from SARS-COV-2 virus envelope, resulting in prevention of infection [15]. Another suggested mechanism is the inhibition of the virus adhesion to the host cell via two ways either by anti-A antibody binding to the SARS-COV-2 S protein, and blocking the interaction between this protein and ACE 2 receptors to prevent the virus from lung entry, or via SARS-COV-2 glycan antigen, which is similar to antigen A but does not exist in the O blood group, so it is proposed that the patients with the A blood group have a greater risk of COVID-19 severity as they lack anti-A antibodies [15].

While the previously mentioned studies found that patients with group O had the least severity and mortality, in our study the O blood group was associated with a higher percentage of fatality (Table 2). A recently published study on the effect of COVID-19 on recovered patients in Palestine found no association between the blood groups and post COVID outcomes [17]. The issue of blood group and severity of COVID-19 complications has not been resolved yet with different studies showing controversial results [15].

Approximately, more than half of the infected patients were males (60%), this is probably because males in Palestine tend to be more socially active than females, and according to many previous studies that had been done in many different countries, it was reported that women were more responsible in dealing with the COVID-19 pandemic than men, who had an irresponsible attitude that manifested by their lower rate of hand washing and wearing of face masks [18]. Also, it was shown that males had a higher risk of death, as two thirds of dead patients were males [18], but in our study this difference was not statistically significant (p = 0.687) (Table 2).

As for the age, there was no statistically significant difference between the age groups (p = 0.236). Many comorbidities were recorded with a significant association with dialysis frequency changes, this outcome can be justified by the age of the patients included in the study as most of them were elderly and suffered from chronic diseases, and according to a nationwide analysis in China, COVID-19 patients with underlying comorbidities had more severe COVID-19 infection and poorer clinical outcomes compared to patients without comorbidities [19].

The most common comorbidity recorded in our study was DM, which significantly affected the outcome on hemodialysis patients increasing the frequency of dialysis or mortality (p-value = 0.031), DM is a risk factor for kidney failure as high levels of sugar in the blood damage the filtering units in kidney and that can lead to a significant damage including end stage kidney failure that requires dialysis [8].

In August 2020, WHO announced that there was an association between cardiovascular disease and COVID-19, as there was an increased risk of both arterial and venous thrombotic complications and after 7 days of COVID-19 diagnosis the risk of MI was doubled [20]. A study in the city of Mus in Turkey recommended that patients who are on dialysis must take prophylactic anticoagulant and antiplatelet agents while they are infected with COVID-19 [21]. Despite the risk of bleeding, the risk of thrombosis is still considered higher compared to the general population. According to our study, there is a significant association between acute MI and COVID-19 outcomes in dialysis patients, and it was associated with a higher mortality rate. Most of the patients in our study were on aspirin or other anticoagulant therapy like enoxaparin, this is important as hemodialysis patients require special attention to prevent the risk of thromboembolic events including MI [21, 22].

Another cardiovascular comorbidity that has a significant correlation with dialysis and COVID-19 outcomes is pre-existing hypertension. The findings of many observational studies in China demonstrated that the majority of the COVID-19 patients with hypertension were at a higher risk of developing severe outcomes of dialysis deterioration, one of them, is the increase in dialysis frequency [23]. All of the hypertensive patients in our study had a significant increase in the number of dialysis sessions after COVID-19 infection. There are two suggested explanations for this either via the renin angiotensin system or by causing endothelial dysfunction by producing high amount of pro-inflammatory agents such as angiotensin II, cytokines, interleukin-6 and tumor necrosis factor-α causing an imbalance between relaxing and constrictor factors, moreover, hypertension is one of main contributing factors to kidney dysfunction, if the blood pressure is not controlled, it can lead to AKI in dialysis patients [23, 24]. However, more studies are required to confirm the association between hypertension and increased risk of complications in dialysis patients who are affected by COVID-19.

