Estimated Glomerular Filtration Rate Research Articles

How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial.

Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear. We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimate glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy, or death due to kidney disease) in EMPA-REG OUTCOME. Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure. In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid, and urine albumin-to-creatinine ratio mediated 79.4%, 33.2%, and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%), and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis. Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.

Early kidney damage in diabetic adolescents with increased blood pressure and glomerular hyperfiltration.

The early impact of type 1 diabetes mellitus (DM1), increased blood pressure and glomerular hyperfiltration (GHF) on kidney damage in adolescents using two urinary markers of kidney injury - neutrophil gelatinase-associated lipocalin (uNGAL) and transferrin (uTransf) - was assessed. The study group consisted of 80 adolescents with DM1, of whom 42 were patients with increased blood pressure (IBP), and 38 were patients with normal blood pressure (NBP). Blood pressure was assessed by 24-hour ambulatory blood-pressure monitoring. All patients showed estimated glomerular-filtration rates (eGFRs) above 90 mL/min/1.73 m2. The control group consisted of 19 healthy, age and gender-matched adolescents. All diabetic children showed a significant increase in uNGAL (P<0.001). This increase was not related to blood pressure. The uNGAL was elevated in all patients with normal albuminuria, normal eGFR and NBP. The concentration of uTransf was not increased in the entire studied group and was not related to blood pressure. Children with GHF had significantly higher levels of both uTransf (P=0.010) and uNGAL (P<0.001). In patients with GHF, blood pressure was normal. Patients with IBP showed a significantly higher value for triglycerides (r=0.247; P=0.032) and a longer duration of diabetes (r=0.264; P=0.019). Diabetes is the leading risk factor for early kidney injury. However, increased blood pressure does not lead to kidney damage, at least in the early stage of DM1. The uNGAL is the early indicator of kidney injury and increases in patients with normal albuminuria, normal glomerular filtration and normal blood pressure. Glomerular hyperfiltration seems to be a marker of diabetic-kidney involvement.

Association of estimated glomerular filtration rate with prostate cancer risk in a cross-ethnic population: a Mendelian randomization study

ObjectiveTo investigate whether a causal relationship exists between the estimated glomerular filtration rate (EGFR) and the occurrence of prostate cancer in East Asian and European populations and to determine if genetic factors influence the association between the EGFR and prostate cancer risk.MethodsIn this Mendelian randomization study, the existence of a causal relationship between the EGFR and prostate cancer occurrence was assessed using five analytical techniques, including Mendelian randomization-Egger regression (MR-Egger), calculation of the weighted median estimator (WME), the maximum likelihood ratio method, the linear median weighting method and the random-effects inverse-variance weighting (IVW) method.ResultsIn the IVW model, no causal relationship was observed between the EGFR and prostate cancer in either the East Asian or European populations.ConclusionsAfter excluding confounding factors and reverse causal associations using two-sample Mendelian randomization, unbiased estimates were obtained, and there was no causal relationship between prostate cancer and the EGFR in the East Asian or European populations. Therefore, for patients with suspected prostate cancer, it is considered unnecessary to improve the detection of glomerular filtration rate, which will effectively reduce the economic burden of patients.

Comparison of different estimated glomerular filtration rates for monitoring of kidney function in oncology patients.

Tyrosine kinase inhibitors (TKIs) are associated with kidney function deterioration. A shift is ongoing towards glomerular filtration rate (GFR) equations based on other protein markers, such as cystatin C (CSTC) and β-trace protein (BTP). We evaluated various GFR equations for monitoring of kidney function in actively treated oncology patients. We monitored 110 patients receiving a TKI. Blood and urine were collected during therapy. Serum analysis included creatinine (Cr), CSTC and BTP; for consequent GFR determination. Urine was analysed for protein, albumin, immunoglobulin G, and α-1-microglobulin. A similar analysis was done in a patient subgroup receiving immune checkpoint inhibitors (ICI) as prior or subsequent line of therapy. Cr remained constant during TKI treatment (P=0.7753), whereas a significant decrease in CSTC (from week 2 onward, P<0.0001) and BTP (at weeks 2 and 4, P=0.0100) were noticed. Consequently, GFR estimations, using CSTC and/or BTP as a biochemical parameter, showed an apparent increase in GFR, whereas this was not observed for Cr-related GFR estimations. As a result, the GFR gap (ΔGFR) was significantly different from week 2 onward between Cr-based and CSTC-based GFR and between BTP-based and CSTC-based GFR. Glomerular damage was noticed with significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio and immunoglobulin G (all P<0.0001). No change in α-1-microglobulin was seen. ICI treatment had no effect on Cr (P=0.2262), CSTC (P=0.7341), and BTP concentrations (P=0.3592). GFR equations, in which CSTC is incorporated, fail to correctly estimate the GFR in oncology patients treated with TKIs. As TKI-treated patients show clear signs of glomerular injury, further assessment is needed on how to correctly monitor the kidney function in actively treated oncology patients.

