Retrospective Evaluation of Cystatin C as a Measure of Renal Function in Pediatric Hematopoietic Stem Cell Transplant Patients Receiving Foscarnet for Cytomegalovirus Reactivation.

BACKGROUND: Cytomegalovirus (CMV) infection following allogeneic hematopoietic cell transplantation has considerable morbidity and mortality, and foscarnet is a treatment option that requires renal dose adjustment. Serum creatinine (SCr)-based estimated glomerular filtration rate (eGFR) equations are used to estimate renal function for patients receiving foscarnet, but cystatin C (cysC) has been shown as a possible alternative. Data examining cysC-based eGFR in this population is sparse. Our primary objective was to evaluate outcomes of patients treated with foscarnet dosed utilizing cysC-based eGFR versus SCr-based eGFR. METHODS: We analyzed patients on the transplantation and cellular therapies service at Memorial Sloan Kettering Kids from January 2011 to September 2021 who received allogeneic hematopoietic cell transplantation and ≥14 days of foscarnet for CMV infection. Patients with cysC-based eGFR were compared to a historical cohort of patients who only had SCr-based eGFR. Outcomes included time to CMV clearance, death or change in anti-CMV therapy. Cumulative incidence curves and cause-specific hazards model were used for analysis. RESULTS: In 61 analyzed patients, no differences were found between the cohorts in cumulative incidence of change in anti-CMV therapy ( P = 0.17) or death ( P = 0.69). After adjustment for multiple confounders, patients in the SCr cohort seemed to have a higher chance of CMV clearance compared with the cysC cohort, but the difference was not statistically significant (hazard ratio = 2.42, P = 0.089). Patients who received corticosteroids appeared to have lower incidence of CMV clearance ( P = 0.056). CONCLUSIONS: We did not find differences in outcomes when dosing foscarnet using cysC versus SCr for treatment of CMV infection.

Does cystatin C have an immunomodulatory role in Hashimoto's thyroiditis?

OBJECTIVES: Studies which report cystatin C's (Cys-C) role in immunological disorders are increasing. However, data in the pediatric age group is limited. In this study, we aimed to evaluate the association between serum Cys-C levels and thyroid autoantibodies in children and adolescents diagnosed with euthyroid Hashimoto's thyroiditis. METHODS: The patient group was included 50 participants aged between 3 and 18 years, and the control group included 50 healthy children matched for age, gender, and body mass index. Patients with hypothyroidism or taking any medication were not included in the study. Fasting glucose, liver enzymes, urea, creatinine, lipid profile, Cys-C, free thyroxine (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibodies (TGAb) levels were recorded in all subjects. RESULTS: The mean age of control group was 13.5 ± 2.5 years, and the mean age of Hashimoto thyroiditis (HT) group was 14.2 ± 2.7 years, no statistically significant differences existed (p=0.205). Cys-C values were significantly higher in the HT group than in the control group (p=0.041). When all cases were evaluated, Cys-C levels were statistically positively correlated with fT3, TPOAb, and TGAb values (p<0.001, p=0.029, p=0.013 respectively). CONCLUSIONS: Based on the results of our study, Cys-C levels in children and adolescents with euthyroid Hashimoto thyroiditis were statistically higher than their healthy peers. In conclusion, it can be said that Cys-C may be a factor in the etiopathogenesis of autoimmune thyroiditis, and even small changes in TSH values affect Cys-C levels.

Ticagrelor and Dapagliflozin Have Additive Effects in Ameliorating Diabetic Nephropathy in Mice with Type-2 Diabetes Mellitus.

