Serum cystatin C and inflammatory factors related to COVID-19 consequences.

BACKGROUND: Besides impaired respiratory function and immune system, COVID-19 can affect renal function from elevated blood urea nitrogen (BUN) or serum creatinine (sCr) levels to acute kidney injury (AKI) and renal failure. This study aims to investigate the relationship between Cystatin C and other inflammatory factors with the consequences of COVID-19. METHODS: A total of 125 patients with confirmed Covid-19 pneumonia were recruited in this cross-sectional study from March 2021 to May 2022 at Firoozgar educational hospital in Tehran, Iran. Lymphopenia was an absolute lymphocyte count of less than 1.5 × 109/L. AKI was identified as elevated serum Cr concentration or reduced urine output. Pulmonary consequences were evaluated. Mortality was recorded in the hospital one and three months after discharge. The effect of baseline biochemical and inflammatory factors on odds of death was examined. SPSS, version 26, was used for all analyses. P-vale less than 0.05 was considered significant. RESULTS: The highest amount of co-morbidities was attributed to COPD (31%; n = 39), dyslipidemia and hypertension (27%; n = 34 for each) and diabetes (25%; n = 31). The mean baseline cystatin C level was 1.42 ± 0.93 mg/L, baseline creatinine was 1.38 ± 0.86 mg/L, and baseline NLR was 6.17 ± 4.50. Baseline cystatin C level had a direct and highly significant linear relationship with baseline creatinine level of patients (P < 0.001; r: 0.926). ). The average score of the severity of lung involvement was 31.42 ± 10.80. There is a direct and highly significant linear relationship between baseline cystatin C level and lung involvement severity score (r = 0.890, P < 0.001). Cystatin C has a higher diagnostic power in predicting the severity of lung involvement (B = 3.88 ± 1.74, p = 0.026). The mean baseline cystatin C level in patients with AKI was 2.41 ± 1.43 mg/L and significantly higher than patients without AKI (P > 0.001). 34.4% (n = 43) of patients expired in the hospital, and the mean baseline cystatin C level of this group of patients was 1.58 ± 0.90 mg/L which was significantly higher than other patients (1.35 ± 0.94 mg/L, P = 0.002). CONCLUSION: cystatin C and other inflammatory factors such as ferritin, LDH and CRP can help the physician predict the consequences of COVID-19. Timely diagnosis of these factors can help reduce the complications of COVID-19 and better treat this disease. More studies on the consequences of COVID-19 and knowing the related factors will help treat the disease as well as possible.

Prognostic potential of creatinine and Cystatin C in COVID-19 - a retrospective cohort study from Karolinska University Hospital.

Acute kidney injury (AKI) is common in COVID-19 and is diagnosed using relative serum creatinine increase. Estimated GFR (eGFR) is a more accurate measure of glomerular filtration due to compensation for age and sex. Serum Cystatin-C, less affected by non-renal factors than creatinine, may further improve renal function estimation and add prognostic information. Our aim is to investigate the importance of a calculated eGFR in relation to creatinine as well as the value of Cystatin-C in patients with severe COVID-19. This study is a retrospective cohort study investigating levels and trends of routine laboratory parameters combined with clinical data from 286 consecutive patients with severe COVID-19 from Karolinska University Hospital. AKI developed in 38% of the patients and 15% were treated with hemodialysis. Mortality in the AKI group was 42% compared to 5% in the non-AKI group. At admission, eGFR, but not creatinine, was significantly associated with AKI development, need of intubation and mortality. Moreover, discrepant results between eGFR creatinine (eGFRCR) and eGFR Cystatin-C (eGFRCYS) was common in the ICU patients compared to non-ICU patients and related to outcome. In addition, we found that daily median Cystatin-C levels during the hospital stay were correlated to neutrophil count. eGFRCR was found to be an overall better prognostic marker than creatinine regarding AKI development and prognosis in severe COVID-19. Fulfillment of Shrunken pore syndrome criteria indicated a higher mortality risk. Cystatin-C may be related to neutrophil count, which could be a clue to the discrepant eGFR results.

Shrunken Pore Syndrome Is Frequently Occurring in Severe COVID-19.

