The Predictive Value of Cystatin C for AKI in Patients with COVID-19.

Objective. To evaluate a potential of cystatin C blood concentration to predict acute kidney injury (AKI) in patients with severe and extremely severe pneumonia associated with a COVID-19. Materials and methods. An observational prospective study of 117 patients with severe and extremely severe pneumonia associated with a COVID-19 in an ICU setting was conducted in 2020-2022 (site: multifunctional Medical Center, 1586 Military Clinical Hospital of the Ministry of Defense of Russia, Moscow Region, Russia). Routine laboratory tests and instrumental examinations were performed according to generally accepted protocols. Cystatin C concentrations in blood (s-CysC) and urine (u-CysC) were measured by immunoturbidimetric method. Results. AKI was diagnosed in 21 (17.9%) patients, kidney dysfunction without AKI was found in 22 (18.8%) patients with severe and extremely severe pneumonia associated with COVID-19. s-CysC and u-CysC levels in the group of patients with AKI were statistically significantly higher compared to the levels in the group of patients without AKI. The levels of s-CysC obtained within Day 1 - T (-1), and Day 2 - T (-2) prior to AKI onset turned out to be the independent factors for AKI development in patients with severe and extremely severe pneumonia associated with COVID-19: OR 5.37, Wald chi-square 5.534 (CI: 1.324;21.788);P=0.019 and OR 3.225, Wald chi-square 4.121 (CI: 1.041;9.989);P=0.042, respectively. s-CysC T (-2) value is informative, and s- CysC T (-1) is a highly informative predictor of AKI development in severe and extremely severe pneumonia associated with COVID-19: ROC AUC 0.853 (95% CI, 0.74-0.966), P_0.001) with 90% sensitivity and 73% specificity at a cut-off of 1.67 mg/L, and ROC AUC 0.905 (95% CI, 0.837-0.973), P_0.001) with 90% sensitivity and 73% specificity at a cut-off of 1.69 mg/l, respectively. Serum CysC levels started increasing 3 days prior to AKI onset, outpacing the increase of SCr levels. The u-CysC levels were not predictive of AKI development. Impaired renal function probability was increasing with patients' age (P_0.0001). Conclusions. Serum CysC seems to be a statistically significant predictor of AKI. s-CysC levels started increasing 3 days prior to AKI onset, surpassing the increase of SCr levels in patients with severe and extremely severe pneumonia associated with COVID-19. Urine CysC did not achieve statistical significance as a predictor for AKI, although u-CysC concentrations were significantly higher on days 3, 2, 1 prior to AKI onset and on the day of AKI onset in the group of patients with AKI.Copyright © 2023, V.A. Negovsky Research Institute of General Reanimatology. All rights reserved.

Biomarkers of renal injury as early predictors of COVID-19 associated AKI: a prospective observational trial (BRICOAKI-trial)

Introduction: Early prediction by the use of serum and urinary biomarkers for the detection of acute kidney injury (AKI) may be very valuable to optimize the management and helps in improving the outcomes. This study aims to investigate whether daily measurement of urinary and plasma renal biomarkers have a role in earlier predicting COVID-19 associated AKI. Method(s): The study was conducted as a single-center, prospective, observational cohort study between August 2020 and December 2020 in hospitalized COVID-19 patients. A total of 65 moderate and severe COVID-19 positive adult (>= 18 years) patients were enrolled for this study. We measured serum creatinine, cystatin C, NGAL, KIM-1, Urine-Klotho, TIMP-2, IL-6 level, and urinary microalbumin/urinary creatinine on various days. The receiver operating characteristic curve (ROC) analysis was used to find the sensitivity and specificity of various markers to predict the incidence of AKI. Result(s): A total of 24 moderate and 41 severe COVID-19 patients were included. Out of which 47 patients developed (72.3%) acute kidney injury (AKI) over the course of COVID-19. Among these subjects, 18/47 (38.2%) developed severe AKI (KDIGO 2 + 3), and 5/47 (10.6%) required RRT. NGAL was found to be the best marker to predict the probability of AKI (Area under curve AUC of 0.713-0.786) with a sensitivity of 76-90% and specificity of 56-79% on different days of assessment from Day 1 to Day 7. IL-6 had moderate accuracy of prediction and cystatin C, KIM-1, Urine-Klotho, TIMP-2, IL-6 had poor accuracy for predicting the incidence of AKI. Conclusion(s): Urinary biomarkers like NGAL have good predictability for AKI.