Optimization of Kidney Health in Liver Transplant Candidates: Pretransplant Considerations and Modalities.

Patients with decompensated end-stage liver disease (ESLD) are at increased risk for mortality, and only liver transplantation (LT) offers meaningful hope for survival. These patients are at risk for kidney dysfunction through the continuum of care for ESLD including LT. We discuss the role of accurate estimation and measurement of baseline glomerular filtration rate in assessment of kidney dysfunction among those with ESLD. Optimizing kidney function is a vital goal in the management of these patients before LT. In this review, we summarize salient aspects of assessing and optimizing kidney function in this patient population. Precipitating factors and different causes of acute kidney injury are discussed, including hepatorenal syndrome. We further review treatment options for acute kidney injury including volume management. The role of vasopressor therapy, renal replacement therapy, and transjugular intrahepatic portosystemic shunting are discussed.

The Impact of Baseline Vitamin D Level in Patients Receiving Gefitinib-Directed Therapy for EGFR-Mutant Non-Small-Cell Lung Cancer.

There is contradicting evidence on vitamin D levels and cancer mortality rates. In this study, we aimed to evaluate the impact of baseline vitamin D level on the outcome in patients with estimated glomerular filtration rate (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC) who received either gefitinib or gefitinib with chemotherapy (pemetrexed and carboplatin) as first-line therapy in a prospective randomized study. This was a post hoc analysis of a phase III randomized trial comparing gefitinib with gefitinib with carboplatin and pemetrexed in patients with advanced NSCLC with activating EGFR mutations in the first-line setting. As a part of regular practice, baseline vitamin D levels were measured using circulating 25(OH) levels in blood. We included 334 patients who had baseline vitamin D levels in the study and evaluated the effect of the vitamin D level on oncologic outcomes. There were 136 (40.7%) patients with a sufficient (>20 ng/mL) baseline vitamin D level, and 198 (59.3%) patients who were deficient in vitamin D (<20 ng/mL). The median progression-free survival (PFS) in patients with normal vitamin D levels was 17 months, whereas that in patients with deficient vitamin D levels was 15 months, with a hazard ratio of 1.45 (95% confidence interval [CI] = 1.03-2.06). The median overall survival (OS) in patients with normal vitamin D levels was 28.6 months, whereas that in patients with deficient vitamin D levels was 28.5 months, with a hazard ratio of 1.17 (95% CI = 0.81-1.68). On multivariate analysis, only 2 factors impacted the PFS, the baseline vitamin D level, and the treatment regimen; other factors like age, sex, disease stage, and performance status did not. Baseline vitamin D levels have a significant impact on PFS, whereas OS is not affected by the baseline vitamin D levels on patients receiving targeted therapy for EGFR-mutant lung cancer. The trial was prospectively registered with the Clinical Trial Registry of India, registration number CTRI/2016/08/007149. The date of the registration was 5 August 2016.

Measurement of Glomerular Filtration Rate in Patients Undergoing Renal Surgery for Cancer: Estimated Glomerular Filtration Rate versus Measured Glomerular Filtration Rate in the Era of Precision Medicine.