PURPOSE: Ticagrelor and dapagliflozin can suppress the activation of the NOD-like receptor 3 (NLRP3)-inflammasome and activate AMP-activated protein kinase (AMPK). The anti-inflammatory effects of dapagliflozin has been shown to depend on AMPK activation. Dapagliflozin and ticagrelor have been shown to have additive effects on the progression of diabetic cardiomyopathy in BTBR ob/ob mice with type-2 diabetes. We assessed whether dapagliflozin and ticagrelor have additive effects on the activation of the NLRP3-inflammasome and the progression of diabetic nephropathy in mice with type-2 diabetes. METHODS: Eight-week-old BTBR received either no-drug, dapagliflozin (1.5 mg/kg/d), ticagrelor (100 mg/kg/d), or their combination for 12 weeks. Blood was assessed weekly for glucose and urine for glucose and albumin. After 12 weeks, blood creatinine, cystatin C, inflammasome activation, and insulin were assessed by ELISA. Renal cortex samples were assessed by hematoxylin and eosin and periodic acid-Schiff staining. RT-PCR and immunoblotting were used to evaluate fibrosis and the activation of Akt, AMPK and the inflammasome. RESULTS: Both ticagrelor and dapagliflozin reduced serum creatinine and cystatin C levels and urinary albumin. Both drugs attenuated the increase in glomerular area and mesangial matrix index. Both drugs decreased collagen-1 and collagen-3 expression and the activation of the NLRP3-inflammasome. Both drugs increased P-AMPK levels, but only dapagliflozin increased P-Akt levels. Overall, the protective effects of dapagliflozin and ticagrelor were additive. CONCLUSIONS: Dapagliflozin and ticagrelor attenuated the progression of diabetic nephropathy in BTBR ob/ob mice with additive effects of the combination. This was associated with AMPK activation and reduced activation of the NLRP3 inflammasome, whereas only dapagliflozin increased Akt activation.

Cistatina C en el derrame pleural / Cystatin C in Pleural Effusion

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[Evaluation of nephrocerebral risk with the use of cystatin C in patients with chronic kidney disease]. / Otsenka nefrotserebral'nogo riska s ispol'zovaniem tsistatina S u bol'nykh khronicheskoi bolezn'iu pochek.

AIM: To study a role of cystatin C in the nephrocerebral risk in chronic kidney disease at the initial stage of the disease. MATERIAL AND METHODS: One hundred and twenty-eight patients (63 men and 65 women) with chronic kidney disease (CKD) were examined at the pre-dialysis stage of the disease. All patients underwent a complex clinical and laboratory examination with determination of the lipid spectrum, uric acid, fibrinogen, calcium and cystatin C, and subsequent calculation of the glomerular filtration rate (GFR). To assess structural changes in carotid arteries, ultrasound dopplerography was performed. Depending on the thickness of the intima-media (TIM), the entire sample is divided into CKD groups with no signs of carotid atherosclerosis (SC), n=70 and on CKD with SC, n=58. RESULTS: Patients of the second group (CKD with SC), had higher body mass index (p<0.05), systolic (p<0.05) and central (p<0.05) arterial pressure (BP) and blood cystatin C (p<0.05). In the same group, there was a significant decrease in the concentration of high-density lipoprotein cholesterol (p<0.05) compared with those of the first group (CKD). The age of patients and the content of cystatin C (p<0.05) influenced the increase in TIM. Significant positive correlations between cystatin C content and TIM, systolic and diastolic blood pressure (p<0.05), and a negative correlation cystatin C content and GFR were noted in patients of the second group. CONCLUSION: The increase in the level of cystatin C in blood plasma in CKD indicates the development of structural changes in the carotid arteries, the increase in the levels of systolic and central arterial pressure, the decrease in the concentration of HDL cholesterol, which is associated with significant inhibition of GFR.

Biomarkers upon discontinuation of renal replacement therapy predict 60-day survival and renal recovery in critically ill patients with acute kidney injury.

