Creatinine-based eGFR Research Articles

Renal function and risk of dementia: a Mendelian randomization study

Background The burgeoning recognition of the nexus between renal functionality and the prevalence of dementia has precipitated a surge in research endeavors. This study aims to substantiate the causal relationship between kidney functionality and dementia. Methods We utilized clinical renal function metrics from the Chronic Kidney Disease Genetics (CKDGen) Consortium and diverse dementia types (Alzheimer’s disease [AD] and vascular dementia) from the FinnGen Biobank by using Mendelian randomization analysis. At the stratum of genetic susceptibility, we tested the causal relationship between variations index in renal function and the occurrence of dementia. Inverse-variance weighted (IVW) method was the main analysis, and several supplementary analyses and sensitivity analyses were performed to test the causal estimates. Results The findings indicate a significant correlation between each unit increase in cystatin C-based estimated glomerular filtration rate (eGFR-cys) levels was significantly associated with a reduction in the incidence of late-onset Alzheimer’s disease (LOAD) (IVW: OR = 0.35, 95% CI: 0.13–0.91, p = 0.031). After adjusting for creatinine-based eGFR (eGFR-cre) and urinary albumin-to-creatinine ratio (UACR), a causal relationship was still identified between elevated levels of eGFR-cys and decreased risk of LOAD (IVW: OR: 0.08; 95% CI: 0.01–0.97, p = 0.047). Sensitivity tests demonstrated the reliability of causal estimates. Conclusions The association between renal function based on cystatin C and the augmented risk of developing AD lends support to the perspective that regular monitoring of cystatin C may be a valuable investigative biomarker.

9360 Evaluating The More Accurate Indicator Of Kidney Function In Mild Autonomous Cortisol Secretion: EGFR Creatinine Versus EGFR Cystatin

Abstract Disclosure: L. Rahimi: None. J. Saini: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None. Introduction: Patients with mild autonomous cortisol secretion (MACS) have higher prevalence of cardiovascular comorbidities including chronic kidney disease. However, considering that patients with MACS may have relative skeletal muscle atrophy, it is unclear whether the creatine-based assessment of kidney function is accurate in this population. Objective: To characterize the differences in assessing estimated glomerular filtration rate using cystatin (eGFRcys) versus creatinine (eGFRcre) in patients with MACS versus referent subjects. Methods: Cross-sectional single-center study, 2019-2022. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST). For each patient, eGFRcre, eGFRcys and eGFRcre/eGFRcys ratio were measured and compared between the two groups. Body composition was measured by DXA scan. The Kruskal-Wallis test was used to compare measurements between groups. Result: A total of 37 patients with MACS (median age 59 years (interquartile range, IQR 47-67), 25 (68%) women) and 45 referent subjects (median age 57 years (IQR 51-66), 30 (67%) women) were included. The distribution of BMI, total body fat mass and total body lean mass were similar between the two groups. In the MACS cohort, the median cortisol following 1-mg DST was 3.0 ug/dL (IQR, 2.2-4.0). While assessment of kidney function with eGFRcre showed no differences between patients with MACS and referent subjects (median 85.1 vs 87.0 ml/min/1.73m2, P=0.431), kidney function using eGFRcys was lower in MACS (median 78.0 vs 89.3 ml/min/1.73m2 in referents, P<0.014), resulting also in a higher eGFRcre/eGFRcys ratio (median 1.07 vs 0.97 in MACS vs referents, P=0.053). After adjusting for age, sex, and BMI, a higher 1 mg DST cortisol level in the MACS cohort was associated with a higher eGFRcre/eGFRcys ratio (Spearman correlation coefficient of 0.35, P = 0.042). Lower eGFRcys was associated with higher fat mass (Spearman correlation of -0.26, P = 0.023), and a higher eGFRcre/eGFRcys ratio showed a trend towards lower lean mass (Spearman correlation of -0.20, P = 0.081). Conclusion: Creatinine-based eGFR assessment in patients with MACS underestimates the degree of kidney dysfunction, likely due to underlying skeletal muscle atrophy. eGFRcys is a more accurate indicator of kidney function in patients with hypercortisolism. Presentation: 6/1/2024