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.

Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome.

Long-COVID syndrome is associated with high healthcare costs, but its pathophysiology is not yet fully understood. Inflammation, renal impairment or disturbance of the NO system emerge as potential pathogenetic factors. We aimed to investigate the relationship between symptoms of long-COVID syndrome and serum levels of cystatin-c (CYSC), orosomucoid (ORM), l-arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). A total of 114 patients suffering from long-COVID syndrome were included in this observational cohort study. We found that serum CYSC was independently associated with the anti-spike immunoglobulin (S-Ig) serum level (OR: 5.377, 95% CI: 1.822-12.361; p = 0.02), while serum ORM (OR: 9.670 (95% CI: 1.34-9.93; p = 0.025) independently predicted fatigue in patients with long-COVID syndrome, both measured at baseline visit. Additionally, the serum CYSC concentrations measured at the baseline visit showed a positive correlation with the serum SDMA levels. The severity of abdominal and muscle pain indicated by patients at the baseline visit showed a negative correlation with the serum level of L-arginine. In summary, serum CYSC may indicate subclinical renal impairment, while serum ORM is associated with fatigue in long-COVID syndrome. The potential role of l-arginine in alleviating pain requires further studies.

Estimated glomerular filtration rates are higher when creatinine-based equations are compared with a cystatin C-based equation in coronavirus disease 2019.

OBJECTIVES: Estimations of glomerular filtration rate (eGFR) are based on analyses of creatinine and cystatin C, respectively. Coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU) often have acute kidney injury (AKI) and are at increased risk of drug-induced kidney injury. The aim of this study was to compare creatinine-based eGFR equations to cystatin C-based eGFR in ICU patients with COVID-19. METHODS: After informed consent, we included 370 adult ICU patients with COVID-19. Creatinine and cystatin C were analyzed at admission to the ICU as part of the routine care. Creatinine-based eGFR (ml/min) was calculated using the following equations, developed in chronological order; the Cockcroft-Gault (C-G), Modified Diet in Renal Disease (MDRD)1999, MDRD 2006, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Lund-Malmö revised (LMR) equations, which were compared with eGFR calculated using the cystatin C-based Caucasian Asian Pediatric Adult (CAPA) equation. RESULTS: The median eGFR when determined by C-G was 99 ml/min and interquartile range (IQR: 67 ml/min). Corresponding estimations for MDRD1999 were 90 ml/min (IQR: 54); MDRD2006: 85 ml/min (IQR: 51); CKD-EPI: 91 ml/min (IQR: 47); and for LMR 83 ml/min (IQR: 41). eGFR was calculated using cystatin C and the CAPA equation value was 70 ml/min (IQR: 38). All differences between creatinine-based eGFR versus cystatin C-based eGFR were significant (p < .00001). CONCLUSIONS: Estimation of GFR based on various analyses of creatinine are higher when compared with a cystatin C-based equation. The C-G equation had the worst performance and should not be used in combination with modern creatinine analysis methods for determination of drug dosage in COVID-19 patients.

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.

Role of cystatin C and calprotectin as potential early prognostic biomarkers in COVID-19 patients admitted to a dedicated COVID care facility.

