Association of serum cystatin C level and major adverse cardiovascular events in patients with percutaneous coronary intervention.

Background: Recurrent acute myocardial infarction requiring unplanned percutaneous coronary intervention (PCI) is one of the major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) after PCI. There is a continuing controversy about the association between serum cystatin C, a biomarker for the evaluation of renal function, and the prognosis of ACS patients following PCI. The retrospective study evaluated the association between serum cystatin C level and MACE in ACS patients after PCI. Methods: Data were retrieved for 330 patients with ACS for primary PCI in a single center. Serum cystatin C levels were measured before PCI. All patients underwent regular follow-ups after PCI, and the studied endpoint was MACE, defined as the need for a repeat revascularization in the heart. The predictive value of serum cystatin C for MACE was analyzed using univariate and multivariate analysis. Restricted cubic spline (RCS) analysis was applied to evaluate the dose-response relationship between serum cystatin C level and MACE in ACS patients following PCI. Results: After a median follow-up of 63 months (range, 1-148 months), 121 of the 330 patients experienced MACE. Compared to patients who did not have MACE, patients who had MACE showed a significant decrease in serum cystatin C levels (0.99±0.32 vs. 1.15±0.78 mg/L, P=0.03). In multivariate regression analysis, serum cystatin C level was an independent risk factor for MACE. According to the serum cystatin C level, patients were divided into 4 categories, Cox regression analysis illustrated that the second quartile of serum cystatin C level indicated an increased risk of MACE in patients with PCI for primary ACS compared to the highest quartile [Q2: adjusted hazard ratio (HR) =2.109; 95% confidence interval (CI): 1.193-3.727; P=0.01]. RCS analysis showed a significant U-shaped dose-response relationship between cystatin C level and MACE in patients with PCI for ACS (P for non-linearity =0.004). Conclusions: These results indicated an association between serum cystatin C level and post-PCI MACE in ACS patients.

The predictive value of the triglyceride glucose index combined with cystatin C for the prognosis of patients with acute coronary syndrome.

Background: Recent studies have shown that the triglyceride glucose index (TyG) and cystatin C (CysC) are closely related to cardiovascular disease, but there is limited research on the prognosis of patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). The aim of this study was to explore the predictive value of the combination of the TyG index and CysC in predicting major adverse cardiovascular events (MACEs) in ACS patients who underwent PCI. Methods: This retrospective study included 319 ACS patients who underwent PCI. The clinical endpoint was the occurrence of MACEs, including all-cause mortality, heart failure, non-fatal myocardial infarction, target vessel revascularization, and angina requiring hospitalization. Patients were classified into MACEs (65 cases) and non-MACEs (254 cases) groups. Univariate factor and multivariate analysis were used to identify predictors of MACEs. The receiver operating curve (ROC) of the prediction model of MACEs was determined. Additionally, the net reclassification improvement and integrated discrimination improvement indexes were calculated to further assess the additional predictive value of the risk factors for MACEs. Subgroup and interaction analysis between the TyG index combined with CysC and MACEs were conducted in various subgroups. Patients were stratified according to the optimal cutoff point value of the TyG index and the CysC determined by ROC curve analysis. The Kaplan-Meier analysis method was used to construct a survival curve 1 year after PCI. Results: During a median follow-up period of 14 months, 65 (20.38%) patients had experienced at least one primary endpoint event. Multivariate logistic regression analysis indicated that the TyG index and CysC were independently associated with an increased risk of MACEs after PCI (OR, 2.513, 95% CI 1.451-4.351, P= 0.001; and OR, 4.741, 95% CI 1.344-16.731, P=0.016, respectively). The addition of the TyG index and CysC to the baseline risk model had the strongest incremental effect for predicting MACEs in terms of the C-statistic from 0.789 (95% CI 0.723-0.855, P<0.001) to 0.799 (95% CI 0.733-0.865, P<0.001). Furthermore, Kaplan-Meier analysis demonstrated that a TyG index greater than 9.325 and a CysC value greater than 1.065 mg/ml were significantly associated with an increased risk of MACEs (log-rank, all P < 0.01). Conclusion: The TyG index predicts MACEs after PCI in patients with ASC independent of known cardiovascular risk factors. Adjustment of the CysC by the TyG index further improves the predictive ability for MACEs in patients with ACS undergoing PCI. Thus, both of them are expected to become new prognostic indicators for MACEs in patients with ACS after PCI.

Human and Mouse Nephrin and Their Interactions With 13 Proteins: An In Silico Study.