Intraindividual Difference between Cystatin C- and Creatinine-Based eGFR Is Associated with All-Cause and Cardiovascular Mortality: The Fukuoka Kidney disease Registry (FKR) Study

Intraindividual Difference between Cystatin C- and Creatinine-Based eGFR Is Associated with All-Cause and Cardiovascular Mortality: The Fukuoka Kidney disease Registry (FKR) Study

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

AimsThis 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).MethodsBeing 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.ResultsAmong 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.ConclusionThese 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.

Proenkephalin A 119-159 (penKid) and mortality in stable patients at high cardiovascular risk

ABSTRACT Background Proenkephalin A 119–159 (penKid) is a novel blood biomarker for real-time assessment of kidney function and was found to be independently associated with worsening kidney function and mortality. A novel penKid-based estimated glomerular filtration rate equation (eGFRPENK-Crea), outperforms current creatinine-based eGFR equations in predicting iohexol or iothalamate plasma clearance-based measured GFR. In this study, we aimed to evaluate the predictive value of penKid and eGFRPENK-Crea for all-cause mortality in stable patients at high cardiovascular risk. Methods Circulating penKid levels were assessed in 615 stable patients hospitalized at the Department of Cardiology at University Hospital Aachen, Germany. The endpoint was all-cause mortality; follow up was 3 years. Results penKid levels were higher in 46 non-survivors [58.8 (IQR 47.5–85.0) pmol/l] compared to 569 survivors [43.8 (IQR 34.0–58.0) pmol/l; P &amp;lt; .0001]. Univariable Cox regression analyses found penKid and eGFRPENK-Crea to be associated with all-cause mortality (C index 0.703, χ2 33.27, P &amp;lt; .00001; C index 0.716, χ2 36.51, P &amp;lt; .00001). This association remained significant after adjustment for significant baseline parameters including age, smoking, chronic heart failure, use of diuretics, leucocytes, body mass index, sex, and creatinine (C index 0.799, χ2 72.06, P &amp;lt; .00001). Importantly, penKid provided significant added value on top of eGFRCKD-EPI 2021 (eGFRCKD-EPI 2021: C index 0.716, χ2 34.21; eGFRCKD-EPI 2021 + penKid: C index 0.727, χ2: 40.02; Delta χ2 5.81; all P &amp;lt; .00001) for all-cause mortality prediction in our cohort. Conclusions penKid levels and eGFRPENK-Crea is associated with all-cause mortality within a 3-year follow-up period and the addition of penKid on top of eGFRCKD-EPI 2021 provided significant added value in mortality prediction.

Disease-specific differences in pharmacokinetics of paromomycin and miltefosine between post-kala-azar dermal leishmaniasis and visceral leishmaniasis patients in eastern Africa.

Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from eastern Africa. VL patients showed 0.55-fold (95%CI: 0.41-0.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (1.23-1.71) adjustment when relating renal clearance to creatinine-based eGFR. Miltefosine bioavailability in VL patients was lowered by 69% (62-76) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74-0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.

Large discordance between creatinine-based and cystatin C-based estimated glomerular filtration rates is associated with falls, hospitalizations, and death in older adults.