In the era of precision medicine, determining reliable renal function assessment remains a critical and debatable issue, especially in nephrology and oncology. This paper delves into the significance of accurately measured glomerular filtration rate (mGFR) in clinical practice, highlighting its essential role in guiding medical decisions and managing kidney health, particularly in the context of renal cancer (RC) patients undergoing nephrotoxic anti-cancer drugs. The limitations and advantages of traditional glomerular filtration rate (GFR) estimation methods, primarily using serum biomarkers like creatinine and cystatin C, are discussed, emphasizing their possible inadequacy in cancer patients. Specifically, newer formulae designed for GFR estimation in cancer patients may not perform at best in RC patients. The paper explores various methods for direct GFR measurement, including the gold standard inulin clearance and alternatives like iohexol plasma clearance. Despite the logistical challenges of these methods, their implementation is crucial for accurate renal function assessment. The paper concludes by emphasizing the need for continued research and innovation in GFR measurement methodologies to improve patient outcomes, particularly in populations with complex medical needs.

Evaluating the renoprotective effectiveness of sodium-glucose co-transporter 2 inhibitor therapy in patients with chronic kidney disease: A prospective study

Background/Aim. Chronic kidney disease (CKD) is a global health concern associated with increased cardio-vascular risks and premature mortality. Proteinuria is a key prognostic indicator for CKD outcome. Sodium-glucose cotransporter 2 (SGLT2) inhibitors show potential for reducing proteinuria and slowing CKD progression. The aim of the study was to determine the impact of SGLT2 inhibitor therapy on CKD patients by evaluating the changes in the level of serum creatinine (sCr), 24-hour (24h) urine protein (UP), estimated glomerular filtration rate (GFR), and blood pressure (BP). Methods. This prospective study monitored 79 patients with CKD on therapy with SGLT2 inhibitors, who were followed up for one year. Patients received an SGLT2 inhibitor (dapagliflozin) once daily (10 mg), and assessment of specific parameters was conducted at baseline, 6 months, and 1 year later during the therapy. The study evaluated the levels of sCr, 24h UP, GFR, systolic BP (BPs), diastolic BP (BPd), uric acid (UA), total cholesterol (TC), triglycerides (Tg), low-density lipoprotein (LDL) cholesterol, sodium (Na+), and potassium (K+). Results. Over the one-year follow-up, significant changes were seen in UA levels (5.36, 4.99, 4.94 mg/dL, respectively; p = 0.032), 24h UP (662.60, 574.11, 417.09 mg/dL, respectively; p = 0.028), as well as BPs (128.44, 125.64, 126.12 mmHg, respectively; p = 0.026). No significant variations were observed in GFR, BPd, sCr, TC, Tg, LDL, and K+ levels. Na+ levels displayed a notable decrease (148.21, 147.57, 146.41 mmol/L, respectively; p = 0.021). Conclusion. The study suggests a potential benefit of SGLT2 inhibitors in managing CKD.

Comparative Determination of Glomerular Filtration Rate Estimation Formulae in Type 2 Diabetic Patients: An Observational Study.

Assessing glomerular filtration rate (GFR) involves collecting timed urine samples for 24 hours, requiring significant time and resources in the clinical setting. Using predictive GFR formulae to assess renal function may be a better alternative. Our goal was to determine which predictive GFR formula had the highest level of concordance with the GFR that has been measured in a resource-poor setting. This is an observational study. We selected fifty (50) individuals diagnosed with type 2 diabetes (T2DM) in Kumasi, Ghana. The sociodemographic and clinical characteristics were obtained using a structured questionnaire. Urine was obtained from each subject over 24 hours. The levels of glucose (FBG) and creatinine in patients' blood, as well as the levels of creatinine in their urine, were measured after the patients had fasted overnight. Participants had a mean age of 57.4 ± 10.7 (years), BMI of 27.8 ± 4.1 (kg/m2), FBG of 9.0 ± 3.1 (mmol/L), and creatinine concentrations of 95.6 ± 29.1 (μmol/L). A Krouwer plot was used to compare the measured GFR with three formulae: Chronic Kidney Disease Epidemiology (CKD-EPI), Modification of Diet in Renal Disease (MDRD), and Cockroft-Gault (CG) for GFR prediction. Among the 3 estimates, CG showed nonsignificance (p > 0.05) with the measured GFR. The primary finding was that the GFR calculated using the CG formula was not different from the GFR measured, suggesting that CG is the most appropriate alternative GFR estimate among a cross-section of T2DM patients in Ghana.