Background Human nephrin (hNeph) (podocyte protein) has been known to be involved in both the formation and maintenance of the slit diaphragm (SD) and also acts as a hub protein in the podocyte by modulating cell polarity, cell survival, cell adhesion, cytoskeletal organization, mechano-sensing, and SD turn-over. Methodology In the present investigation, we aimed to analyse the hNeph and mouse nephrin (mNeph) and their interactions with 13 proteins using the molecular docking method. The 13 selected human proteins which include matrix metalloproteinases (MMP 2 and 9), retinol-binding proteins (RBP 3 and 4), kallikrein 1 (KLK 1), uromodulin, insulin-like growth factor binding protein 7 (IGFBP7), cystatin C, podocin, beta arrestin 1, vang-like protein 2 (VANGL2), dynamin 1, and tensin-like C1 domain-containing phosphatase (TENC1) were studied on the docking analysis of hNeph and mNeph by using the HDOCK (protein-protein) docking method. In addition, the physicochemical (PC) properties of 15 proteins were performed using the ProtParam web server. Results In the present investigation, five chosen human proteins, namely, IGFBP7, cystatin C, podocin, VANGL2, and TENC1, have exhibited theoretical isoelectric point (PI) values greater than 7.0. The protein-protein docking analysis has shown that hKLK and hVANGL2 exhibited the maximum docking score of -206.39 kcal/mol and -329.28 (kcal/mol) with the target proteins mNeph and hNeph, respectively. Conclusions Thus, the current finding highlights the interactions of hNeph and mNeph with 13 chosen proteins, which may help in renal disease management.

Sex and Age Influence the Relationship Between Serum Creatinine/Cystatin C and Carotid Plaque in Patients With Type 2 Diabetes Mellitus.

We investigated the effect of sex and age on the association between serum creatinine/cystatin C (CCR) ratio and carotid plaque in patients with type 2 diabetes mellitus (T2DM). The carotid plaque group and the non-plaque group were divided according to cervical vascular ultrasound; the general and biochemical data of the two groups were compared according to CCR, gender, and age. Binary logistic regression was used to analyze the factors influencing carotid plaque. A total of 1429 patients with T2DM were included in this study. On multivariate analysis, CCR was an independent predictor of carotid plaque with an adjusted odds ratio (OR) of 1.681 [1.250-2.260]. The risk of carotid plaque in men with T2DM increased significantly (P < .05) with decreasing levels of CCR. In addition, an association between CCR and carotid plaque was found in individuals with T2DM <65 years of age (P < .05). CCR is strongly associated with the risk of carotid plaques in persons with T2DM and are an independent risk factor for carotid plaques in men and people aged <65 years with T2DM.

How to Assess the Glomerular Filtration Rate, and Which Method is Deemed Most Reliable?

The prevalence of chronic kidney disease (CKD) continues to rise globally, paralleled by an increase in associated morbidity and mortality, as well as significant implications for patient quality of life and national economies. Chronic kidney disease often progresses unrecognized by patients and physicians, despite diagnosis relying on two simple laboratory measures: estimated glomerular filtration rate (eGFR) and urine analysis. GFR measurement has been grounded in renal physiology, specifically the concept of clearance, with creatinine identified as a suitable endogenous marker for estimating creatinine clearance (CrCl). On this foundation, various equations have been developed to calculate CrCl or estimated GFR (eGFR) using four variables that incorporate creatinine and certain demographic information, such as sex and age. However, creatinine measurement requires standardization to minimize assay variability across laboratories. Moreover, the accuracy of these equations remains contentious in certain patient subgroups. For these reasons, additional mathematical models have been devised to enhance CrCl estimation, for example, when urine collection is impractical, in elderly or debilitated patients, and in individuals with trauma, diabetes, or obesity. Presently, eGFR in adults can be immediately measured and reported using creatinine-based equations traceable through isotope dilution mass spectrometry. In conclusion, leveraging insights from renal physiology, eGFR can be employed clinically for early diagnosis and treatment of CKD, as well as a public health tool to estimate its prevalence.

Comparison of the correlation of creatinine- and cystatin C-Based estimated GFR and their differences with new-onset heart failure in a community-based population with type 2 diabetes.