INTRODUCTION: There is no consensus on the specific indications for weaning critically ill patients with acute kidney injury (AKI) off renal replacement therapy (RRT). This study aimed to explore the prognostic value of several biomarkers measured upon discontinuation of RRT for their value in predicting 60-day survival and renal recovery in an effort to add knowledge to the decision-making process regarding RRT withdrawal. METHODS: We prospectively enrolled 102 patients with AKI who required RRT from the intensive care unit. Serum osteopontin (sOPN), serum interleukin 6 (sIL-6), serum cystatin C (sCysC), sIL-18, serum neutrophil gelatinase-associated lipocalin and urinary IL-18 and urinary neutrophil gelatinase-associated lipocalin were measured upon discontinuation of RRT. Patients were followed up at 60 days for survival and renal recovery. FINDINGS: Patients who survived showed lower levels of all serum and urinary biomarkers. Serum OPN (OR 1.029, 95% CI 1.013-1.047, P = 0.001), diabetes (OR 23.157, 95% CI 4.507-118.981, P < 0.001) and APACHE II score (OR 1.308, 95% CI 1.121-1.527, P = 0.001) were independent predictors of 60-day mortality. Patients whose sOPN values fell within the highest and middle tertiles showed 5.25- and 2.31-fold increased risks of mortality, respectively, compared with that of patients in the lowest tertile. The addition of sOPN to the clinical model resulted in significant net reclassification improvement of 0.453 (P = 0.026) and an integrated discriminative index of 0.155 (P = 0.032). Lower levels of sOPN and sIL-6 were associated with greater odds of 60-day survival (AUC 0.812 and 0.741). The AUC value for predicting survival reached its highest level when all biomarkers were combined with urine output (UO) and urinary and serum creatinine upon discontinuation of RRT (0.882). Lower sCysC performed as well as higher UO in predicting 60-day renal recovery with the greatest AUC of 0.743. DISCUSSION: Upon discontinuation of RRT, serum and urinary biomarkers, particularly sOPN, may predict 60-day survival and renal recovery in critically ill patients with AKI. The serum levels of OPN, IL-6 and CysC may be useful when considering withdrawal of RRT on the basis of conventional indicators.

Cystatins 9 and C as a Novel Immunotherapy Treatment That Protects against Multidrug-Resistant New Delhi Metallo-Beta-Lactamase-1-Producing Klebsiella pneumoniae.

Multidrug-resistant (MDR) bacterial pneumonia can induce dysregulated pulmonary and systemic inflammation leading to morbidity and mortality. Antibiotics to treat MDR pathogens do not function to modulate the extent and intensity of inflammation and can have serious side effects. Here we evaluate the efficacy of two human cysteine proteinase inhibitors, cystatin 9 (CST9) and cystatin C (CSTC), as a novel immunotherapeutic treatment to combat MDR New Delhi metallo-beta-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae Our results showed that mice infected intranasally (i.n.) with a 90% lethal dose (LD90) challenge of NDM-1 K. pneumoniae and then treated with the combination of human recombinant CST9 (rCST9) and rCSTC (rCSTs; 50 pg of each i.n. at 1 h postinfection [p.i.] and/or 500 pg of each intraperitoneally [i.p.] at 3 days p.i.) had significantly improved survival compared to that of infected mice alone or infected mice treated with individual rCSTs (P < 0.05). Results showed that both of our optimal rCST treatment regimens modulated pulmonary and systemic proinflammatory cytokine secretion in the serum, lungs, liver, and spleen in infected mice (P < 0.05). Treatment also significantly decreased the bacterial burden (P < 0.05) while preserving lung integrity, with reduced inflammatory cell accumulation compared to that in infected mice. Further, rCST treatment regimens reduced lipid peroxidation and cell apoptosis in the lungs of infected mice. Additionally, in vitro studies showed that rCSTs (50 or 500 pg of each) directly decreased the viability of NDM-1 K. pneumoniae In conclusion, the data showed that rCST9/rCSTC worked synergistically to modulate host inflammation against MDR NDM-1 K. pneumoniae pneumonia, which significantly improved survival. Therefore, rCST9/rCSTC is a promising therapeutic candidate for the treatment of bacterial pneumonia.

Cistatina C, muchas respuestas y algunas cuestiones pendientes / Cystatin C, many answers but some unmet questions

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Comparative performances of the new chronic kidney disease epidemiology equations incorporating cystatin C for use in cancer patients.