A selective decrease in the renal filtration of larger molecules is attributed to the shrinkage of glomerular pores, a condition termed Shrunken Pore Syndrome (SPS). SPS is associated with poor long-term prognosis. We studied SPS as a risk marker in a cohort of patients with COVID-19 treated in an intensive care unit. SPS was defined as a ratio < 0.7 when the estimated glomerular filtration rate (eGFR), determined by cystatin C, calculated by the Cystatin C Caucasian-Asian-Pediatric-Adult equation (CAPA), was divided by the eGFR determined by creatinine, calculated by the revised Lund−Malmö creatinine equation (LMR). Clinical data were prospectively collected. In total, SPS was present in 86 (24%) of 352 patients with COVID-19 on ICU admission. Patients with SPS had a higher BMI, Simplified Physiology Score (SAPS3), and had diabetes and/or hypertension more frequently than patients without SPS. Ninety-nine patients in the total cohort were women, 50 of whom had SPS. In dexamethasone-naïve patients, C-reactive protein (CRP ), TNF-alpha, and interleukin-6 did not differ between SPS and non-SPS patients. Demographic factors (gender, BMI) and illness severity (SAPS3) were independent predictors of SPS. Age and dexamethasone treatment did not affect the frequency of SPS after adjustments for age, sex, BMI, and acute severity. SPS is frequent in severely ill COVID-19 patients. Female gender was associated with a higher proportion of SPS. Demographic factors and illness severity were independent predictors of SPS.

Prognostic Performance of Cystatin C in COVID-19: A Systematic Review and Meta-Analysis.

Cystatin C is a specific biomarker of kidney function. We perform this meta-analysis to determine the association of Cystatin C with the COVID-19 severity. In this systematic review and meta-analysis, we searched PubMed, EMBASE, Cochrane library, and Web of Science for studies published until 2nd September 2022 that reported associations between Cystatin C levels and COVID-19 severity. The analysis was performed using a random-effects model to calculate pooled standard mean difference (SMD). Twenty-five studies were included in the meta-analysis. Pooled analysis showed statistically significant differences of Cystatin C levels among survive vs. decreased patients (0.998 ± 0.225 vs. 1.328 ± 0.475 mg/dL, respectively; SMD = -2.14; 95%CI: -3.28 to -1.01; p < 0.001). Cystatin C levels in COVID-19 severe vs. non-severe groups varied and amounted to 1.485 ± 1.191 vs. 1.014 ± 0.601 mg/dL, respectively (SMD = 1.81; 95%CI: 1.29 to 2.32; p < 0.001). Additionally, pooled analysis showed that Cystatin C levels in patients with acute kidney injury (AKI) was 1.562 ± 0.885 mg/dL, compared to 0.811 ± 0.108 mg/dL for patients without AKI (SMD = 4.56; 95%CI: 0.27 to 8.85; p = 0.04). Summing up, Cystatin C is a potentially very good marker to be used in the context of COVID-19 disease due to the prognosis of patients' serious condition, risk of AKI and mortality. In addition, Cystatin C could be used as a marker of renal complications in COVID-19 other than AKI due to the need to monitor patients even longer after leaving the hospital.

Impaired kidney function biomarkers and risk of severe COVID-19: Analysis of population-based cohort data.

