The relationship between dialysis adequacy and covid-19 onset and mortality risk: single center experience

Abstract

AimWe primarily aimed in this study to evaluate risk factors for COVID-19 infection and any association between dialysis inadequacy and COVID-19 infection in maintenance hemodialysis (MHD) patients. Secondly, we aimed to describe prevalence and risk factors associated with long-lasting symptoms of non-deceased COVID-19 MHD patients before vaccination.MethodsOne hundred one MHD patients infected with COVID-19 and 100 MHD patients without infection were enrolled in this retrospective cross-sectional study. Risk factors for mortality, need for intensive care unit (ICU) stay, and long-lasting symptoms were analyzed.ResultsThe mean age of patients was 59.13 ± 13.58 years. COVID-19 infected patients had significantly higher rates of DM, COPD, and CHF. The need for ICU was statistically significantly higher in patients with COPD and DM. Patients who had lower Kt/V at hospital admission had more than a 5-fold higher rate of COVID-19 compared to those with higher Kt/V. Risk factors for one-year mortality included higher age, higher CRP, and lower baseline Kt/V. Older MHD patients had a higher frequency of long-lasting symptoms. Low Kt/V, low hemoglobin level, and high CRP level were associated with a higher risk of long-lasting symptoms (p=0.00, p=0.001, p=0.02).ConclusionDM, CHF, COPD, older age, and obesity were poor prognostic factors in COVID-19 infected MHD patients. Dialysis adequacy parameters such as Kt/V, serum albumin level, and hemoglobin level were significantly lower in patients requiring ICU and in deceased patients.

Keywords

Introduction

Coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization (WHO) in March 2020.^1-2-3 COVID-19 may present asymptomatically or cause a variety of infection findings ranging from mild infection to severe pneumonia.
Patients with kidney disease appear to be at high risk for COVID-19 and its related complications, as most of them are older and have multiple co-morbidities such as hypertension, diabetes, and cardiovascular diseases. Dialysis patients have additional risk factors, including chronic immune dysfunction, the need to go to the hospital for hemodialysis three times a week, and these comorbidities increase the risk of developing severe disease, ICU admission, and mortality from COVID-19 infection.^4-5-6
The pathophysiological mechanism of COVID-19 disease is poorly understood, but various studies have reported that infected patients have abnormal levels of cytokines. Inflammation is associated with disease progression and poor clinical outcomes.⁷
Globally, dialysis adequacy has been recognized as a combination of parameters including middle molecule clearance, control of mineral metabolism, anemia correction, and quality of life. Clinicians mostly use Kt/V for measurement of dialysis adequacy.⁸
Dialysis dose as measured by Kt/V can be affected by many factors, including treatment time (TT), blood flow rate (BFR), dialysate flow, hypotension, vascular access function, dialyzer characteristics, and proper blood sampling. In the literature, some studies have demonstrated that lower than recommended Kt/V may increase mortality, especially in females.^9-10 Many studies have reported that inflammation is closely related to dialysis adequacy.¹¹
In this study, we primarily aimed to determine risk factors for COVID-19 infection, ICU admission, and mortality rate among MHD patients, and to document whether a relationship exists between dialysis inadequacy and COVID-19 infection in MHD patients.

Materials and Methods

Our study was designed retrospectively. COVID-19 was diagnosed according to the Turkey Ministry of Health COVID-19 guideline. A total of 201 patients undergoing maintenance hemodialysis (MHD) for at least 3 months were recruited; 78 patients were confirmed COVID-19 cases, 23 suspected (PCR test negative but chest computed tomography positive), and 100 non-infected COVID-19 control hemodialysis patients. Exclusion criteria were patients with incomplete data and hematological or hemostatic disease.
For each patient, the following clinical parameters were recorded from the medical file: age, gender, primary kidney disease, co-morbidities, complaints during hospitalization, vital signs at admission, chest CT findings, and COVID-19 PCR results. Charlson’s comorbidity index (CCI) was calculated to estimate 10-year survival. Routine blood examinations included complete blood count, coagulation profile, and serum biochemistry (including liver function tests, total proteins, albumin, ferritin, pro-calcitonin, C-reactive protein (CRP), D-dimer, white blood cell (WBC), lymphocyte), Kt/V, and UF volume.
Hypoalbuminemia was defined as serum albumin < 3.5 g/dL (N: 3.5–5.5 g/dL). Serum CRP < 10 mg/L was considered normal. Weekly average Kt/V was used as a dialysis adequacy parameter. The accuracy of dialysis (Kt/V) was calculated according to the formula: –ln(R – 0.008 × T) + (4 – 3.5 × R) × 0.55 × UF/V. Kt/V data were analyzed by taking the mean of the last three months before COVID-19 infection and hospital admission.
All patients received standard therapy according to the Turkey Ministry of Health COVID-19 guideline. Favipiravir was administered (2 × 1600 mg loading, 2 × 600 mg maintenance) to all confirmed and suspected COVID-19 patients for 5 or 10 days. Other treatment modalities such as high-dose vitamin C, immune plasma, antibiotics, glucocorticoids, and tocilizumab were recorded. Patients with abnormal gas exchange (paO2 < 300 or arterial blood oxygen < 400) or those with higher serum CRP, ferritin, corticosteroids, and/or tocilizumab were added to treatment.
Patients were divided into two groups according to COVID-19 status: PCR-confirmed positive group, suspected group with negative PCR but positive CT, and non-infected hemodialysis patients as controls.
This study was approved by the Bahçeşehir University Faculty of Medicine Ethics Committee (2022-03/12) and complied with the Declaration of Helsinki.Statistical AnalysisSPSS software (version 22.0, SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The Kolmogorov-Smirnov test was used to detect normality in data distribution. Descriptive analyses were given as mean ± standard deviation (SD) for normally distributed variables. The Mann-Whitney U test was used to compare differences in nonparametric data between groups. For parameters without normal distribution, Student’s t-test was used. Chi-square test was used for categorical variables. A p-value < 0.05 was considered statistically significant. T-tests, analysis of variance (MANOVA), multivariate Cox regression analysis, and χ² tests were used to compare continuous and categorical variables by COVID-19 status.