AIMS: This study aimed to investigate the impact of different estimated glomerular filtration rate (eGFR) values like cystatin C-based eGFR (eGFRcys), creatinine-based eGFR (eGFRcr), and their difference (eGFRdiff; eGFRcys -eGFRcr), on the incidence of heart failure (HF) in patients with type 2 diabetes(T2D). METHODS: Being a prospective cohort study, it included 7,967 patients with T2D who underwent serum creatinine and cystatin C tests as part of the Kailuan Group's 6th annual health examination (2016). Subsequently, eGFRcys, eGFRcr, and eGFRdiff were calculated. Patients were categorized into three groups: negative (<-15 mL/min/1.73 m2), midrange (-15 to 15 mL/min/1.73 m2), and positive (> 15 mL/min/1.73 m2) eGFRdiff groups, respectively. Furthermore, the relationship between the various eGFR measurements and new-onset HF were studied using Cox proportional hazards regression, and the potential improvement in predictive capability was evaluated by adding these eGFR metrics to established HF risk models. RESULTS: Among 7967 participants with mean age of 60.51 years, there were 20.92% women and 79.08% men. At baseline, eGFRcys and eGFRcr values differed by more than 15 mL/min/1.73m2 in 41.3% of participants. During a median follow-up period of 3.76 years, there were 172 (2.16%) new HF cases and 517 (6.49%) all-cause deaths. The cumulative incidence of HF in the midrange, negative, and positive eGFRdiff groups was 1.74%, 4.10%, and 0.61%, respectively (p < 0.001). In multivariable adjusted models, participants in the negative eGFRdiff group had higher risk of HF compared with the midrange eGFRdiff group (HR, 2.15; 95% CI, 1.57-2.94). Conversely, participants in the positive eGFRdiff group had lower risk for HF (HR, 0.40; 95% CI, 0.17-0.93). And each 15 mL/min/ 1.73 m2 higher eGFRdiff was associated with 34% (HR, 0.66; 95% CI, 0.58 - 0.47)lower risk of incident HF. The predictive capacity for HF risk in diabetic individuals was enhanced by adding eGFRcys or eGFRdiff to established HF risk models, with eGFRcys showing more significant additional predictive value. CONCLUSION: These findings suggest that large differences between eGFRcys and eGFRcr were common in community-based population with T2D. Different eGFR metrics can independently predict HF incidence in patients with T2D. Additionally, metrics like eGFRcys and eGFRdiff provide significant predictive value for HF risks beyond traditional risk factors, with eGFRcys showing more pronounced benefits in such cases.

Creatinine-to-cystatin C ratio and frailty in older adults: a longitudinal cohort study.

BACKGROUND: Creatinine-to-cystatin C ratio (CCR) has been associated with multiple adverse outcomes. However, little is known about its relationship with frailty. We aimed to explore the association between CCR and frailty among older adults. METHODS: A total of 2599 participants aged ≥ 60 years (mean age 67.9 ± 6.0 years, 50.4% males) were included from the China Health and Retirement Longitudinal Study (2011-2015). Baseline CCR was calculated as plasma creatinine (mg/dL) / cystatin C (mg/L) × 10 and was grouped by quartiles. Frailty was evaluated by the validated physical frailty phenotype (PFP) scale and was defined as PFP score ≥ 3. The generalized estimating equations model was used to explore the relationship between CCR and frailty. RESULTS: The frailty risk decreased gradually with increasing CCR in the quartiles (P for trend = 0.002), and the fourth CCR quartile was associated with a significantly lower risk of frailty compared with the lowest quartile (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.19-0.70). When modeling as a continuous variable, per 1-unit increase in CCR was related to 17% decreased odds of frailty (OR 0.83, 95% CI 0.74-0.93). The association was consistent in male and female participants (P for interaction = 0.41). Poisson models revealed that frailty score was negatively associated with CCR (ß= -0.11, 95% CI= -0.19 to -0.04), and sex did not significantly moderate the associations (P for interaction = 0.22). The results were not affected by further adjusting for high-sensitivity C-reactive protein. Similar results were observed by analyses with multiple imputation technique and analyses excluding participants with baseline frailty. CONCLUSIONS: Higher CCR was associated with a lower frailty risk. CCR may be a simple marker for predicting frailty in older adults.

Effectiveness of sarcopenia screening markers in predicting out-of-hospital death in the oldest (≥80 years) older.

