Since the outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, more than 162 million cases and 3.3 million deaths have been reported as of May 19, 2021 in the world.1 Also, with 5,117,374 confirmed cases and 44,760 deaths, Turkey is one of the most affected countries during the COVID-19 pandemic.2 The clinical manifestations of COVID-19 include fever, cough, fatigue, muscle aches, diarrhea, and pneumonia, which can develop into acute respiratory distress syndrome (ARDS), metabolic acidosis, and even liver, kidney or heart failure.3 Comorbidities such as hypertension (HT), diabetes mellitus (DM), coronary heart disease (CHD), cerebrovascular disease, chronic obstructive pulmonary disease, and kidney disorders are risk factor for disease severity and fatality.4 The risk for COVID-19 death in patients with chronic kidney disease (CKD) is greater than the risk for COVID-19 death in patients with DM and CHD and the risk increases as the eGFR decreases, with the highest risk in patients on renal replacement therapy.5 Increased risk of infectious complications and more adverse outcomes in CKD patients can be attributed to older age, additional comorbidities, pro-inflammatory state and the alterations of the innate and adaptive immune response associated with uremia.6–9 Therefore, early detection and accurate evaluation of the severity of SARS-CoV-2 infection in CKD patients may facilitate appropriate clinical decision making.

Although, primarily it was documented as a respiratory tract infection, COVID-19 is a systemic disease with a significant impact on the hematopoietic and immune system. The alterations in circulating blood cells related with inflammation and immune status of COVID-19 positive patients have been reported.10 Hematological parameters, such as white blood cells and their subpopulations, red cell distribution width, mean platelet volume, and platelet, and combined ratios of these parameters such as neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are widely used for risk stratification, diagnosis, and determination of prognosis.10,11 Systemic immune inflammation index (SII) based on peripheral lymphocyte, neutrophil and platelet counts has been considered as a better index to reflect the local immune response and systemic inflammation. Recently, it was reported that the elevated SII was a prognostic indicator in predicting in-hospital mortality of COVID 19.12

To date, few studies have assessed the prognostic capacity of blood cell count derived inflammation indexes in CKD patients. Therefore, we aimed to investigate changes in hematological parameters and indexes in CKD patients with SARS-CoV-2 infection, in comparison with patients without CKD and to evaluate their utility as prognostic markers of disease mortality in CKD patients. To the best of our knowledge, this is the first time that these markers have been investigated simultaneously in a single study conducted on CKD patients.

This study is important because, it is the first study to investigate association between SII and disease mortality in CKD patients with SARS-CoV-2 infection. Recently, SII has been shown to be a potential indicator of survival in COVID 19.12 We believe our study may extend the relevance of SII to predicting in-hospital mortality of COVID-19.

Viral nucleic acid test by RT-PCR assay plays a vital role in diagnosis and isolation of individuals with COVID 19. However, lower sensitivity, insufficient stability, and long processing time were detrimental to the control of the pandemic. In the current study, nearly half of the study population were diagnosed based on RT-PCR test. RT-PCR negative patients were only included if the clinical and CT findings were strongly suggestive of COVID 19. Since the previous studies demonstrated that the sensitivity of CT for diagnosis of COVID-19 infection was higher compared with RT-PCR sensitivity,14,15 chest CT was used at the first-line evaluation of the patients with a high clinical probability of COVID-19 pneumonia for rapid diagnosis, isolation and administration of appropriate treatment.

To date, several studies have reported worse clinical outcomes, including more ICU admissions and higher mortality rate among CKD patients with COVID-19.16,17 In agreement with previous reports, the current study showed that mortality was significantly higher in CKD patients than in those without CKD (36.6 vs 10.8%). This may be explained by a pro-inflammatory state with functional defects in the natural and adaptive immunity. Although the highest mortality rate was observed in non-dialysis CKD group compared to HD group, it didn’t reach statistical significance. This difference may be attributed to older age of nondialysis-CKD patients.

Evidence from the global outbreak showed that individuals with older age, male gender and CKD associated morbidities such as HT, DM and CHD are at much greater risk of dying from COVID 19.18–20 On the contrary, the distribution of risk factors for COVID-19 mortality was differed in patients with CKD from the general population. Previous studies have suggested that some commonly reported comorbidities including HT, DM, chronic lung disease and CHD had no influence on mortality among CKD patients with COVID 19.21–23 On the other hand, some studies conducted on hemodialysis patients with COVID 19 reported that only heart failure, CHD and lung disease were risk factors for worse outcome.24 In agreement with COVID-19 database analysis of Turkish Society of Nephrology and European Renal Association,21,22 we found that male sex, HT, CHD and DM do not confer an independent increased risk of mortality. There were conflicting reports whether CKD is a risk factor for death in COVID 19. While initial reports failed to assess the impact of CKD on severity of COVID 19, OpenSAFELY project showed that the top three risk categories for death from COVID 19 were, in order from the highest to the lowest risk, dialysis patients (aHR 3.69), transplant recipients (aHR 3.53) and CKD (aHR 2.52 for patients with eGFR<30mL/min/1.73m2, CKD Grade 4–5).5 This finding emphasize the immunosuppressive nature of the uremic milieu in CKD patients, resulting in increased vulnerability to hyperinflammation and cytokine storm upon SARS-CoV-2 infection, eventually severe disease and death.