AIM: In cancer patients receiving chemotherapy treatment, accurate assessment of kidney function is required. The aim of our study was to investigate whether the inclusion of cystatin C together with creatinine in prediction equations would improve the prediction of glomerular filtration rate (GFR). METHODS: Plasma creatinine and cystatin C were analyzed in 155 patients (cancer, n = 80, kidney donors, n = 75) undergoing (99m) Technetium diethylenepentaacetic (Tc-DTPA) GFR clearance. Equations by the CKD-EPI (chronic kidney disease epidemiology) group (creatinine-, creatinine + cystatin C-, cystatin C-based, respectively) and Cockcroft-Gault were compared with Tc-DTPA GFR by difference plots, receiver operator characteristics curve analysis, root mean square error, chi-squared analysis and percentage concordance according to carboplatin dosage. Comparisons between two creatinine methodologies (enzymatic vs Jaffe) were also performed. RESULTS: In the overall group, the combination creatinine and cystatin C equation had 69% of results within 20% of GFR (P20), a sensitivity of 86.3% and a specificity of 73.1% to detect reduced GFR at <90 mL/min/1.73 m(2), and a concordance of 78%. In contrast, the traditional Cockcroft-Gault equation had a P20 of 38.0%, with a large underestimation to predict GFR, thereby accounting for approximately 45% of dosing discordance. No obvious differences were obtained when comparing the performance of equations using the two creatinine methodologies. CONCLUSION: The inclusion of cystatin C in the CKD-EPI equations improved the prediction of kidney function in the overall population, although probably not sufficiently for it to be favored over radioisotopic GFR for guiding chemotherapy. More research is warranted to further improve estimated GFR equations for these purposes.

Attenuation of early brain injury and learning deficits following experimental subarachnoid hemorrhage secondary to Cystatin C: possible involvement of the autophagy pathway.

Cystatin C (CysC) is a cysteine protease inhibitor and previous studies have demonstrated that increasing endogenous CysC expression has therapeutic implications on brain ischemia, Alzheimer's disease, and other neurodegenerative disorders. Our previous reports have demonstrated that the autophagy pathway was activated in the brain after experimental subarachnoid hemorrhage (SAH), and it may play a beneficial role in early brain injury (EBI). This study investigated the effects of exogenous CysC on EBI, cognitive dysfunction, and the autophagy pathway following experimental SAH. All SAH animals were subjected to injections of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20 s. As a result, treatment with CysC with low and medial concentrations significantly ameliorated the degree of EBI when compared with vehicle-treated SAH rats. Microtubule-associated protein light chain-3 (LC3), a biomarker of autophagosomes, and beclin-1, a Bcl-2-interacting protein required for autophagy, were significantly increased in the cortex 48 h after SAH and were further up-regulated after CysC therapy. By ultrastructural observation, there was a marked increase in autophagosomes and autolysosomes in neurons of CysC-treated rats. Learning deficits induced by SAH were markedly alleviated after CysC treatment with medial doses. In conclusion, pre-SAH CysC administration may attenuate EBI and neurobehavioral dysfunction in this SAH model, possibly through activating autophagy pathway.

Protective mechanisms by cystatin C in neurodegenerative diseases.

Neurodegeneration occurs in acute pathological conditions such as stroke, ischemia, and head trauma and in chronic disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. While the cause of neuronal death is different and not always known in these varied conditions, hindrance of cell death would be beneficial in the prevention of, slowing of, or halting disease progression. Enhanced cystatin C (CysC) expression in these conditions caused a debate as to whether CysC up-regulation facilitates neurodegeneration or it is an endogenous neuroprotective attempt to prevent the progression of the pathology. However, recent in vitro and in vivo data have demonstrated that CysC plays protective roles via pathways that are dependent on inhibition of cysteine proteases, such as cathepsin B, or by induction of autophagy, induction of proliferation, and inhibition of amyloid-beta aggregation. Here we review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced under various conditions. These data suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.