OBJECTIVE: The goal of this investigation was to elucidate the correlation between sarcopenia screening indicators (aspartate transaminase/alanine transaminase (AST/ALT) and creatinine/cystatin C*100 (Cr/CysC*100)) and the risk of out-of-hospital (OFH) death among the very advanced age (≥80 years) population. METHODS: We conducted a retrospective cohort investigation, involving internal medicine inpatients aged ≥80 years of age, who sought treatment at a teaching hospital in western China. We obtained OFH mortality information from telephonic interviews. Subsequently, we employed Cox proportional hazards models to analyze the links between AST/ALT and Cr/CysC*100 and OFH all-cause mortality among the very advanced age (≥80 years old) population. RESULTS: In all, we recruited 398 subjects, among which 51.51% were male. The median age of OFH deceased male patients was 85 years, and the same for female patients was 87 years. The total quantity of OFH deaths was 164 (41.21%). Among the oldest male population, those who died OFH exhibited enhanced AST/ALT, relative to those who survived (death vs. survival: 1.5 vs 1.3, P=0.008). However, among the oldest female, there was no difference in AST/ALT between patients who expired OFH, and those who survived. Among the oldest elders (male and female), Cr/CysC*100 did not significantly differ between surviving and OFH deceased patients. Additional analysis involving the Cox proportional hazards model revealed that among the oldest male population, an enhanced AST/ALT denoted an augmented risk of OFH death (hazard ratios (HRs) =1.797, 95%CI: 1.2-2.691). However, Cr/CysC*100 was not correlated with OFH mortality risk. Among the oldest female population, neither AST/ALT nor Cr/CysC*100 was correlated with OFH mortality risk. CONCLUSIONS: Enhanced AST/ALT was correlated with an augmented OFH mortality risk among the oldest male, but not female population. Alternately, Cr/CysC*100 was not linked to OFH mortality risk among any population.

Estimated glomerular filtration rate in clinical practice: Consensus positioning of the Brazilian Society of Nephrology (SBN) and Brazilian Society of Clinical Pathology and Laboratory Medicine (SBPC/ML) / Estimativa da taxa de filtração glomerular na prática clínica: posicionamento consensual da Sociedade Brasileira de Nefrologia (SBN) e Sociedade Brasileira de Patologia Clínica e Medicina Laboratorial (SBPC/ML)

ABSTRACT Chronic kidney disease (CKD) represents one of today's main public health problems. Serum creatinine measurement and estimation of the glomerular filtration rate (GFR) are the main tools for evaluating renal function. There are several equations to estimate GFR, and CKD-EPI equation (Chronic Kidney Disease - Epidemiology) is the most recommended one. There are still some controversies regarding serum creatinine measurement and GFR estimation, since several factors can interfere in this process. An important recent change was the removal of the correction for race from the equations for estimating GFR, which overestimated kidney function, and consequently delayed the implementation of treatments such as dialysis and kidney transplantation. In this consensus document from the Brazilian Societies of Nephrology and Clinical Pathology and Laboratory Medicine, the main concepts related to the assessment of renal function are reviewed, as well as possible existing controversies and recommendations for estimating GFR in clinical practice.

RESUMO A doença renal crônica (DRC) representa um dos principais problemas de saúde pública da atualidade. A dosagem da creatinina sérica e a estimativa da taxa de filtração glomerular (TFG) são as principais ferramentas para avaliação da função renal. Para a estimativa da TFG, existem diversas equações, sendo a mais recomendada a CKD-EPI (Chronic Kidney Disease - Epidemiology). Existem ainda algumas controvérsias com relação à dosagem da creatinina sérica e da estimativa da TFG, uma vez que vários fatores podem interferir nesse processo. Uma importante mudança recente foi a retirada da correção por raça das equações para estimativa da TFG, que superestimavam a função renal, e consequentemente retardavam a implementação de tratamentos como diálise e transplante renal. Neste documento de consenso da Sociedade Brasileira de Nefrologia e Sociedade Brasileira de Patologia Clínica e Medicina Laboratorial são revisados os principais conceitos relacionados à avaliação da função renal, possíveis controvérsias existentes e recomendações para a estimativa da TFG na prática clínica.

Methods for monitoring protein-membrane binding. Comparison based on the interactions between amyloidogenic protein human cystatin C and phospholipid liposomes.

A cell membrane is an essential cellular component providing protection against the outer environment. It is also a host for proteins and carbohydrates responsible for, e.g. transporter, receptor, or enzymatic functions. In parallel, the membrane may also be implicated in pathological processes leading, e.g. to the oligomerization of amyloid-forming proteins, a hallmark of i.a. Alzheimer's disease. The increasing need for detailed information on mechanisms driving the amyloid formation and the potential role of cell membranes in the process proves the research on protein-membrane interactions biologically relevant. Considering the potential and limitations of the relatively well established and newly developed methods, this study focused on selecting methods that allow a broad and comprehensive description of interactions between amyloidogenic protein human cystatin C and lipid bilayers. In the first step, dot-blot and ELISA tests were selected as techniques allowing fast screening for protein-ligand interactions. Next, surface plasmon resonance, spectral shift, biolayer interferometry, and switchSENSE® technology were used to determine kinetic parameters and binding constants for interactions between human cystatin C and the selected lipid bilayers. Based on the obtained results we have proposed the most promising candidates for monitoring of interactions and determining affinity between amyloidogenic proteins and membrane mimetics.