BACKGROUND: Patients with impaired kidney function were found at a high risk of COVID-19 hospitalization and mortality in many observational, cross-sectional, and hospital-based studies, but evidence from large-scale prospective cohorts has been lacking. We aimed to examine the association of kidney function-related biomarkers and their genetic predisposition with the risk of developing severe COVID-19 in population-based data. METHODS: We analyzed data from UK Biobank to examine the prospective association of abnormal kidney function biomarkers with severe COVID-19, defined by laboratory-confirmed COVID-19 hospitalizations. Using genotype data, we constructed polygenic risk scores (PRS) to represent an individual's overall genetic risk for these biomarkers. We also identified tipping points where the risk of severe COVID-19 began to increase significantly for each biomarker. RESULTS: Of the 502,506 adults, 1650 (0.32%) were identified as severe COVID-19, before August 12, 2020. High levels of cystatin C (OR: 1.3; 95% CI: 1.2-1.5; FDR = 1.5 × 10-5 ), serum creatinine (OR: 1.7; 95% CI: 1.3-2.1; p = 3.5 × 10-4 ; FDR = 3.5 × 10-4 ), microalbuminuria (OR: 1.4; 95% CI: 1.2-1.6; FDR = 4 × 10-4 ), and UACR (urinary albumin creatinine ratio; OR: 1.4; 95% CI: 1.2-1.6; p = 3.5 × 10-4 ; FDR = 3.5 × 10-4 ) were found significantly associated with severe COVID-19. Individuals with top 10% of PRS for elevated cystatin C, urate, and microalbuminuria had 28% to 43% higher risks of severe COVID-19 than individuals with bottom 30% PRS (p < 0.05). Tipping-point analyses further supported that severe COVID-19 could occur even when the values of cystatin C, urate (male), and microalbuminuria were within their normal value ranges (OR >1.1, p < 0.05). CONCLUSIONS: Findings from this study might point to new directions for clinicians and policymakers in optimizing risk-stratification among patients based on polygenic risk estimation and tipping points of kidney function markers. Our results call for further investigation to develop a better strategy to prevent severe COVID-19 outcomes among patients with genetic predisposition to impaired kidney function. These findings could provide a new tool for clinicians and policymakers in the future especially if we need to live with COVID-19 for a long time.

Serum cystatin C and CRP are early predictive biomarkers for emergence of hypoxia in COVID-19.

BACKGROUND: In Japan, during the coronavirus disease 2019 (COVID-19) pandemic, patients with non-hypoxia are recommended to recuperate at home or in pre-hospital facilities. However, it was observed that unexpected hypoxia may occur and become severe subsequently in patients whose symptoms were initially expected to improve naturally. The aim of this study is to validate biomarkers that can predict at an early stage the emergence of hypoxia in COVID-19 patients without hypoxia. METHODS: We retrospectively enrolled 193 patients with COVID-19, excluding patients with hypoxia and severe disease from the onset. Participants were classified into two groups according to the emergence of hypoxia during the clinical course, and the laboratory data were compared to identify biomarkers that could predict early the emergence of hypoxia. RESULTS: The areas under the curve for serum cystatin C (CysC) and C-reactive protein (CRP) levels for the emergence of hypoxia during the clinical course were higher than those for other biomarkers (CysC, 0.84 and CRP, 0.83). Multivariate analysis showed that high serum CysC and CRP levels were associated with the emergence of hypoxia during the clinical course. CONCLUSIONS: Elevated serum CysC and CRP levels were associated with the emergence of hypoxia during the clinical course in COVID-19 patients without hypoxia. These findings may help determine the need for hospitalization in initially non-hypoxic COVID-19 patients.

TFPI and FXIII negatively and S100A8/A9 and Cystatin C positively correlate with D-dimer in COVID-19.

D-dimer is an established biomarker of thromboembolism and severity in COVID-19. We and others have recently reported the dysregulation of tissue factor pathway inhibitor (TFPI), FXIII, fibrinolytic pathway, inflammatory markers, and tissue injury markers, particularly in severe COVID-19. However, association of these markers with thromboembolism in COVID-19 remains elusive. The correlation analyses between these markers in patients with moderate (non-ICU) and severe COVID-19 (ICU) were performed to delineate the potential pathomechanisms and impact of thromboembolism. We observe a negative correlation of plasma TFPI (r2 = 0.148, P = 0.035), FXIII (r2 = 0.242, P = 0.006), and plasminogen (r2 = 0.27, P = 0.003) with D-dimer, a biomarker of thromboembolism, levels in these patients. Further analysis revealed a strong positive correlation between fibrinolytic markers tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) (r2 = 0.584, P < 0.0001). Interestingly, a significant positive correlation of PAI-1, but not tPA, was observed with platelets and endothelial cells dysfunction markers P-selectin (r2 = 0.184, P = 0.01) and soluble CD40 ligand (sCD40 L) (r2 = 0.163, P = 0.02). Moreover, calprotectin (S100A8/A9) and cystatin C (CST3), previously linked with thromboembolism, exhibited positive correlations with each other (r2 = 0.339, P = 0.0007) and with the level of D-dimer independently in COVID-19. Finally, the tissue injury marker myoglobin demonstrated a strong positive correlation with D-dimer (r2 = 0.408, P = 0.0001). Taken together, inverse correlations of TFPI and FXIII with D-dimer suggest the TF pathway activation and aberrant fibrin polymerization in COVID-19 patients. The elevated level of PAI-1 is potentially contributed by activated platelets and endothelial cells. S100A8/A9 may also play roles in impaired fibrinolysis and thromboembolism, in part, through regulating the CST3. These findings strengthen the understanding of thromboembolism and tissue injury and may help in better management of thromboembolic complications in COVID-19 patients.