Results

The study groups consisted of 78 confirmed, 23 suspected COVID-19, and 101 non-infected COVID-19 MHD patients. Demographic and clinical parameters of all MHD patients are shown in Table 1. The mean age of patients was 59 ± 13.58 years; 58.7% were male, and the mean dialysis duration was 59.58 ± 47.41 months. In the COVID-19 infected group, hypertension was present in 43%, diabetes mellitus (DM) in 51.5%, congestive heart failure (CHF) in 30%, and chronic obstructive pulmonary disease (COPD) in 38.4%. The most common symptoms were cough (61%), fever (38%), and myalgia (34%). All confirmed and suspected COVID-19 patients were hospitalized. Eighty-three patients had pulmonary involvement (68 bilateral, 15 unilateral). Eighty-eight patients required oxygen support, and 34 patients were transferred to the intensive care unit (ICU).
To identify risk factors for COVID-19 among MHD patients, infected patients were compared to non-infected controls (Table 2). Confirmed and suspected COVID-19 patients had significantly lower Kt/V (p=0.04), higher CCI scores (p=0.03), lower estimated 10-year survival (p=0.01), and lower hemoglobin levels (p=0.01). COVID-19 infected patients had significantly higher rates of DM (p=0.01), COPD (p=0.04), and CHF (p=0.02). Patients with lower Kt/V at admission had more than a 5-fold higher rate of COVID-19 infection (p=0.00).
Patients requiring ICU stay were compared to those who did not. ICU need was significantly higher in patients with COPD (p=0.01) and DM (p=0.03). ICU patients had higher CCI scores (p=0.04), lower estimated 10-year survival (p=0.01), and lower Kt/V (p=0.03). They also had significantly lower lymphocyte counts (p=0.02), lower oxygen saturation (p=0.01), higher WBC (p=0.03), higher CRP (p=0.00), and higher bilateral pulmonary involvement (p=0.00).
The mortality rate in the cohort was 31.6%. Deceased patients were older (>65 years) (p=0.01). COPD and DM were the most common co-morbidities in deceased patients (p=0.00, p=0.06, p=0.02). CRP and ferritin were significantly higher, while albumin was significantly lower in non-survivors (p=0.04, p=0.03, p=0.00, p=0.01, p=0.02). Deceased patients had significantly lower Kt/V (p=0.04), higher CCI scores (p=0.02), and lower estimated 10-year survival (p=0.00). No significant differences were found for gender or mortality rates between patients who received corticosteroids/tocilizumab and those who did not (p=0.2, p=0.09).
No differences were found in pre-dialysis serum potassium, phosphate, and bicarbonate values among confirmed, suspected, and non-infected patients. Compared to non-infected deceased patients, COVID-19 deceased patients had significantly lower Kt/V, higher WBC, ferritin, and D-dimer levels (p=0.03, p=0.01, p=0.00).
Multivariable analysis (MANOVA) showed that older age (>65 years), lower Kt/V, higher CRP, higher CCI scores, DM, and COPD were significantly associated with ICU need.
One-year mortality was 41.5% (42 of 101 patients). Thirty-one patients died during hospitalization. Of the 42 deaths, 3 (7.14%) occurred in the first six months (2 heart attacks, 1 cerebrovascular event), and 8 occurred in the following six months (3 respiratory failure, 2 cerebrovascular events, 3 heart attacks). The 12-month mortality rate for non-COVID MHD patients was 12% (12 of 100), significantly lower than COVID-19 MHD patients (p=0.032). Deceased COVID-19 patients were older (p=0.042) and more frequently had pulmonary involvement on chest tomography.
During one-year follow-up, 23 of 59 patients (38.9%) experienced at least one additional event, including respiratory, cardiovascular, or non-specific symptoms (fatigue, myalgia). Risk factors for one-year mortality included higher age, higher CRP, and lower baseline Kt/V (p=0.03, p=0.01, p=0.00).
At 12 months, 13 patients (22.4%) had at least one long-lasting symptom. The most common were muscle weakness, cough, and shortness of breath. Patients with long-lasting symptoms were older and had higher CRP levels than others.