Perinatal risk factors of renal outcome in former extremely low birth weight neonates.

Former Extremely Low Birthweight (ELBW) neonates suffer from adverse renal and cardiovascular outcomes later in life. Less is known about additional perinatal risk factors for these adverse outcomes which we have investigated in this study. We compared renal outcome between ELBW children and controls, to find perinatal risk factors for poorer renal outcome and to unveil associations between kidney function and blood pressure. This study included 93 former ELBW children and 87 healthy controls with a mean age of 11 years at assessment. We measured cystatin C-based estimated glomerular filtration rate (eGFR) and blood pressure. Blood pressure and eGFR levels were compared between cases and controls. We subsequently investigated perinatal risk factors for adverse outcome amongst ELBW children. ELBW children have significantly higher blood pressure (mean SBP percentile 75th vs. 47th, p <0.001) and lower mean eGFR (94 vs. 107 ml/min/1.73 m2, p = 0.005) compared to the control group. Elevated blood pressure did not correlate with perinatal characteristics and none of them had microalbuminuria. ELBW children with eGFR <90 ml/min/1.73 m2 were ventilated longer (17 vs. 9 days, p = 0.006), more frequently male (OR = 3.33, p = 0.055) and tended to suffer more from intraventricular hemorrhage (40% vs. 15.8%, p = 0.056). There was no association between blood pressure and kidney dysfunction. CONCLUSIONS: Understanding risk profiles for unfavorable outcomes may help to identify children at increased risk for kidney dysfunction. Poorer eGFR was associated with longer ventilation, male sex, and intra-ventricular hemorrhage but not with blood pressure. This knowledge can lead to safer neonatal therapeutic regimens for ELBW infants, a more intensive follow-up and earlier treatment initiation for children at highest risk. WHAT IS KNOWN: • Extremely Low Birthweight (ELBW) neonates suffer later in life from adverse renal and cardiovascular outcomes. • Perinatal risk factors that further predict the individual risk for adverse outcomes are not well known. WHAT IS NEW: • Poorer eGFR in adolescence was associated with male sex, longer ventilation and intra-ventricular hemorrhage at birth but not with blood pressure. • Former ELBW infants had higher blood pressures compared to controls, but no microalbuminuria. • This knowledge can lead to potential precision medicine, safer neonatal therapeutic regimens for ELBW infants, a more intensive follow-up and earlier treatment initiation for children at highest risk.

Peripheral Dopamine Suppression and Elevated Cystatin C in Early Diabetic Nephropathy in Spontaneously Diabetic Rats.

Intrarenal dopamine plays a protective role against the development of diabetic nephropathy during the early stages of the disease. In streptozotocin-induced diabetic mice with a renal-specific catechol-O-methyl transferase knockout, intrarenal dopamine was found to suppress glomerular hyperfiltration, reduce oxidative stress and inflammation, and inhibit fibrosis. However, while dopamine activation in streptozotocin-induced diabetic models has been shown to provide renal protection, the role of dopamine in models of naturally induced diabetes mellitus is still unclear. In the present study, we administered 10 mg/kg p.o. benserazide, a peripheral decarboxylase inhibitor, to Spontaneously Diabetic Torii rats daily, in order to investigate the activation of the renal dopaminergic system during diabetic nephropathy progression. Our findings show that peripheral dopamine decreased urinary 8-iso-prostaglandin F2a and suppressed increases in plasma cystatin C levels. This study demonstrates that a reduction in peripheral dopamine can exacerbate renal dysfunction, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration, thereby clarifying the pivotal role of endogenous peripheral dopamine in modulating oxidative stress and kidney performance.

Prognostic values of blood urea nitrogen/creatinine and cystatin C in patients with radical nephrectomy for renal cell carcinoma.