Estimated glomerular filtration rate (eGFR) calculated using creatinine and cystatin C often differ in older adults. We hypothesized that older adults with cystatin-based eGFR (eGFRcys) values significantly lower than creatinine-based eGFR (eGFRcr) values may have higher risk for aging-related adverse outcomes, independent of kidney function. We conducted a longitudinal cohort study of adults ≥65 years old from the Health and Retirement Study, a cohort of older American adults, to determine the relationship between eGFR discordance and aging-related adverse outcomes. We calculated eGFRcr and eGFRcys using baseline creatinine and cystatin C measurements. A large eGFR discordance was defined as eGFRcys >30% lower than eGFRcr. We assessed four aging-related adverse outcomes over a two-year follow-up: falls, hip fractures, hospitalizations, and death. We fit separate multivariable regression models to determine the association between having a large eGFR discordance and each outcome adjusting for confounders including kidney function. Of 5574 older adults, 1683 (30%) had a large eGFR discordance. Those with a large eGFR discordance were more likely to be older, female, and White. The prevalence of a large eGFR discordance increased with age, from 20% among those 65-69 years to 44% among those 80 years and older. Over a two-year follow-up, there were 305 deaths (5.5%), 2013 falls (39.2%), 69 hip fractures (1.3%), and 1649 hospitalizations (32.2%). In adjusted analyses, large eGFR discordance was associated with a higher hazard ratio for death (HR 1.43, 95% CI 1.12-1.82) and significantly higher odds of falls (odds ratio [OR] 1.32, 95% CI 1.16-1.51) and hospitalizations (OR 1.32, 95% CI 1.15-1.51). A large eGFR discordance was not associated with hip fractures. In a large, nationally representative cohort of older adults, prevalence of eGFR discordance increased with age and was associated with higher risk of falls, hospitalization, and death, independent of kidney function.

Creatinine, cystatin C, muscle mass, and mortality: Findings from a primary and replication population-based cohort.

Serum creatinine is used as initial test to derive eGFR and confirmatory testing with serum cystatin C is recommended when creatinine-based eGFR is considered less accurate due to deviant muscle mass. Low muscle mass is associated with increased risk of premature mortality. However, the associations of serum creatinine and cystatin C with muscle mass and mortality remain unclear and require further investigation to better inform clinical decision-making. We included 8437 community-dwelling adults enrolled in the Dutch PREVEND study and 5033 in the US NHANES replication cohort. Associations of serum creatinine and/or cystatin C with muscle mass surrogates and mortality were quantified with linear and Cox proportional hazards regression, respectively. Missing observations in covariates were multiply imputed using Substantive Model Compatible Fully Conditional Specification. Mean (SD) age of PREVEND and NHANES participants (50% and 48% male) were 49.8 (12.6) and 48.7 (18.7) years, respectively. Median (Q1-Q3) serum creatinine and cystatin C were 71 (61-80)and 80 (62-88) μmol/L and 0.87 (0.78-0.98) and 0.91 (0.80-1.10) mg/L, respectively. Higher serum creatinine was associated with greater muscle mass, while serum cystatin C was not associated with muscle mass. Adjusting both markers for each other strengthened the positive relationship between serum creatinine and muscle mass and revealed an inverse association between serum cystatin C and muscle mass. In the PREVEND cohort, 1636 (19%) deaths were registered over a median follow-up of 12.9 (5.8-16.3) years with a 10-year mortality rate (95% CI) of 7.6% (7.1-8.2%). In the NHANES, 1273 (25%) deaths were registered over a median follow-up of 17.9 (17.3-18.5) years with a 10-year mortality rate of 13.8% (12.8-14.7%). Both markers were associated with increased mortality. Notably, when adjusted for each other, higher serum creatinine was associated with decreased mortality, while the association between serum cystatin C and increased mortality strengthened. The shapes of the associations in the PREVEND study and NHANES were almost identical. The strong association between serum creatinine and muscle mass challenges its reliability as GFR marker, necessitating a more cautious approach in its clinical use. The minimal association between serum cystatin C and muscle mass supports its increased use as a more reliable alternative in routine clinical practice.