Correlation between Kidney Uptake at [18F]FDG PET/CT and Renal Function.

Different insights into the connection between kidney [18F]fluorodesoxyglucose ([18F]FDG) uptake at positron emission tomography/computed tomography (PET/CT) and renal function have been proposed in the past. The aim of this study was therefore to assess the presence of a correlation between these two parameters. Kidney uptakes were assessed and compared to the creatinine (Cr) values and estimated glomerular filtration rate (EGFR) among different classes of renal functional impairment or kidney status. A total of 339 patients and 385 different PET/CT scans were included in this study. Significant correlations between kidney uptakes and renal function parameters were reported in most of the groups studied, with the exception of patients with Cr < 1.2 mg/dL and subjects with a kidney transplantation. Strong concordance in the assessment of renal parenchymal uptakes between the different readers was reported. To conclude, strong correlations for renal [18F]FDG uptake with Cr levels and the EGFR were reported, with the exception of the group of patients with a Cr value < 1.2 mg/dL and for the group with a kidney transplantation.

RIGHT VENTRICULAR FUNCTION ASSESSMENT BY SPECKLE TRACKINGECHOCARDIOGRAPHY IN PATIENTS ON REGULAR HEMODIALYSIS WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION

Aims: To investigate right ventricular function in hemodialysis patients with preserved left ventricular ejection fraction (LVEF) using twodimensional speckle tracking echocardiography.&#x0D; Methods: Patients with end-stage kidney disease (ESKD) who were on regular hemodialysis and had preserved LVEF and a group of age- and sex-matched control subjects were recruited for the study in Bach Mai Hospital. All subjects were interviewed and examined comprehensively. Echocardiography was performed in all patients and controls. Right ventricular function was evaluated using conventional and speckletracking echocardiography. Estimate glomerular filtration rate (eGFR) was calculated according to the MDRD GFR equation.&#x0D; Results: From 6/2022 to 11/2022, a total of 61 ESKD receiving hemodialysis regularly and 32 controls were evaluated. The mean age of the hemodialysis patients was 51.2±13.8. Men account for 54.1% (33/61). Hemodialysis patients had larger right ventricular diameters, lower RV fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE), and decreased S velocities of the tricuspid valve compared to the controls (p&lt;0.05 for all). Systolic pulmonary artery pressure (sPAP) of the hemodialysis group was higher when compared to the controls (p&lt;0.05 for all). Absolute values of right ventricular global strain (RVGS) and right ventricular free wall strain (RVFWS) were significantly lower in the hemodialysis group than in the control (p&lt;0.05 for all). Absolute values of RVGS and RVFWS inversely correlated to LV mass index (r = -0.42, p&lt;0.05 and r=-0.46, p&lt;0.05, respectively) while they positively correlated to eGFR (r = 0.57, p&lt;0.05 and r = 0.59, p&lt;0.05, respectively), hemoglobin level (r = 0.41, p&lt;0.05 and r = 0.43, p&lt;0.05, respectively), RVFAC (r = 0.54, p&lt;0.05 and r = 0.51, p&lt;0.05, respectively).&#x0D; Conclusion: Right ventricular function assessed by speckle tracking echocardiography reduced in hemodialysis patients. Right ventricular myocardial strain strongly correlated with glomerular filtration rate, RVFAC, and moderately correlated with hemoglobin level and LV mass index..

Discrepancies among equations to estimate the glomerular filtration rate for drug dosing decision making in aged patients: a cross sectional study

BackgroundPatients often require adjustments to drug doses due to impaired renal function. Glomerular filtration rate (GFR) estimation using various equations can result in discrepancies, potentially leading to different dose adjustment recommendations.AimTo determine the clinical significance of discrepancies observed between different equations used to estimate GFR for drug dose adjustments in a real-world group of patients over 65 years in primary care.MethodThe Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Berlin Initiative Study 1 equations were applied to estimate GFR in a group of patients over 65 years old attending a primary care center. Results were compared using Bland–Altman plots, and limits of agreement (LoA) and overall bias were calculated. Regression analyses were conducted to identify the null difference GFR and the slope of differences for each pairwise comparison.ResultsA total of 1886 patients were analyzed. Differences between patient-adjusted and body surface area (BSA)-normalized versions of the equations were not clinically relevant for dose adjustments, with LoAs below 20 mL/min. However, discrepancies among the original versions of several equations presented LoAs over 30 mL/min. Greater differences were found between CG and MDRD or CKD-EPI equations.ConclusionClinically relevant differences in GFR estimation were observed among different equations, potentially impacting drug dose adjustments. However, discrepancies were not considered significant when comparing patient-adjusted and BSA-normalized versions of the equations, particularly for patients with BSA close to the average.