Background: To evaluate the prognostic value of blood urea nitrogen/creatinine ratio (BUN/SCr) and cystatin C (Cys C) in patients with renal cell carcinoma (RCC) after radical nephrectomy. Methods: The study analysed 348 patients with RCC who underwent radical nephrectomy. The optimal cut-off was obtained based on the ROC of specific survival outcomes and the maximum Youden index. The patients were divided into four groups: Group 1 (low BUN/SCr-low Cys C), Group 2 (low BUN/SCr-high Cys C), Group 3 (high BUN/SCr-low Cys C), and Group 4 (high BUN/SCr-high Cys C). The primary endpoint was cancer-specific survival (CSS), and the secondary endpoint was disease-free survival (DFS).

Serum Cystatin C levels increase with increasing visceral fat area in patients with type 2 diabetes mellitus.

The present study aimed to explore the association between serum cystatin C (Cys-C) levels and visceral fat area (VFA) in patients with type 2 diabetes mellitus (T2DM). A total of 208 previously diagnosed T2DM patients who visited our hospital from September 2019 to December 2021 were included and divided into three groups based on tertiles of Cys-C levels, namely, Groups C1, C2, and C3. The clinical data of the subjects were collected, biochemical parameters such as Cys-C levels were determined, and bioelectrical impedance analysis was applied to determine the VFA and subcutaneous fat area (SFA). The VFA in Group C1 was lower than that in Groups C2 and C3 (all P < 0.05), with no significant difference in VFA between Groups C2 and C3 (P > 0.05). Spearman's correlation analysis revealed that the serum Cys-C level was positively correlated with age, VFA, SFA, insulin resistance index, waist circumference, body mass index, systolic blood pressure, serum creatinine level, and blood uric acid level (r = 0.543, 0.353, 0.168, 0.148, 0.365, 0.264, 0.25, 0.497, and 0.155, respectively; P < 0.05) and negatively correlated with glycated haemoglobin levels (r = -0.175, P < 0.05). Univariate linear regression analysis revealed that VFA was positively correlated with the Cys-C level (ß = 0.002, 95% CI = 0.001-0.003, P < 0.05), with an increase of 0.002 mg/L in the Cys-C level for each 1 cm2 increase in VFA. Further multivariate linear regression analysis was performed with the serum Cys-C level as the dependent variable and age, VFA, SFA, insulin resistance (HOMA-IR), WC, BMI, SBP, Cr, UA, and HbA1c as the independent variables. The results suggested that VFA was positively correlated with serum Cys-C level (ß = 0.001, 95% CI = 0.000-0.002, P < 0.05), with serum Cys-C levels increasing by 0.001 mg/L for every 1 cm2 increase in VFA. Using a VFA ≥ 100 cm2 as the criterion for visceral obesity, ROC analysis revealed that the Cys-C level was a better predictor of visceral obesity, with an area under the ROC curve (AUC) of 0.701 (95% CI = 0.631-0.771, P < 0.05), an optimal cut-off of 0.905 mg/L, and a sensitivity and specificity of 58.3% and 75.2%, respectively. The results suggested that the serum Cys-C level was correlated with the VFA in patients with T2DM and that Cys-C may play a vital role in T2DM patients with visceral obesity.

Integrating multiple kidney function markers to predict all-cause and cardiovascular disease mortality: prospective analysis of 366 758 UK Biobank participants.

Background: Reduced kidney function is a risk factor of cardiovascular and all-cause mortality. This association was demonstrated for several kidney function markers, but it is unclear whether integrating multiple measured markers may improve mortality risk prediction. Methods: We conducted an exploratory factor analysis (EFA) of serum creatinine- and cystatin C-based estimated glomerular filtration rate [eGFRcre and eGFRcys; derived by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) equations], blood urea nitrogen (BUN), uric acid and serum albumin among 366 758 participants in the UK Biobank without a history of kidney failure. Fitting Cox proportional hazards models, we compared the ability of the identified latent factors to predict overall mortality and mortality by cardiovascular disease (CVD), also considering CVD-specific causes like coronary heart disease (CHD) and cerebrovascular disease. Results: During 12.5 years of follow-up, 26 327 participants died from any cause, 5376 died from CVD, 2908 died from CHD and 1116 died from cerebrovascular disease. We identified two latent factors, EFA1 and EFA2, both representing kidney function variations. When using the CKD-EPI equation, EFA1 performed like eGFRcys, with EFA1 showing slightly larger hazard ratios for overall and CVD-related mortality. At 10 years of follow-up, EFA1 and eGFRcys showed moderate discrimination performance for CVD-related mortality, outperforming all other kidney indices. eGFRcre was the least predictive marker across all outcomes. When using the EKFC equation, eGFRcys performed better than EFA1 while all other results remaining similar. Conclusions: While EFA is an attractive approach to capture the complex effects of kidney function, eGFRcys remains the most practical and effective measurement for all-cause and CVD mortality risk prediction.