Sex and the Relationship Between Cardiometabolic Risk Factors and Estimated GFR Decline: A Population-Based Cohort Study

Rationale & ObjectiveFemales have a higher prevalence of chronic kidney disease (CKD) than males, but are less likely to be treated with kidney replacement therapy (KRT). We studied the interaction between sex and the association of cardiometabolic risk factors for the decline in kidney function over time. Study DesignA population-based cohort study. Setting & Participants1,127,731 adults living in Wales, UK, within the Secure Anonymised Information Linkage Databank. ExposuresSex and risk factors including age, estimated glomerular filtration rate (eGFR), cardiometabolic conditions, smoking, and socioeconomic deprivation. These risk factors were defined using primary care records. OutcomesThe yearly declines in eGFR and the risk of incident kidney failure defined as long-term KRT and/or sustained eGFR<15mL/min/1.73m2. Analytical ApproachLinear mixed effects models and Cox proportional hazards analysis. ResultsThe average decline in eGFR age ≤73 was equal in males and females. After age 73, eGFR decline was faster in males than females, particularly for males with heart failure (males -1.22 mL/min/1.73m2 per year: 95% confidence interval (CI) -1.25 to -1.20 versus females -0.87mL/min/1.73m2: CI -0.89 to -0.85) and current smokers (males -1.58 mL/min/1.73m2 per year: CI -1.60 to -1.55 versus females -1.27 mL/min/1.73m2: CI -1.29 to -1.25). Socioeconomic deprivation was one of the most impactful risk factors on eGFR decline among females age >73, whereas cardiometabolic risk factors were more important among males. Older females at baseline were less likely to develop incident kidney failure than older males (p-value for age<0.001). LimitationsStudy of people who were almost exclusively White and who had blood laboratory test data. Reliance on creatinine-based eGFR. Albuminuria and body mass index data were incomplete. ConclusionseGFR decline was faster in males than in females especially in the setting of heart failure and smoking. Socioeconomic deprivation was an important risk factor associated with eGFR decline, particularly for females. While further work is required to explore less well-recognised risk factors these findings may inform clinical management strategies of CKD overall and within sex-specific groups.

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients.

The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Therapeutic drug monitoring data from initial vancomycin therapy (first 3days of treatment) in adult obese (BMI ≥ 30kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.

#908 The effect of obesity and fat distribution on estimated glomerular filtration rate (eGFR): A Mendelian randomization and image data analysis study

Abstract Background and Aims Obesity is intimately linked to the initiation and progression of chronic kidney disease, but questions on causality still remain. The diagnosis of chronic kidney disease is often based solely on creatinine- and/or cystatin C-based estimated glomerular filtration rate (eGFR), but both these endogenous biomarkers are also known to be related to body composition. This study aims to further investigate how obesity causally affects eGFR, derived from both biomarkers. Method Methods used were: Traditional cross-sectional analyses and magnetic resonance imaging data analyses performed in the POEM study (502 subjects, all aged 50 years), and two-sample Mendelian randomization using already published summary data. Outcome variables for all analyses were eGFR indexed to body surface area, based on creatinine and cystatin C, respectively. In both the traditional cross-sectional and the Mendelian randomization analyses body mass index and waist circumference were used as exposure variables. In the image data analyses, eGFR was regressed nonparametically on fat content and tissue volume for each 3D voxel. Results were visualized as a correlation “imiomics” map. Results Results from the POEM study showed in an adjusted model a negative correlation between cystatin C calculated eGFR and both body mass index [beta = −0.190 (95% CI: −0.280 to −0.100)] and waist circumference [beta = −0.160 (95% CI: −0.250 to −0.060)]. In contrast, a positive association was found for eGFR when using creatinine levels [beta = 0.120 (95% CI: 0.030 to 0.210) for body mass index; beta = 0.160 (95% CI: 0.070 to 0.260) for waist circumference]. This pattern was repeated in the image data analysis, which was visualized in the imiomics map: both visceral and subcutaneous adipose tissue were negatively correlated to eGFR based on cystatin C but positively correlated to eGFR based on creatinine (Fig. 1). Mendelian randomization implied a negative causal effect of obesity-related measures on cystatin C-based eGFR, with statistically significant estimates for both body mass index [beta = −0.031 (95% CI: −0.037 to −0.026)] and waist circumference [beta = −0.038 (95% CI: −0.045 to −0.031)]. No statistically significant effects was found on creatinine-based eGFR (Fig. 2). Conclusion This study indicates a causal negative effect of obesity on cystatin C-based eGFR, but not on eGFR calculated from creatinine. This discrepancy is further highlighted by analyses of adipose tissue from magnetic resonance imaging. These findings thus warrant further research on the impact of using the endogenous biomarkers creatinine and cystatin C to estimate renal function when assessing the link between obesity and chronic kidney disease.