Cell-Free DNA, Neutrophil extracellular traps (NETs), and Endothelial Injury in Coronavirus Disease 2019- (COVID-19-) Associated Acute Kidney Injury.

Introduction: Neutrophil extracellular traps (NETs) release (i.e., NETosis) has been recently implicated in the pathomechanism underlying severe end-organ damage in Coronavirus Disease 2019 (COVID-19) and could present a novel therapeutic target. We aimed to determine whether circulating levels of cell-free DNA (cfDNA), a surrogate for NETosis, may be associated with the development of acute kidney injury (AKI), a major contributor to poor outcomes and mortality in COVID-19. Methods: Blood samples were collected prospectively from adult patients infected with SARS-CoV-2 presenting to the emergency department (ED). Circulating levels of cfDNA were quantified from patients' serum. Further assessment of correlations between cfDNA levels and markers of AKI (i.e., serum creatinine (SCr), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL)), biomarkers of thrombotic microangiopathy and of inflammation in patients' serum was performed. Results: Fifty-one COVID-19 patients were enrolled. cfDNA levels were found to be significantly higher in those who developed severe AKI (p < 0.001) and those needing renal replacement therapy (p = 0.020). cfDNA positively correlated with ED SCr, NGAL, cystatin C, neutrophil count, neutrophil-to-lymphocyte ratio, C3a, C5a, Scb5-9, IL-6, IL-8, IL-10, TNF-α, LDH, CRP, ferritin, and fibrinogen and negatively correlated with ADAMTS13/von-Willebrand factor ratio and lymphocyte count. In a multivariate logistic regression, a one-unit increase in cfDNA value was associated with 4.6% increased odds of severe AKI (OR = 1.046; p = 0.040). Finally, cfDNA significantly correlated with established NETs components, myeloperoxidase, and neutrophil elastase. Conclusion: Intravascular NETosis could be an important contributing factor in the development of microthrombosis and COVID-19-associated AKI. Further research is urgently needed to understand the role of NETosis in COVID-19 and evaluate therapeutic avenues for targeting this process.

Cystatin C is a marker for acute kidney injury, but not for mortality among COVID-19 patients in Mexico.

BACKGROUND: Patients infected with SARS-CoV-2 can develop acute kidney injury (AKI), associated with adverse clinical outcomes. In Mexico, an AKI incidence of 60.7% was reported in patients with COVID-19. Serum cystatin C is a well-known marker for AKI. It has been postulated as a marker for mortality in Chinese patients with COVID-19. Information regarding levels of cystatin C in COVID-19-infected patients is nonexistent among Mexican or Latin American populations. AIM: This work aimed to assess the level of cystatin C as an indicator of AKI and mortality among COVID-19 patients from Mexico. METHODS: A cross-sectional study among 38 adults was performed in the Regional High Specialty Hospital of the Yucatan Peninsula in Merida, Yucatan, Mexico. Baseline characteristics and clinical and biomechanical parameters were collected, and serum levels of cystatin C were measured by ELISA. RESULTS: A total of 71% (27 patients) with COVID-19 developed AKI; 78% were men, and 22% were women. In addition, 60% of individuals (16 men; 7 women) died due to COVID-19 complications. Serum levels of cystatin C were higher in those individuals who developed AKI (p = 0.001). A logistic regression model indicated that individuals with serum levels of cystatin C above 0.84 ng/mL had a 23-fold increased risk of developing AKI (OR, 23.7, 95% CI, 2.59-217.00, p = 0.005). However, increased cystatin C was not independently associated with mortality in the Mexican population (HR, 1.01, 95% CI, 0.66-1.56, p = 0.959). CONCLUSION: The results suggest that serum levels of cystatin C indicate AKI in COVID-19 patients. Although we recommend caution when using serum cystatin C levels as an indicator of mortality among the Mexican population, it is essential to note that cystatin C elevates earlier than creatinine, which is an advantage for timely clinical interventions.