Urinary biomarkers in metastatic bone pain: Results from a multicentre randomized trial of ibandronate compared to single dose radiotherapy for localized metastatic bone pain in prostate cancer (RIB).

Background: The Radiotherapy IBandronate (RIB) trial compared single dose radiotherapy and a single infusion of ibandronate in 470 bisphosphonate naïve patients with metastatic bone pain from prostate cancer randomised into a non-inferiority two arm study. Results for the primary endpoint of pain score response at 4 weeks showed that the ibandronate arm was non-inferior to single dose radiotherapy. Patients and method: In addition to pain assessments including analgesic use made at baseline, 4, 8, 12, 26 and 52 weeks, urine was collected at baseline, 4 and 12 weeks. It was subsequently analysed for urinary N-telopeptide (NTx) and cystatin C. Linear regression models were used to compare the continuous outcome measures for urinary markers within treatment arms and baseline measurements were included as covariates. Interaction terms were fitted to allow for cross-treatment group comparisons. Results: The primary endpoint of the RIB trial was worst pain response at 4 weeks and there was no treatment difference seen. Urine samples and paired pain scores at 4 weeks were available for 273 patients (radiotherapy 168; ibandronate 159)The baseline samples measured for the RIB trial had an average concentration of 193 nM BCE/mM creatinine (range of 7.3-1871) compared to the quoted normal range of 33 nM BCE/mM creatinine (3 to 63). In contrast the average value of Cystatin C was 66 ng/ml (ranges ND - 1120 ng/ml) compared to the quoted normal range of 62.9 ng/ml (ranges 12.6-188 ng/ml). A statistically significant reduction in NTx concentrations between baseline and 4 weeks was seen in the ibandronate arm but not in the radiotherapy arm. No correlation between pain response and urinary marker concentration was seen in either the ibandronate or radiotherapy cohort at any time point. Conclusion: NTx was significantly raised compared to the normal range consistent with a role as a biomarker for bone metastases from prostate cancer. A significant reduction in NTx 4 weeks after ibandronate is consistent with its action in osteoclast inhibition which was not seen after radiotherapy implying a different mode of action for radiation. There was no correlation between bone biomarker levels and pain response.

DPPA as a Potential Cell Membrane Component Responsible for Binding Amyloidogenic Protein Human Cystatin C.

A phospholipid bilayer is a typical structure that serves crucial functions in various cells and organelles. However, it is not unusual for it to take part in pathological processes. The cell membrane may be a binding target for amyloid-forming proteins, becoming a factor modulating the oligomerization process leading to amyloid deposition-a hallmark of amyloidogenic diseases-e.g., Alzheimer's disease. The information on the mechanisms governing the oligomerization influenced by the protein-membrane interactions is scarce. Therefore, our study aims to describe the interactions between DPPA, a cell membrane mimetic, and amyloidogenic protein human cystatin C. Circular dichroism spectroscopy and differential scanning calorimetry were used to monitor (i) the secondary structure of the human cystatin C and (ii) the phase transition temperature of the DPPA, during the protein-membrane interactions. NMR techniques were used to determine the protein fragments responsible for the interactions, and molecular dynamics simulations were applied to provide a molecular structure representing the interaction. The obtained data indicate that the protein interacts with DPPA, submerging itself into the bilayer via the AS region. Additionally, the interaction increases the content of α-helix within the protein's secondary structure and stabilizes the whole molecule against denaturation.

CYSTATIN C-A Monitoring Perspective of Chronic Kidney Disease in Patients with Diabetes.