AKI was defined, based on KDIGO classification, as a change in either SCr, by 0.3mg/dL over two days or an increase in SCr 1.5 times more than the baseline within the last 7 days, or urine output less than 0.5mL/kg/hr. for 6 hours. In addition, being elderly with hypertension and DM are considered as risk factors for AKI. COVID-19 targets ACE receptors which can be associated with adverse clinical outcomes in COVID patients including AKI [25]. In our study there was no significant relation between AKI and frequency of dialysis (p = 0.463), this could be due to the small sample size, nevertheless many studies indicate a significant association between kidney abnormalities and COVID-19 complications [25–27].

Our study included six patients who had a kidney transplant, and after COVID-19 infection 3 of them died and 3 continued to live with kidney failure, according to a multi-center study done in France, a high mortality rate was reported among the recipients of kidney transplant who got coronavirus infection [28].

Both SCr and BUN are indicators for kidney function. In the healthy patient, SCr normal level is between 0.59 to 1.35 mg/dL and BUN is between 6–24 mg/dL. According to our study, more than half of the patients who had a high BUN and raised level of SCr had an increase in the number of their dialysis frequency which indicate there is an association between them (Table 2).

Our results show that lower serum calcium in patients with COVID-19 increased dialysis frequency (Table 2), while the mechanism behind this is still unknown in detail, a few studies have demonstrated that SARS-COV specific gene (E) encodes a small transmememium protein that translate onto a permeable calcium channel, resulting in more calcium entery from inside the cells [29].

In our study, there were five patients with hypokalemia, three of them died after COVID-19 infection, the number of patients is too small and the association was not statistically significant (p = 0.498), another study found that hypokalemia was common among COVID-19 patients and it was accompanied with hypocalcemia [30].

Conclusion

Among all PMC hemodialysis patients infected with COVID-19, there was a higher fatality rate than observed in the general population. Moreover, there was a significant correlation between comorbidities such as DM and hypertension and increased dialysis frequency, hence the comorbidities should be kept under control as much as possible in hemodialysis patients. As the precautions and restrictions for COVID-19 are decreasing worldwide and in Palestine in particular, care should be given to highly vulnerable populations including hemodialysis patients. In addition, more studies need to be conducted on complications of infections and other comorbidities in hemodialysis patients, and regular screening tests as well as other preventive measures should be practiced to protect hemodialysis patients.

Abbreviations

ACE: angiotensin converting enzyme

AKI: acute kidney injury 

AP: angina pectoris  

BUN: blood urea nitrogen

CHF: congestive heart failure

CKD: chronic kidney disease 

COVID-19: coronavirus disease 2019 

DM: diabetes mellitus

GFR : glomerular filtration rate 

IHD: ischemic heart disease 

KDIGO: kidney disease improving global outcomes 

MI: myocardial infarction 

N/V: nausea and vomiting 

PMC: Palestine Medical Complex 

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

SCr: serum creatinine 

SOB: shortness of breath 

SPSS: statistical package for the social sciences

Declarations

Ethics approval and consent to participate

Data was gathered from Palestine Medical Complex electronic medical records after obtaining the approval of the research ethics committee at the college of Pharmacy at Birzeit University, approval number BZU-PNH-2135, the informed consent was waived by the College of Pharmacy research ethics committee as the data was collected from hospital electronic medical records. The approval of the Palestinian Ministry of Health and Palestine Medical Complex was also obtained prior to data collection. The privacy of the patients was maintained and their identities remained unknown. All methods were conducted in accordance with relevant guidelines and regulations

Consent for publication

Not applicable.

Availability of data and materials

The data used in this study is available from the corresponding author upon reasonable request and after obtaining the approval of the Palestinian Ministry of Health and Palestine Medical Complex.

Competing interests

The authors declare that they have no competing interests. 

Funding

The authors did not receive any funding for this research study.

Authors' contributions

TA, SS, and LA were involved in the planning and design of the study. TA and SS performed the data collection, interpretation and analysis. NA supervised the data analysis. LA, TA, SS did the drafting and revising of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors thank the Palestinian Ministry of Health and Palestine Medical Complex for their help in approving and facilitating data collection.

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