Background: The COVID-19 pandemic has claimed millions of lives. A tool for early prediction of severity and mortality risk is desirable for better utilization of health care facilities. Several biomarkers like D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP) and some recently explored biomarkers like serum cystatin C and serum calprotectin have been proposed as prognostic markers of COVID-19, but their role as prognostic markers is so far undefined. The present work attempted to investigate the possible role of serum cystatin C and serum calprotectin as prognostic tools to predict severity and outcome ahead of time. Material and Methods: This observational cohort study was carried out on 95 COVID-19 patients admitted to a dedicated COVID care facility from mid-October 2020 to January 2021. Serial estimations of serum cystatin C and serum calprotectin levels were done and assessed for significant difference between severe (NEWS 2 score ≥5) and non-severe (NEWS 2 score <5) groups, survivors and deceased and on the basis of comorbidities at each time points. Survival analysis was done based on the optimal thresholds for severity and mortality, calculated from the receiver operating characteristic (ROC). Result: The results showed that median cystatin C levels were significantly higher on the first day in the severe group (P < 0.001) and in patients with cardiovascular disease (P < 0.05), chronic lung disease (P = 0.009) and among patients who died (P < 0.05). It remained raised on day 3 in severe (P < 0.05) and deceased (P < 0.05) group. Serum calprotectin levels were significantly higher in patients with chronic lung disease (P = 0.008) and in those who died (P < 0.05). Conclusion: Serum cystatin C could be used as a tool for early prognosis and therapeutic decision-making for COVID-19 patients. Serum calprotectin seems to be a better marker of critical illness.

Circulating Serum Cystatin C as an Independent Risk Biomarker for Vascular Endothelial Dysfunction in Patients with COVID-19-Associated Multisystem Inflammatory Syndrome in Children (MIS-C): A Prospective Observational Study.

INTRODUCTION: Multisystem inflammatory syndrome in children (MIS-C) is a new clinical entity that has emerged in the context of the COVID-19 pandemic. Despite the less severe course of the disease, varying degrees of cardiovascular events may occur in MIS-C; however, data on vascular changes occurring in MIS-C are still lacking. Endothelial dysfunction (ED) is thought to be one of the key risk factors contributing to MIS-C. BACKGROUND: We conducted a prospective observational study. We investigated possible manifestations of cardiac and endothelial involvement in MIS-C after the treatment of the acute stage and potential predictive biomarkers in patients with MIS-C. METHODS: Twenty-seven consecutive pediatric subjects (≥9 years), at least three months post-treated MIS-C of varying severity, in a stable condition, and twenty-three age- and sex-matched healthy individuals (HI), were enrolled. A combined non-invasive diagnostic approach was used to assess endothelial function as well as markers of organ damage using cardiac examination and measurement of the reactive hyperemia index (RHI), by recording the post- to pre-occlusion pulsatile volume changes and biomarkers related to ED and cardiac disease. RESULTS: MIS-C patients exhibited a significantly lower RHI (indicative of more severe ED) than those in HI (1.32 vs. 1.80; p = 0.001). The cutoff of RHI ≤ 1.4 was independently associated with a higher cardiovascular risk. Age and biomarkers significantly correlated with RHI, while serum cystatin C (Cys C) levels were independently associated with a diminished RHI, suggesting Cys C as a surrogate marker of ED in MIS-C. CONCLUSIONS: Patients after MIS-C display evidence of ED, as shown by a diminished RHI and altered endothelial biomarkers. Cys C was identified as an independent indicator for the development of cardiovascular disease. The combination of these factors has the potential to better predict the cardiovascular consequences of MIS-C. Our study suggests that ED may be implicated in the pathophysiology of this disease.

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.

Differential Bias for Creatinine- and Cystatin C- Derived Estimated Glomerular Filtration Rate in Critical COVID-19.

COVID-19 is a systemic disease, frequently affecting kidney function. Dexamethasone is standard treatment in severe COVID-19 cases, and is considered to increase plasma levels of cystatin C. However, this has not been studied in COVID-19. Glomerular filtration rate (GFR) is a clinically important indicator of renal function, but often estimated using equations (eGFR) based on filtered metabolites. This study focuses on sources of bias for eGFRs (mL/min) using a creatinine-based equation (eGFRLMR) and a cystatin C-based equation (eGFRCAPA) in intensive-care-treated patients with COVID-19. This study was performed on 351 patients aged 18 years old or above with severe COVID-19 infections, admitted to the intensive care unit (ICU) in Uppsala University Hospital, a tertiary care hospital in Uppsala, Sweden, between 14 March 2020 and 10 March 2021. Dexamethasone treatment (6 mg for up to 10 days) was introduced 22 June 2020 (n = 232). Values are presented as medians (IQR). eGFRCAPA in dexamethasone-treated patients was 69 (37), and 74 (46) in patients not given dexamethasone (p = 0.01). eGFRLMR was not affected by dexamethasone. eGFRLMR in females was 94 (20), and 75 (38) in males (p = 0.00001). Age and maximal CRP correlated negatively to eGFRCAPA and eGFRLMR, whereas both eGFR equations correlated positively to BMI. In ICU patients with COVID-19, dexamethasone treatment was associated with reduced eGFRCAPA. This finding may be explained by corticosteroid-induced increases in plasma cystatin C. This observation is important from a clinical perspective since adequate interpretation of laboratory results is crucial.