#2370 Creatinine, cystatin C, muscle mass, and mortality: findings from a primary and replication population-based cohort

Abstract Background and Aims Creatinine measures are used as initial test to derive eGFR and confirmatory testing with circulating cystatin C is recommended when creatinine-based eGFR is considered less accurate due to deviant muscle mass. Low muscle mass is associated with increased risk of premature mortality. However, the associations of circulating creatinine and cystatin C with muscle mass and mortality remain unclear and require further investigation to better inform clinical decision-making. This study aimed to disentangle these complex relationships and better inform clinical decisions on marker reliability in varying settings by investigating whether cystatin C adjustment could clarify the associations of circulating creatinine with muscle mass and mortality. Method We conducted a prospective, observational cohort study including 8, 437 community-dwelling adults enrolled in the Dutch PREVEND study and 5, 033 in the U.S. NHANES. Associations of serum creatinine and/or cystatin C with muscle mass surrogates and mortality were quantified with linear and Cox proportional-hazards regression, respectively. Missing observations in covariates were multiply imputed using Substantive Model Compatible Fully Conditional Specification. Results Mean (SD) age of PREVEND and NHANES participants (50% and 48% male) were 49.8 (12.6) and 48.7 (18.7) years, respectively. Median (Q1-Q3) serum creatinine and cystatin C were 0.79 (0.69-0.90) and 0.90 (0.70-1.00) mg/dl and 0.87 (0.78-0.98) and 0.91 (0.80-1.10) mg/l, respectively. Higher serum creatinine was associated to greater muscle mass, while serum cystatin C was not associated with muscle mass. Adjusting both markers for each other strengthened the positive relationship between serum creatinine and muscle mass and revealed an inverse association between serum cystatin C and muscle mass. In the PREVEND cohort, 1, 636 (19%) deaths were registered over a median follow-up of 12.9 (5.8-16.3) years with a 10-year mortality rate (95% CI) of 7.6% (7.1-8.2%). In the NHANES, 1, 273 (25%) deaths were registered over a median follow-up of 17.9 (17.3-18.5) years with a 10-year mortality rate of 13.8% (12.8-14.7%). Both markers were associated with increased mortality (Fig. panels A and B). Notably, when adjusted for each other, higher serum creatinine was associated with decreased mortality (Fig. panel C), while the association between serum cystatin C and increased mortality strengthened (Fig. panel D). The shapes of the associations in the PREVEND study and NHANES were almost identical. Conclusion The strong association between serum creatinine and muscle mass challenges its reliability as GFR marker, necessitating a more cautious approach in its clinical use. The minimal association between serum cystatin C and muscle mass supports its increased use as a more reliable alternative in routine clinical practice.