Lipocalin-2, S100A8/A9, and cystatin C: Potential predictive biomarkers of cardiovascular complications in COVID-19.

Severe coronavirus (SARS-COV-2) infection often leads to systemic inflammation accompanied by cardiovascular complications including venous thromboembolism (VTE). However, it is largely undefined if inflammatory markers such as lipocalin-2 (LNC2), calprotectin (S100A8/A9), and cystatin C (CST3), previously linked with VTE, play roles in cardiovascular complications and advancement of COVID-19 severity. To investigate the same, hospitalized moderate and severe (presented pneumonia and required intensive care) COVID-19 patients were recruited. The levels of plasma LNC2, S100A8/A9, CST3, myoglobin, and cardiac Troponin I (cTnI) were assessed through enzyme-linked immunosorbent assay (ELISA). The investigation revealed a significantly upregulated level of plasma LNC2 at the moderate stage of SARS-CoV-2 infection. In contrast, the levels of S100A8/A9 and CST3 in moderate patients were comparable to healthy controls; however, a profound induction was observed only in severe COVID-19 patients. The tissue injury marker myoglobin was unchanged in moderate patients; however, a significantly elevated level was observed in the critically ill COVID-19 patients. In contrast, cTnI level was unchanged both in moderate and severe patients. Analysis revealed a positive correlation between the levels of S100A8/A9 and CST3 with myoglobin in COVID-19. In silico analysis predicted interactions of S100A8/A9 with toll-like receptor 4 (TLR-4), MyD88 LY96, and LCN2 with several other inflammatory mediators including MMP2, MMP9, TIMP1, and interleukins (IL-6, IL-17A, and IL-10). In summary, early induction of LCN2 likely plays a role in advancing the COVID-19 severity. A positive correlation of S100A8/A9 and CST3 with myoglobin suggests that these proteins may serve as predictive biomarkers for thromboembolism and tissue injury in COVID-19.

The predictive value of serum level of cystatin C for COVID-19 severity.

To investigate the potential prognostic value of Serum cystatin C (sCys C) in patients with COVID-19 and determine the association of sCys C with severe COVID-19 illness. We performed a retrospective review of medical records of 162 (61.7 ± 13.5 years) patients with COVID-19. We assessed the predictive accuracy of sCys C for COVID-19 severity by the receiver operating characteristic (ROC) curve analysis. The participants were divided into two groups based on the sCys C cut-off value. We evaluated the association between high sCys C level and the development of severe COVID-19 disease, using a COX proportional hazards regression model. The area under the ROC curve was 0.708 (95% CI 0.594-0.822), the cut-off value was 1.245 (mg/L), and the sensitivity and specificity was 79.1% and 60.7%, respectively. A multivariable Cox analysis showed that a higher level of sCys C (adjusted HR 2.78 95% CI 1.25-6.18, p = 0.012) was significantly associated with an increased risk of developing a severe COVID-19 illness. Patients with a higher sCys C level have an increased risk of severe COVID-19 disease. Our findings suggest that early assessing sCys C could help to identify potential severe COVID-19 patients.

Altered kidney function induced by SARS-CoV-2 infection and acute kidney damage markers predict survival outcomes of COVID-19 patients: a prospective pilot study.

BACKGROUND: Literature with regard to coronavirus disease 2019 (COVID-19) associated morbidities and the risk factors for death are still emerging. In this study, we investigated the presence of kidney damage markers and their predictive value for survival among hospitalized subjects with COVID-19. METHODS: Forty-seven participants was included and grouped as: 'COVID-19 patients before treatment', 'COVID-19 patients after treatment', 'COVID-19 patients under treatment in intensive care unit (ICU)', and 'controls'. Kidney function tests and several kidney injury biomarkers were compared between the groups. Cumulative rates of death from COVID-19 were determined using the Kaplan-Meier method. The associations between covariates including kidney injury markers and death from COVID-19 were examined, as well. RESULTS: Serum creatinine and cystatin C levels, urine Kidney Injury Molecule-1 (KIM-1)/creatinine ratio, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C levels demonstrated significant difference among the groups. The most significant difference was noted between the groups 'COVID-19 patients before treatment' and 'COVID-19 patients under treatment in ICU'. Advancing age, proteinuria, elevated serum cystatin C, and urine KIM-1/creatinine ratio were all significant univariate correlates of death (p < 0.05, for all). However, only elevated urine KIM-1/creatinine ratio retained significance in an age, sex, and comorbidities adjusted multivariable Cox regression (OR 6.11; 95% CI: 1.22-30.53; p = 0.02), whereas serum cystatin C showing only a statistically non-significant trend (OR 1.42; 95% CI: 0.00-2.52; p = 0.09). CONCLUSIONS: Our findings clearly demonstrated the acute kidney injury related to COVID-19. Moreover, urine KIM-1/creatinine ratio was associated with COVID-19 specific death.