Chronic kidney disease (CKD) is a microvascular complication that frequently affects numerous patients diagnosed with diabetes. For the diagnosis of CKD, the guidelines recommend the identification of the urinary albumin/creatinine ratio and the determination of serum creatinine, based on which the estimated rate of glomerular filtration (eGFR) is calculated. Serum creatinine is routinely measured in clinical practice and reported as creatinine-based estimated glomerular filtration rate (eGFRcr). It has enormous importance in numerous clinical decisions, including the detection and management of CKD, the interpretation of symptoms potentially related to this pathology and the determination of drug dosage. The equations based on cystatin C involve smaller differences between race groups compared to GFR estimates based solely on creatinine. The cystatin C-based estimated glomerular filtration rate (eGFRcys) or its combination with creatinine (eGFRcr-cys) are suggested as confirmatory tests in cases where creatinine is known to be less precise or where a more valid GFR estimate is necessary for medical decisions. Serum creatinine is influenced by numerous factors: age, gender, race, muscle mass, high-protein diet, including protein supplements, and the use of medications that decrease tubular creatinine excretion (H2 blockers, trimethoprim, fenofibrate, ritonavir, and other HIV drugs). The low levels of creatinine stemming from a vegetarian diet, limb amputation, and conditions associated with sarcopenia such as cirrhosis, malnutrition, and malignancies may lead to inaccurately lower eGFRcr values. Therefore, determining the GFR based on serum creatinine is not very precise. This review aims to identify a new perspective in monitoring renal function, considering the disadvantages of determining the GFR based exclusively on serum creatinine.

Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: a pilot study.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset, progressive, multisystemic condition caused by TTR pathogenic variants. Reliable biomarkers are needed to allow early diagnosis and to monitor disease severity and progression. We measured serum concentrations of growth differentiation factor-15 (GDF-15) and uromodulin (Umod) in ATTRv patients to evaluate correlations with standard markers of disease severity (FAP stage and PND score). Blood samples were collected from 16 patients diagnosed with ATTRv amyloidosis and a verified TTR variant and from 26 healthy controls. ATTRv patients were stratified by clinical phenotype (neurologic vs. mixed), genotype (V30M vs. non-V30M), and disease severity. We found significantly higher levels of serum GDF-15 in ATTRv patients compared with controls. Mean serum Umod levels were significantly lower in patients with ATTRv than controls. A positive correlation was found between serum Umod and estimated glomerular filtration rate (eGFR), while an inverse correlation was found with cystatin C levels. Conversely, GDF-15 showed a negative correlation with eGFR, and a direct correlation with cystatin C levels. No correlation was demonstrated between GDF-15 or Umod levels and traditional cardiac biomarkers. The results identify alteration of serum levels of GDF-15 and Umod in ATTRv amyloidosis.

[The Relationship Between Serum CysC, ß2-MG and the Efficacy of Demethylation Therapy in Patients with Acute Myeloid leukemia].

OBJECTIVE: To analyze the relationship between serum cystatin C (CysC), ß2-microglobulin (ß2-MG) and the efficacy of demethylation therapy in patients with acute myeloid leukemia (AML). METHODS: A prospective cohort study was conducted on 98 AML patients admitted to the Affiliated Hospital of Inner Mongolia Medical University from February 2019 to January 2022. All patients were treated with decitabine (DAC) + HAG regimen, 28 days as a course and treated for 3-4 courses. At the end of each course of treatment, the treatment effect of the patients was evaluated, and the patients who achieved complete remission (CR) transferred to consolidation therapy, while the patients who did not reach CR at the end of the course of treatment were considered as treatment failure. The examination items before treatment include routine blood parameters, serum CysC, and ß2-MG, and general clinical data of the patients were collected. According to the statistical results, logistic regression model was used to analyze the relationship between serum CysC, ß2-MG and the efficacy of demethylation therapy in AML patients. The ROC curves were drawn, and the predictive efficacy of serum CysC, ß2-MG on demethylation therapy in AML patients was evaluated by the area under the curve (AUC). RESULTS: Of the 98 AML patients enrolled in the study, 5 cases were excluded during the treatment period, and 93 cases finally completed the chemotherapy courses. Among them, 23 patients achieved CR after the initial induction chemotherapy (course 1-2), and 11 patients achieved CR after the re-induction chemotherapy (course 3-4). The success rate of demethylation therapy was 36.56 % (34/93). Compared with the patients in treatment success group, patients in treatment failure group had a higher proportion of intermediate- and adverse-risk, lower levels of platelet (PLT) and hemoglobin (Hb), and higher expression levels of serum CysC and ß2-MG, all of which were statistically significant (P < 0.05). Logistic regression analysis showed that high expression of serum CysC, ß2-MG and adverse-risk were independent risk factors for failure of demethylation treatment in AML patients (OR >1, P < 0.05). The ROC curves showed that the AUC values of serum CysC, ß2-MG alone and combined in predicting the efficacy of demethylation therapy in AML patients were 0.788, 0.785 and 0.834, respectively. CONCLUSION: The failure of demethylation therapy in AML patients is related to the high expression of serum CysC and ß2-MG, and detection of serum CysC and ß2-MG before treatment can predict the risk of demethylation therapy failure in AML patients.