Estimation of Glomerular Filtration Rate Using the New Ekfc Equation in Healthy and Chronic Kidney Disease Adult Subjects from Sub-Saharan Africa

Introduction: Since the publication of the first equation for estimate creatinine clearance in 1957, several other equations estimating glomerular filtration rate have followed in succession. To date, a new equation has been published by the European Kidney Function Consortium (EKFC) in 2021, which would have the advantage of being adaptable to any type of population. In this study, we aimed to evaluate the performance of this new equation in our black African population of healthy subjects and subjects with chronic kidney disease.&#x0D; Material and Methods: This was a cross-sectional study involving 192 healthy subjects and 183 subjects with chronic kidney disease. Plasma iohexol clearance (mGFR) constituted́ the reference method used to measure glomerular filtration rate and allowed evaluation of all equation variants (EKFC crea, EKFC cys, EKFC crea-cys). Equation performance was studied by calculating the 95% CI bias, the interquartile range (25% percentile, 75% percentile) and the 30% accuracy (P30) compared with the reference method.&#x0D; Results: All EKFC variants in both populations (healthy subjects and chronic kidney disease subjects) had biases below 5 ml/min/1.73 m2. Biases were therefore acceptable. On the other hand, P30s were less good in subjects with chronic kidney disease.&#x0D; Conclusion: Thus, the EKFC equation performs well in the healthy population, but its evaluation in the chronic kidney disease population needs to be strengthened on the basis of larger cohorts.

The pathogenesis of albuminuria in cadmium nephropathy

BackgroundUrinary cadmium excretion (ECd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β2-microglobulinuria (Eβ2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (Ealb) to Eβ2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins. MethodsTo depict excretion rates per functional nephron, ECd, Ealb, and Eβ2M were normalized to creatinine clearance (Ccr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate Ealb/Ccr, Eβ2M/Ccr, and eGFR to several independent variables. Simple linear regressions of eGFR, Ealb/Ccr, and Eβ2M/Ccr on ECd/Ccr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in Ealb/Ccr and Eβ2M/Ccr and decrements in eGFR were quantified through four quartiles of ECd/Ccr. ResultsAs age or ECd/Ccr rose, Ealb/Ccr and Eβ2M/Ccr also rose, and eGFR fell. In linear regressions, slopes relating Ealb/Ccr and Eβ2M/Ccr to ECd/Ccr were similar. After adjustment of dependent variables for age, coefficients of determination (R2) for all regressions rose by a multiple, and slopes approached unity. Ealb/Ccr and Eβ2M/Ccr were similarly associated with each other. Mean Ealb/Ccr and Eβ2M/Ccr rose and mean eGFR fell in stepwise fashion through quartiles of ECd/Ccr. Whereas Eβ2M/Ccr did not vary with blood pressure, Ealb/Ccr rose in association with hypertension in two of the four quartiles. ConclusionsOur data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β2M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.

Cystatin C and eGFRCKD-EPI-CysC: novel biomarkers for renal impairment diagnosis and two-year progression-free survival in multiple myeloma