Early prediction of COVID-19-associated acute kidney injury: Are serum NGAL and serum Cystatin C levels better than serum creatinine?

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with a high risk of acute kidney injury (AKI), often requiring renal replacement therapy (RRT). Serum Cystatin C (sCysC) and serum Neutrophil Gelatinase-Associated Lipocalin (sNGAL) are emerging biomarkers for kidney injury, and were suggested to be superior to serum creatinine (sCr) in several clinical settings. Moreover, elevated sCysC is associated with disease severity and mortality in COVID-19. We aimed to assess the utility of sCysC and sNGAL for predicting COVID-19-associated AKI, need for RRT, and need for intensive care unit (ICU) admission, when measured at presentation to the emergency department (ED). METHODS: Patients presenting to the ED with laboratory-confirmed COVID-19 were included. The primary outcome was development of COVID-19-associated AKI, while the secondary outcomes were need for RRT and ICU admission. RESULTS: Among 52 COVID-19 patients, 22 (42.3%) developed AKI with 8/22 (36.4%) requiring RRT. Both sCr and sCysC demonstrated excellent performance for predicting AKI (AUC, 0.86 and 0.87, respectively) and need for RRT (AUC, 0.94 and 0.95, respectively). sNGAL displayed acceptable performance for predicting AKI (AUC, 0.81) and need for RRT (AUC, 0.87). CONCLUSIONS: SCr and sCysC measured at ED presentation are both highly accurate predictors of AKI and need for RRT, whereas sNGAL demonstrated adequate diagnostic performance. While sCyC was previously shown to be superior to sCr as a diagnostic biomarker of kidney injury in certain etiologies, our findings demonstrate that sCr is comparable to sCyC in the context of predicting COVID-19-associated AKI. Given the high sensitivity of these biomarkers for predicting the need for RRT, and as sCysC is associated with mortality in COVID-19 patients, we recommend their measurement for enabling risk stratification and early intervention.

Cystatin C, COVID-19 severity and mortality: a systematic review and meta-analysis.

BACKGROUND: Combined markers of renal dysfunction and inflammation, e.g., cystatin C, might assist with risk stratification and clinical decisions in patients with coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression of serum cystatin C in COVID-19. METHODS: We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum cystatin C concentrations, measures of clinical severity and survival outcomes in hospitalized COVID-19 patients (PROSPERO registration number: CRD42021245295). RESULTS: Thirteen studies in 2510 COVID-19 patients, 1972 with low severity or survivor status and 538 with high severity or non-survivor status during follow up, were included in the meta-analysis. The pooled results showed that serum cystatin C concentrations were higher in patients with high disease severity or non-survivor status (standard mean deviation, SMD, 1.71, 95% CI 0.95 to 2.46, p < 0.001). Extreme between-study heterogeneity was observed (I2 = 97.5%, p < 0.001). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not substantially modified. The Begg's and Egger's t tests did not show publication bias. In meta-regression, the SMD of serum cystatin C was not associated with age, proportion of males, C-reactive protein, neutrophils, lymphocytes, aspartate aminotransferase, alanine aminotransferase, albumin, creatinine, creatine kinase-MB, lactate dehydrogenase, and proportion of patients with diabetes or hypertension. CONCLUSIONS: Higher concentrations of serum cystatin C were associated with higher COVID-19 severity and mortality.

Divergence between serum creatine and cystatin C in estimating glomerular filtration rate of critically ill COVID-19 patients.