Cytokine storm has been linked to severity in COVID 19. A rapid and coordinated innate immune response is the first line of defense mechanism against viral infections. However, when the immune response is dysregulated, it leads to excessive systemic inflammation, and even cause death.25 Previous researches on non-CKD patients with COVID-19 proposed several biomarkers for severe disease, including lymphopenia and increased levels of CRP, LDH, PCT and cytokines (IL-6, IL-10 and tumor necrosis factor), emphasizing the role of the immuno-inflammatory responses in the pathogenesis and progression of COVID-19.26,27 Similarly, in our cohort, higher leukocyte and neutrophil count as well as lower lymphocyte count were observed in CKD patients who died. Blood cell count-derived inflammation indexes, including NLR and PLR have been reported to be a more sensitive biomarker of inflammation than the individual levels of blood cell line.28 Up to now, the potentials of blood cell count-derived inflammation indexes as a predictor of mortality in CKD patients with COVID 19 have been assessed in a few reports. Davila-Collado et all have analyzed the impact of NLR, monocyte to lymphocyte ratio (MLR), and PLR on 37 CKD patients with SARS-CoV-2 infection and noticed that only an elevation in MLR was consistently correlated with increased mortality among patients with CKD.29 In a report of 10 maintenance HD patients, NLR and LCR were associated with the severe form and mortality of COVID 19.30 Another study conducting on 62 HD patients showed that higher NLR was associated with the most severe form of COVID-19.31 In line with the literature, mortality was associated with a lower LCR but higher NLR in our study group. It was also remarkable that SII was significantly higher in CKD cases developing mortality. To the best of our knowledge, to date, no study has been carried out to evaluate the feasibility of SII to assess COVID-19 disease mortality in CKD patients.

As a new systemic inflammation indicator, SII, based on lymphocyte, neutrophile, and platelet counts has been reported as prognostic factor in COVID 19.12 Utility of SII to identify COVID 19 patients at higher risk of death is given by the differential roles that lymphocyte, neutrophil and platelet playing during immune response. Lymphocytes are known to be responsible for eliminating virus infected cells.32 Although neutrophils are the most important cellular defense against infections, it is not clear whether neutrophils play a role in anti-viral defense in viral pneumonia.33 However, neutrophil recruitment into the lungs has been observed only in pneumonia patients with ARDS, support that neutrophils play a role defending the airway epithelium in the presence of severe SARS-CoV-2 virus infection.33 Platelets contribute to hemostasis and also participate in the inflammation and host defense. Decreased platelet production and increased consumption due to diffuse alveolar damage are thought to cause thrombocytopenia in COVID-19 patients.34,35 In consideration of these factors, SII might be better able to reflect the balance of host inflammatory and immune status in COVID 19. The current study revealed that the discriminative performance of SII and NLR were the highest among the hematological indexes evaluated, in predicting disease mortality. There seems to be some evidence to indicate that SII was not inferior to NLR which is widely used to predict the severity of COVID-19 disease.36 Our results are in line with recently published studies identifying the value of SII to predict the risk of in-hospital mortality of COVID-19 patients and confirms the reliability of SII as a powerful predictor of survival.37,38 As SII is based on the results of complete blood count analysis, it is inexpensive, more simple, easily applicable and more suitable for widespread use. Quantification of SII at admission would guide the physician for early identification and timely management of the patients with worse survival.

In addition, we found that the AUC was significant with the PLR and LCR. Qu R. et al. reported that the PLR may predict mortality in COVID-19 patients.39 Although PLR, which increase thrombosis development and responsible for the cytokine and chemokine cascade, was significantly higher in CKD patients developing mortality, it didn’t predict disease mortality.40 It can be explained by the relatively low number of the patients. As such, Fois et al. observed higher value of PLR in deceased patients with COVID 19. However, after adjusting for confounders, they found a borderline significance between worse survival and PLR (p=0.058).37 Since the SARS-CoV-2 viral load has been highly correlated with lymphocyte count and CRP value, LCR can help to predict disease severity.41 In the current study LCR showed a reasonable ability to predict disease mortality.

There were several limitations to our study that warrant consideration. First, it was a retrospective, single-center study of CKD patients with COVID 19 admitted to the hospital. Large- scale multicenter prospective studies should be performed to support our findings. Second, patients without a positive RT-PCR were also included in the study but all RT-PCR-negative patients had clinical features and chest CT findings strongly suggestive of COVID-19.

We report for the first time that SII is able to distinguish COVID-19 infected CKD patients of worse survival and it is as powerful as NLR in this regard. Since SII can be easily quantified from blood sample data, it can provide significant benefits for early identification and timely management of CKD patients with worse survival.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors declare that they have no conflict of interest.