To evaluate cystatin C (CysC) and estimation of glomerular filtration rate (GFR) calculated using the formula, CKD-EPI-CysC (eGFRCKD-EPI-CysC) for renal impairment diagnosis and predicting the prognosis of patients with multiple myeloma (MM). One hundred-fourteen patients with MM and 38 healthy individuals were recruited for the study. Data on clinical characteristics and renal function-related biochemical indicators were collected and analyzed. Patients with MM had increased levels of CysC (1.25 (0.97–2.31) vs. 0.84 (0.80–0.92), respectively, p < 0.001) and decreased levels of eGFRCKD-EPI-CysC (53.0 (24.4–81.1) vs. 97.2 (87.0–104.5), respectively, p < 0.001), compared with healthy individuals. There were significantly more patients with elevated CysC levels than with elevated sCr levels (64.9% vs. 41.2%, respectively, p < 0.001). The CKD-EPI-CysC formula detected more patients with eGFR < 60 ml/(min × 1.73 m2) than the CKD-EPI-sCr formula (52.63% vs. 37.72%, respectively, p < 0.001). Correlation analysis found that only CysC, eGFRCKD-EPI-CysC, and eGFRCKD-EPI-sCr-CysC strongly correlated with β2-microglobulin in group ISS-I. Logistic regression analysis was used to screen CysC (OR = 1.495, 95% CI = 1.097–2.038, p = 0.011) and eGFRCKD-EPI-CysC (OR = 0.980, 95% CI = 0.967–0.993, p = 0.003) as independent prognostic indicators for 2-year-progression-free survival (PFS) of patients with MM. Receiver operating characteristic curve analysis found that CysC values >1.70 mg/L had 67.6% sensitivity and 65.2% specificity and eGFRCKD-EPI-CysC values <38.62 ml/(min × 1.73 m2) had 65.2% sensitivity and 67.6% specificity for 2-year PFS of patients with MM. In summary, CysC and eGFRCKD-EPI-CysC were more sensitive than sCr and eGFRCKD-EPI-sCr for predicting renal impairment in patients newly diagnosed with MM. Increased CysC and decreased eGFRCKD-EPI-CysC levels were effective predictors of 2-year PFS of patients with MM.

Renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural older adults in China: a population‐based study

AbstractBackgroundEmerging evidence has linked impaired renal function with dementia, but the neuropathological mechanisms underlying the association remains poorly understood. We sought to examine the relationships of renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural Chinese older adults.MethodThis population‐based cross‐sectional study included 5715 participants (age ≥60 years; 57.15% women; 40.49% illiteracy) in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND‐China). We calculated the estimate glomerular filtration rate (eGFR) using serum creatinine and the simplified modification of diet in renal disease equation specifically for individuals from China, and impaired renal function was defined as eGFR &lt;60 mL/min/1.73 m2. Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were diagnosed following the international criteria. Plasma amyloid‐β (Aβ) 40, Aβ42, total tau, and neurofilament light chain (NfL) concentrations were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, the general linear regression, and mediation models.ResultOf the 5715 participants, 283 (4.95%) were detected with renal function impairment, and 326 (5.70%) were diagnosed with dementia (195 with AD and 10 with VaD). The multivariable‐adjusted odds ratios of eGFR &lt;60 mL/min/1.73 m2 (vs. &gt;90mL/min/1.73 m2) were 2.43 (95% confidence interval [CI] 1.56‐3.72) for all‐cause dementia, 2.74 (1.64‐4.49) for AD, and 1.30 (0.50‐2.98) for VaD. In the plasma biomarkers subsample, controlling for demographic factors, impaired renal function was significantly associated with higher levels of plasma Aβ40 (demographic‐adjusted β‐coefficient = 59.06; 95%CI 46.93‐71.19), Aβ42 (3.41; 2.62‐4.20), NfL (14.57; 9.08‐20.05), and total tau (0.74; 0.48‐1.01), and the observed associations remained significant even in the multivariable‐adjusted model (P&lt;0.001). The mediation analysis showed that total tau mediated 12.77% of the association between impaired renal function and AD.ConclusionImpaired renal function is associated with an increased risk of dementia and AD. Plasma total tau may partly underlie the association of renal function with Alzheimer’s dementia.