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.

THE CRITICAL ROLE OF CYTOKINE DYSREGULATION IN ACUTE KIDNEY INJURY DEVELOPMENT IN PATIENTS WITH COVID-19

BACKGROUND AND AIMS: One of the complications described in critically ill patients in intensive care units with severe COVID-19 was acute kidney injury (AKI). The pathophysiology of AKI in patients with COVID-19 is multifactorial. In addition to the direct virulence of SARS-CoV-2 in renal cells, the tissue inflammation and local immune cell infiltration, cytokine storm, secondary infections and nephrotoxicity associated drugs may contribute to AKI [1]. Mounting evidence throughout the pandemic suggests that patients with severe COVID-19 may have a cytokine storm syndrome, one of the possible causes of AKI in these patients [2]. The present prospective cohort study analysed the correlation between circulating cytokine profile and estimated glomerular filtration rate (eGFR) in patients with COVID-19. METHOD: After signing the informed consent, patients positive for SARS-CoV- 2 infection (n = 74) had blood samples (n = 139) collected at hospital admission until the day of the outcome. ELISA measured the cytokines IL-10, IL-4, L-6, TNF- α and IFN-γ , and the eGFR was calculated by the CKD-EPI Cystatin C equation. Statistics description: Continuous variables were checked for normality and presented as mean ± standard deviation or median and interquartile range. The association between continuous variables is shown in scatterplots, and a predicted response with 95% confidence interval (95% CI) is plotted using fractional polynomials. For linear correlations, we obtained P-values using Pearson's correlation coefficient. RESULTS: There is a more significant distribution of eGFR below 90 mL/min in the population studied, associated with older patients. Glomerular filtration rates were negatively correlated with age as expected (-0.60;P < 0.0001). Lower eGFR was correlated with levels of proinflammatory cytokines such as IL-6 (-0.33;P < .0007) and TNF- α (-0.21;P < .03);but without positive correlation with IL-10 (0.04;P < 0.68) or IFN-γ (-0.14;P < .16), even though higher IFN-γ levels have been linked to a worse prognosis in patients with severe COVID-19 [3]. Curiously, a positive correlation was observed between lower eGFR and IL-4 levels. CONCLUSION: These results demonstrate that a shift in the immune response profile, cytokines with a Th2 profile such as IL-4, and cytokines with systemic functions such as IL-6 and TNF-α can be related to renal failure. The elucidation of the potential pathophysiological mechanisms of AKI associated with COVID-19 as well as monitoring of cytokine levels can (a) help to identify patients with severe COVID-19 at risk of loss of renal function, (b) provide information on specific therapeutic strategies. (Figure Presented).

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.

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.

Cystatin C and Neutrophil Gelatin-associated Lipocalin (NGAL) Can Predict Acute Kidney Injury and In-Hospital Mortality in COVID-19 Patients