BACKGROUND: The clinical use of serum creatine (sCr) and cystatin C (CysC) in kidney function evaluation of critically ill patients has been in continuous discussion. The difference between estimated glomerular filtration rate calculated by sCr (eGFRcr) and CysC (eGFRcysc) of critically ill COVID-19 patients were investigated in this study. METHODS: This is a retrospective, single-center study of critically ill patients with COVID-19 admitted in intensive care unit (ICU) at Wuhan, China. Control cases were moderate COVID-19 patients matched in age and sex at a ratio of 1:1. The eGFRcr and eGFRcysc were compared. The association between eGFR and death were analyzed in critically ill cases. The potential factors influencing the divergence between eGFRcr and eGFRcysc were explored. RESULTS: A total of 76 critically ill COVID-19 patients were concluded. The mean age was 64.5 ± 9.3 years. The eGFRcr (85.45 (IQR 60.58-99.23) ml/min/1.73m2) were much higher than eGFRcysc (60.6 (IQR 34.75-79.06) ml/min/1.73m2) at ICU admission. About 50 % of them showed eGFRcysc < 60 ml/min/1.73 m2 while 25% showed eGFRcr < 60 ml/min/1.73 m2 (χ2 = 10.133, p = 0.001). This divergence was not observed in moderate group. The potential factors influencing the divergence included serum interleukin-6 (IL-6), tumor necrosis factor (TNF-α) level as well as APACHEII, SOFA scores. Reduced eGFRcr (<60 mL/min/1.73 m2) was associated with death (HR = 1.939, 95%CI 1.078-3.489, p = 0.027). CONCLUSIONS: The eGFRcr was generally higher than eGFRcysc in critically ill COVID-19 cases with severe inflammatory state. The divergence might be affected by inflammatory condition and illness severity. Reduced eGFRcr predicted in-hospital death. In these patients, we advocate for caution when using eGFRcysc.

Association Between the Concentration and Rangeability of Cystatin C and Mortality of COVID-19 Patients With or Without Type 2 Diabetes Mellitus: A Retrospective Analysis.

Background: We investigated if the concentration and "rangeability" of cystatin C (CysC) influenced the prognosis of coronavirus disease 2019 (COVID-19) in patients suffering from, or not suffering from, type 2 diabetes mellitus (T2DM). Methods: A total of 675 T2DM patients and 572 non-T2DM patients were divided into "low" and "high" CysC groups and low and high CysC-rangeability groups according to serum CysC level and range of change of CysC level, respectively. Demographic characteristics, clinical data, and laboratory results of the four groups were analyzed. Results: COVID-19 patients with a high level and rangeability of CysC had more organ damage and a higher risk of death compared with those with a low level or low rangeability of CysC. Patients with a higher level and rangeability of CysC had more blood lymphocytes and higher levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase. After adjustment for possible confounders, multivariate analysis revealed that CysC >0.93 mg/dL was significantly associated with the risk of heart failure (OR = 2.231, 95% CI: 1.125-5.312) and all-cause death (2.694, 1.161-6.252). CysC rangeability >0 was significantly associated with all-cause death (OR = 4.217, 95% CI: 1.953-9.106). These associations were stronger in patients suffering from T2DM than in those not suffering from T2DM. Conclusions: The level and rangeability of CysC may influence the prognosis of COVID-19. Special care and appropriate intervention should be undertaken in COVID-19 patients with an increased CysC level during hospitalization and follow-up, especially for those with T2DM.

Could urinary kidney injury molecule-1 be a good marker in subclinical acute kidney injury in mild to moderate COVID-19 infection?