Evaluation of novel candidate filtration markers from a global metabolomic discovery for glomerular filtration rate estimation

Creatinine and cystatin-C are recommended for estimating glomerular filtration rate (eGFR) but accuracy is suboptimal. Here, using untargeted metabolomics data, we sought to identify candidate filtration markers for a new targeted assay using a novel approach based on their maximal joint association with measured GFR (mGFR) and with flexibility to consider their biological properties. We analyzed metabolites measured in seven diverse studies encompasing 2,851 participants on the Metabolon H4 platform that had Pearson correlations with log mGFR and used a stepwise approach to develop models to< -0.5 estimate mGFR with and without inclusion of creatinine that enabled selection of candidate markers. In total, 456 identified metabolites were present in all studies, and 36 had correlations with mGFR< -0.5. A total of 2,225 models were developed that included these metabolites; all with lower root mean square errors and smaller coefficients for demographic variables compared to estimates using untargeted creatinine. Seventeen metabolites were chosen, including 12 new candidate filtration markers. The selected metabolites had strong associations with mGFR and little dependence on demographic factors. Candidate metabolites were identified with maximal joint association with mGFR and minimal dependence on demographic variables across many varied clinical settings. These metabolites are excreted in urine and represent diverse metabolic pathways and tubular handling. Thus, our data can be used to select metabolites for a multi-analyte eGFR determination assay using mass spectrometry that potentially offers better accuracy and is less prone to non-GFR determinants than the current eGFR biomarkers.

External Validation of a Novel Multimarker GFR Estimating Equation.

Using multiple markers may improve accuracy in glomerular filtration rate (GFR) estimation. We sought to externally validate and compare the performance a novel multi-marker estimated GFR (panel eGFR) among Black and White persons using the Genetic Epidemiology Network of Arteriopathy cohort. We included 224 sex, race/ethnicity, and measured GFR (mGFR)-category-matched persons, with GFR measured using urinary clearance of iothalamate. We calculated panel eGFR using serum creatinine, valine, myo-inositol, cystatin C, age, and sex. We compared its reliability with current eGFR equations (2021 CKD-EPI creatinine [eGFR-Cr] and creatinine with cystatin C [eGFR-Cr-CysC]) using median bias, precision, and accuracy metrics. We evaluated each equation's performance in age, sex, and race subgroups. In the overall cohort, 49% were Black individuals and mean mGFR was 79 ml/min/1.73m2. Panel eGFR overestimated mGFR (bias: -2.4 ml/min/1.73m2; 95% confidence interval [CI]: -4.4, -0.7), eGFR-Cr-CysC underestimated mGFR (bias: 4.8 ml/min/1.73m2; 95% CI: 2.1, 6.7), while eGFR-Cr was unbiased (bias: 2.0 ml/min/1.73m2; 95% CI: -1.1, 4.6). All equations had comparable accuracy. Among Black males age <65 years, both eGFR-Cr (bias: 17.0 ml/min/1.73m2; 95% CI: 8.6, 23.5) and eGFR-Cr-CysC (bias: 14.5 ml/min/1.73m2; 95% CI: 6.0, 19.7) underestimated mGFR whereas panel eGFR was unbiased (bias: 1.7 ml/min/1.73m2; 95% CI: -3.4, 10.0). Metrics of accuracy for all eGFRs were acceptable in all subgroups except for panel eGFR in Black females <65 years (P30: 73.3%). Panel eGFR can be used to estimate mGFR and may have utility among Black males age <65 years where current CKD-EPI equations are biased.

Estimating the extent to which chronic kidney disease mediates the association between metabolic syndrome and heart failure: the Atherosclerosis Risk in Communities (ARIC) Study