Discussion

COVID-19 is an infectious disease caused by a new coronavirus (SARS-CoV-2) and can progress from variables symptoms such as fever, dry cough, joint pain, severe picture such as shortness of breath, respiratory failure, and multiple organ dysfunction syndromes. The main risk groups for mortality and developing complications during the COVID-19 pandemic are older age and people with chronic health problems.¹¹ Dialysis adequacy is described by clinical and laboratory measures along with solute clearance. These are including the following parameters; blood pressure control, uremic symptoms, inflammatory markers, serum albumin, and hemoglobin levels, metabolic acidosis, urea reduction ratio (URR), and Kt/V.^12-13-14 In our study, we primarily aimed to detect the presence of any difference in dialysis inadequacy between COVID-19 MHD patients and non-infected COVID-19 MHD patients. We secondarily aimed to define the possible relation of dialysis adequacy and other laboratory parameters or co-morbidities in COVID-19 MHD patients. A few studies reported that Kt/V inadequacy (< 1.2) is associated with a chronic inflammatory state.¹¹ The increase of Kt/V 0.1 is associated with a reduced risk of mortality from cardiovascular, cerebrovascular, and infectious diseases.¹⁵ Among dialysis patients, those had lower Kt/V at admission hospital had a more than 5 fold higher rate of COVID-19 those who have higher Kt/V, a pattern that although commented on, has not been well quantified in national studies. Also, we did find a statistically significant association with lower Kt/V and need to ICU and mortality rate among the COVID-19 MHD patients. Therefore we describe that dialysis inadequacy is an important risk factor for mortality among the COVID-19 MHD patients. In many studies reported that chronic inflammation is an important factor for inadequate dialysis and HD dosage (Kt/V) has been shown to have a significant impact on the morbidity and mortality rate in patients on MHD patients.¹¹ Additionally in the literature has been reported that the occurrence of inflammation is higher in patients who were on dialysis for a long time.¹⁶ But in our study, there was no statistically significant relationship between Kt/V and dialysis vintage. Although, dialysis inadequacy is related to a more extended hospitalization time and higher medical costs, 3 while the inverse denotes effective patient hemodialysis.¹⁷ In our study we did not find an association between hospital stays and Kt/V, serum albumin, or CRP levels in infected with COVID-19 MHD patients. Serum albumin and hemoglobin levels are used as parameters of dialysis adequacy in MHD patients.¹⁸ According to our results, serum albumin and hemoglobin level were statistically significant higher in infected with COVID-19 MHD patients. However, we did not find associations were observed between serum albumin, hemoglobin level and need to ICU stay. Within the groups of patients non-survived, the mortality rate was higher in a patient with low albumin levels. UF volume is another important marker for dialysis adequacy in MHD patients.^19-20 The median UF was 2.9 liters in our study groups. We did not find any differences in compared MHD patients infected with and non-infected with COVID-19 for UF volume. Until now, there have been many reports of COVID-19 disease in MHD patients. Can et al, showed that risk factors that were significantly associated with infection risk were older age, higher CCI score, and lower estimated 10-year survival.²¹ In our study risk factors for COVID-19 infection were lower Kt/V, lower hemoglobin level, higher CCI score, diabetic nephropathy, COPD, and CHF. During the first time of pandemic, some of the studies indicated that corticosteroids caused delayed viral clearance, on the other hand, a few authors observed prescribing corticosteroids in COVID-19 patients.^22-23-24 The RECOVERY trial was showed that corticosteroids were a clear beneficial effect for viral clearance in COVID-19 patients.²⁵ According to our results, the patients receiving corticosteroids, the mortality rate was similar to non-receiving corticosteroids patients. Hyperglycemia and seconder bacterial infection were more frequent in corticosteroid receiving patients. In this study, 101 MHD patients diagnosed with COVID-19, 33.6% of them were transferred to the ICU. It is seen that there is a positive correlation between advanced age (<65 y.o.) and ICU requirement. And also it has been shown that mortality risk related to COVID-19 was significantly higher in older age (>65), and in patients with higher CRP, ferritin, and WBC. Also, mortality risk significantly rises in patients with diabetic nephropathy, COPD, CHF. The main difference is in our study from the other studies published until now the low Kt/V value, which is an indicator of dialysis adequacy, increases both the mortality ris, the need for ICU and high risk of long-lasting symptoms associated COVID-19.

Limitations

In our knowledge, this study is the first that investigates the relationship between Kt/V and inflammation in COVID-19 MHD patients and non-infected MHD patients. We detect a significant difference among Kt/V between the COVID-19 MHD patients and non-infected MHD patients. We claim that adequate and effective dialysis treatment both reduces the risk of being infected with COVID-19 in MHD patients and reduces the risk of intensive care unit need and mortality in MHD patients infected with COVID-19.

Conclusion

Firstly this was a retrospective study and limited participiants number . Some of the data such as changes in blood pressure, oxygen saturation, residual renal function, body weight, D-dimer and IL-6 levels were not included in the data. And also we do not evaluated antibody seroposivity for ımmunglobulin M (Ig M) and ımmunglobulinG (Ig G).

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