PURPOSE: To evaluate urinary kidney injury molecule-1 (uKIM-1), which is a proximal tubule injury biomarker in subclinical acute kidney injury (AKI) that may occur in COVID-19 infection. METHODS: The study included proteinuric (n = 30) and non-proteinuric (n = 30) patients diagnosed with mild/moderate COVID-19 infection between March and September 2020 and healthy individuals as a control group (n = 20). The uKIM-1, serum creatinine, cystatin C, spot urine protein, creatinine, and albumin levels of the patients were evaluated again after an average of 21 days. RESULTS: The median (interquartile range) uKIM-1 level at the time of presentation was 246 (141-347) pg/mL in the proteinuric group, 83 (29-217) pg/mL in the non-proteinuric group, and 55 (21-123) pg/mL in the control group and significantly high in the proteinuric group than the others (p < 0.001). Creatinine and cystatin C were significantly higher in the proteinuric group than in the group without proteinuria, but none of the patients met the KDIGO-AKI criteria. uKIM-1 had a positive correlation with PCR, non-albumin proteinuria, creatinine, cystatin C, CRP, fibrinogen, LDH, and ferritin, and a negative correlation with eGFR and albumin (p < 0.05). In the multivariate regression analysis, non-albumin proteinuria (p = 0.048) and BUN (p = 0.034) were identified as independent factors predicting a high uKIM-1 level. After 21 ± 4 days, proteinuria regressed to normal levels in 20 (67%) patients in the proteinuric group. In addition, the uKIM-1 level, albuminuria, non-albumin proteinuria, and CRP significantly decreased. CONCLUSIONS: Our findings support that the kidney is one of the target organs of the COVID-19 and it may cause proximal tubule injury even in patients that do not present with AKI or critical/severe COVID-19 infection.

Neurological and psychiatric presentations associated with COVID-19.

The objective is to investigate coronavirus disease 2019 (COVID-19)-associated neurological and psychiatric effects and explore possible pathogenic mechanisms. This study included 77 patients with laboratory-confirmed COVID-19 in Wuhan, China. Neurological manifestations were evaluated by well-trained neurologists, psychologists, psychiatric presentations and biochemical changes were evaluated using the Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire-9, Brief Psychiatric Rating Scale, and electronic medical records. Eighteen (23.4%) patients presented with neurological symptoms. Patients with neurological presentations had higher urea nitrogen, cystatin C, and high-sensitivity C-reactive protein levels and lower basophil counts. Among them, patients with muscle involvement had higher urea nitrogen and cystatin C levels but lower basophil counts. In addition, patients with psychiatric presentations were older and had higher interleukin (IL)-6 and IL-10 levels and higher alkaline phosphatase, R-glutamate transferase, and urea nitrogen levels. Moreover, patients with anxiety had higher IL-6 and IL-10 levels than those without, and patients with moderate depression had higher CD8 + T cell counts and lower CD4 + /CD8 + ratios than other patients. This study indicates that the central nervous system may be influenced in patients with COVID-19, and the pathological mechanisms may be related to direct virus invasion of the central nervous system, infection-mediated overreaction of the immune system, and aberrant serum pro-inflammatory factors. In addition, basophils and cystatin C may also play important roles during these pathological processes. Our findings suggest that neurological and psychiatric presentations should be evaluated and managed in patients with COVID-19. Further studies are needed to investigate the underlying mechanisms.

Early predictors of acute kidney injury in COVID-19 patients.

AIM: This study aims to determine the frequency of COVID-19 related AKI and to identify the early predictors of AKI. METHODS: This study is a single-center, retrospective, observational study. Hospitalized COVID-19 patients between 24/03/2020 and 31/05/2020 were included in the study. All patients were evaluated for renal dysfunctions with urine dipstick, protein/creatinine ratio, albumin/creatinine ratio in spot urine, serum cystatin C, serum creatinine level on hospital admission, and 28th day of hospital admission. To assess the utility of these parameters to predict AKI, a receiver-operating characteristic curve was generated and the area under the curve (AUC) was calculated. RESULTS: 348 patients were included. The average incidence of AKI was 4.9% (n = 17). The incidence of AKI in mild, moderate and severe COVID-19 cases was 1.3% (n = 4), 9.0% (n = 3) and 76.9% (n = 10), respectively. Proteinuria was detected in 7.8% (n = 27) of patients with a urine dipstick test. In spot urine analysis, proteinuria was found in 20.1% (n = 70) of patients. The frequency of persistent proteinuria was 5.2% (n = 18). The AUC alue of serum cystatin C, D-dimer and albumin/creatinine ratio to predict COVID-19 related AKI were 0.96 (0.90 to 1.0), 0.94 (0.89-0.98), and 0.95 (0.91-0.98). CONCLUSION: In COVID-19 patients with normal serum creatinine levels on hospital admission, albuminuria, serum cystatin C and D-dimer levels may be an early predictor of COVID-19 related AKI and these patients should be monitored closely for AKI. Since the sample size in the AKI group was small, our study results should be confirmed with larger cohort studies.