Abstract Background/Introduction Metabolic Syndrome (MetS) is linked to increased risk of developing heart failure (HF), underscoring a need to implement more aggressive lifestyle and pharmacotherapeutic HF prevention strategies. Chronic kidney disease (CKD) is associated with MetS and is a risk factor for HF; however, therapies protective against both kidney function decline and HF risk such as ACEi/ARBs and SGLT2i are underutilized among individuals with MetS. A potential contributor to this underutilization is that creatinine (Cr)- based estimates of glomerular filtration rate (eGFR) may underestimate the role of CKD as a mediator of HF risk relative to Cystatin-C (CysC) based eGFR. Purpose To compare estimations of the relationship between MetS and kidney function, and of the extent to which eGFR mediates the link between MetS and incident HF, using CysC-based versus Cr-based eGFR. Methods Among ARIC Visit 4 (1996-1998) participants without baseline HF, we used linear regression to assess the cross-sectional association of MetS severity (measured using an established z-score, modeled in quartiles and continuously) with eGFR, with comparisons across 3 different eGFR equations (CKD-Cr 2021, CKD-Cr-CysC 2021 and CKD-CysC 2012). In prospective analyses, we used Cox regression and mediation analyses to estimate the extent to which kidney function mediated the association between MetS and incident HF after Visit 4 through 12/31/2019, with comparisons across the 3 eGFR equations. Results Among 8,582 participants (mean age 63.1 years, 56.9% women, 18.4% Black adults), 1,803 developed HF over a median follow-up of 21 years. MetS was more strongly associated with eGFR when using eGFR estimates that included CysC, with the 4th vs 1st quartile of MetS Z-score associated with an adjusted eGFR difference of -2.55 ml/min/1.73m2 (95% CI -3.36 to -1.73) for CKD-Cr, -8.07 ml/min/1.73m2 (95% CI -8.95 to -7.19) for CKD-Cr-CysC and -10.74 ml/min/1.73m2 (95% CI -11.67 to -9.80) for CKD-CysC. In prospective analyses, we also estimated greater mediation by kidney function of the association between MetS and incident HF when using eGFR equations that included CysC. The strength of the association between MetS and HF potentially mediated by kidney function increased from 3.0% to 15.2% to 24.2%, respectively, when using eGFR-Cr vs eGFR-Cr-CysC vs eGFR-CysC (Table and Figure). These estimates were not significantly attenuated after additional adjustment for coronary heart disease and C-reactive protein. Conclusion(s) The degree of kidney function reduction associated with MetS, and the subsequent implications of kidney dysfunction for HF risk in those with MetS, are underestimated using eGFR-Cr equations compared to eGFR equations including CysC. Greater appreciation by clinicians of the impact of kidney disease on HF risk among individuals with MetS could help increase utilization of kidney-protective therapies that can lower HF risk.

Social, behavioral, and metabolic risk factors for racial disparities in cardiovascular disease mortality in US adults

Abstract Background Cardiovascular disease (CVD) mortality is persistently higher in the Black population than in other race and ethnicity groups in the US. Purpose To determine whether social, behavioral, and metabolic risk factors mediate racial disparities in CVD mortality and to assess the contribution of these risk factors to CVD mortality in the US general population. Methods A nationally representative sample of 50,808 individuals aged ≥20 years from National Health and Nutrition Examination Surveys (NHANES) 1999-2018 were included in the analysis. Data on social, behavioral, and metabolic factors were collected in each NHANES survey using standard methods. CVD deaths were ascertained from linkage to the National Death Index with follow-up through 2019. Results Over an average of 9.4 years of follow-up, 2,598 CVD deaths were confirmed. In a multivariable Cox regression model stratified by NHANES cycle and adjusted for age, sex, race, and social, behavioral, and metabolic risk factors simultaneously, individuals who were unemployed, had a lower family income, did not own a home, were not married nor living with a partner, were current smokers, reported no leisure-time physical activity, slept &amp;lt;6 or &amp;gt;8 hours/day, had obesity, hypertension, or diabetes, or had an albumin-to-creatinine ratio ≥30 mg/g or estimated-glomerular filtration rate &amp;lt;60 ml/min/1.73 m2 were at significantly higher risk for CVD mortality. After adjusting for these risk factors, hazard ratios (95% CI) of CVD mortality for Black individuals compared to White individuals decreased from 1.54 (1.34-1.77) to 0.86 (0.75-1.00). Social risk factors explained 72.9% Black-White differences in CVD mortality in a multivariable mediation analysis. The population attributable fractions (95% CI) for the top five risk factors for CVD mortality were 12.5% (5.6-19.3%) for hypertension, 10.6% (6.9-14.3%) for albuminuria, 9.4% (5.3-13.6) for physical inactivity, 9.1% (4.6-13.7%) for family income-to-poverty ratio &amp;lt;300%, and 7.2% (4.5-9.9%) for estimated-glomerular filtration rate &amp;lt;60 ml/min/1.73 m2 in the US general population. Conclusion Social, behavioral, and metabolic risk factors fully explained the Black-White difference in CVD mortality. Hypertension, albuminuria, physical inactivity, low family income, and reduced kidney function are leading risk factors for CVD mortality in the US population.