Background: Prediction and early diagnosis of acute kidney injury (AKI) in critically ill Coronavirus disease 2019 (COVID-19) patients are of great importance. Therefore, using promising renal biomarkers such as cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) to identify the risk of future AKI is crucial. Materials and Methods: A total of 89 adult patients with COVID-19 were included in this study. Serum cystatin C and NGAL concentration were assessed on intensive care unit (ICU) admission then repeated after 48 hours. Serum creatinine was followed for 7 days to report the development of AKI. Results: Among the COVID-19 patients, 28.1% developed AKI. Although admission serum creatinine was not significantly different between the AKI group and the non-AKI group (p=0.375), admission Cystatin C (p=0.018), and NGAL (p<0.001) were significantly different between both groups. After 48 hours, a change in Cystatin C level (p<0.001) but not NGAL (p=0.4) was a predictor for AKI. Logistic regression model including age (p=0.031), Cystatin C on 48 hrs (p=0.003) and NGAL on admission (p=0.015) could predict AKI in COVID-19 patients. Conclusion: Serum Cystatin C and NGAL in ICU could be used to predict AKI in COVID-19 patients. A logistic regression model including age, Cystatin C on 48hrs, and NGAL on admission might be a tool for individualized risk estimation of AKI in COVID-19 patients.

Microneedle patches integrated with lateral flow cassettes for blood-free chronic kidney disease point-of-care testing during a pandemic.

Chronic kidney disease (CKD) is the most neglected chronic disease affecting over 750 million persons in the world. Currently, many patients with cancers or other chronic diseases (i.e., CKD) struggle to receive clinical treatment or examination due to hospitals cancelling or delaying in the COVID-19 pandemic, which may increase the risk of death. Cystatin C (Cys C) has been proposed as a potential glomerular filtration rate (GFR) marker for the early detection of acute kidney injury and CKD. However, most traditional methods for Cys C detection are immunoassays using serum as a sample and are tedious to perform and economically burdensome. To diagnose the disease in the early stage and carry out daily management during the current pandemic, we developed an integration of hydrogel microneedle patch (HMNP) and lateral flow cassette (LFC) to rapidly detect Cys C in skin interstitial fluid (ISF) in 25 min for blood-free CKD management anytime and anywhere by the naked eye that can reduce the impact of an individual's quality of life and life expectancy. Conceivably, this strategy presents a wide scope in the application of numerous other diseases if corresponding analytes are available in skin ISF.

Renal and Inflammation Markers-Renalase, Cystatin C, and NGAL Levels in Asymptomatic and Symptomatic SARS-CoV-2 Infection in a One-Month Follow-Up Study.

The aim of our study was to evaluate the influence of asymptomatic infection and the occurrence of symptomatic COVID-19 on specific biochemical, renal, and immune parameters-renalase, neutrophil gelatinase-associated lipocalin (NGAL) cystatin C (CysC), and creatinine-and their weekly fluctuations during a one-month observation period in COVID-19 patients admitted to hospital. The study involved 86 individuals: 30 patients with diagnosed COVID-19, 28 people with asymptomatic infection confirmed with IgG antibodies-the IG(+) group-and 28 individuals without any (IgG, IgE) anti-SARS-CoV-2 antibodies-the IG(-) group. In the COVID-19 group, blood was drawn four times: (1) on day 0/1 after admission to hospital (C1 group), (2) 7 days later (C7 group), (3) 14 days later (C14 group), and (4) 28 days later (C28 group). In the IG(-) and IG(+) groups, blood was drawn once. There were no significant differences in creatinine, Cys C, and uric acid between any of the analyzed groups. NGAL levels were significantly higher in IG(+) and at all time-points in the COVID-19 groups than in controls. A similar observation was made for renalase at the C7, C14, and C28 time-points. Plasma renalase, NGAL, and CysC are unrelated to kidney function in non-critically ill COVID-19 patients and those with asymptomatic infection. Renalase and NGAL are most likely related to the activation of the immune system rather than kidney function. Asymptomatic SARS-CoV-2 infection causes a rise in plasma NGAL levels similar to those observed in symptomatic COVID-19 patients. Therefore, more attention should be paid to tracking and monitoring the health of these people.

RENIN-ANGIOTENSIN SYSTEM MARKERS AND NONPULMONARY ORGAN INJURY IN SEVERE COVID-19 PNEUMONIA

Proximity extension assays measured plasma renin, ACE2, and renin-receptor, as well as >40 markers of endothelial, alveolar, cardiac, and renal injury. Over time, critically ill patients develop higher RAS markers that are associated with non-pulmonary organ injury and worse 28-day outcome. B Introduction: b The renin-angiotensin system (RAS) is not well characterized over the course of severe COVID-19 illness. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)