#2119 Long-term efficacy of tolvaptan therapy in patients with ADPKD

Abstract Background and Aims Currently, the only available therapy to ameliorate disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) is tolvaptan, a vasopressin V2 receptor antagonist. Real-life data on tolvaptan treatment effect is sparce, with several limitations including restricted follow-up, relatively small patient groups, no control groups, or only data reported on kidney function without total kidney volume. We studied, therefore, the long-term effect of tolvaptan on kidney function as well as kidney growth in a relatively large number of real-life ADPKD patients and controls. Moreover, we investigated the effect of salt and protein intake on long-term treatment efficacy. Method Data from two national ADPKD cohorts were pooled. Kidney function (creatinine-based eGFR) was measured at least yearly and total kidney volume (TKV, measured by MRI or CT) at least 3-yearly. Salt and protein intake were measured by 24 h urine excretion. To investigate the long-term effects of tolvaptan we assessed change in eGFR and TKV before as well as after start of tolvaptan using linear mixed effects models. For this purpose, we excluded the acute treatment effect from start to 6 months after initiation of tolvaptan. As a control group, we included all patients who were not treated with tolvaptan, assessing change in eGFR and TKV before and after the theoretical start of treatment (based on the average time of tolvaptan initiation observed in the tolvaptan-treated group) as well as a matched control group. Subgroup analyses of salt and protein intake were based on the median urinary excretion of sodium or urea. Results 697 patients (47 ± 12 years, 59.1% female) were included, of which 104 patients used tolvaptan. Mean duration of tolvaptan use was 6.0 ± 4.5 years (range: 0.8 to 15.6). Tolvaptan use reduced yearly eGFR decline by 17.4% (−4.43 to −3.66 mL/min/1.73 m2/year, p = 0.03, number of measurements: n = 817), whereas in the non-tolvaptan control group after the theoretical start of treatment, eGFR decline increased by 13.3% (−1.95 to −2.21 mL/min/1.73 m2/year, p = 0.2, n = 2804). Long-term TKV growth did not change after start of tolvaptan treatment (4.90 to 5.53%/year, p = 0.5, n = 316). Similar results were obtained in the matched control group. A more substantial treatment effect of tolvaptan on eGFR slope was noted in patients with high compared to low salt intake (assessed as ≥ versus &amp;lt; median urinary sodium excretion of 146 mmol/24 h (difference 1.62 (0.22 to 3.02) mL/min/1.73 m2/year, p = 0.02). Subgroup analysis according to median protein intake did not show a significant difference in tolvaptan treatment effect. Conclusion In this study, with real-life patient data, long-term follow-up, and a control group, we found that tolvaptan attenuated long-term kidney function decline but, notably, did not influence kidney growth. Higher daily salt intake was associated with a more substantial tolvaptan treatment effect, perhaps due to higher vasopressin levels before treatment, and consequently more vasopressin antagonism by tolvaptan.

#1880 Disease outcomes associated with decreased estimated glomerular filtration rate: a Phenome-wide association study

Abstract Background and Aims This study aimed to identify associations between decreased creatinine-based estimated glomerular filtration rate (eGFR) and a broad range of related outcomes. Method Polygenic risk score (PRS) was calculated using PLINK1.9 software according to the tutorial with summing of risk alleles weighted by the effect sizes of 347308 white participants in UK Biobank. Genome-wide association study (GWAS) summary statistical data of creatinine-based eGFR from CKDGen consortium was utilized as base data. The phenome codes of disease outcomes were derived from the primary and secondary diagnoses of ICD-10 and ICD-9 codes in the HSE records in the U.K. Biobank. Then, the association between genetically predicted eGFR and following disease outcomes were evaluated using logistic regression adjusting for age (continuous variables), sex (male/female), assessment cancer (category variables), and the first 10 genetic principal components (PCs) (continuous variables). PRS of eGFR was scaled to a unit reflecting one SD (equals to 1) decrease of PRS. We applied the Bonferroni correction (P threshold = 0.05/665 phe codes = 7.52 × 10−5) to correct for multiple testing. Results Totally, 19857 SNPs (pruned by r2 &amp;lt; 0.1 within the 250 kb region, P &amp;lt; 0.01) from base data were retained for PRS calculation. Our Phe was identified that one standard deviation (SD) decrease in the PRS of eGFR significantly associated with chronic renal failure (OR = 1.27, 95% CI: 1.25-1.30, P = 1.66 × 10−158), intestinal malabsorption (OR = 1.18, 95% CI: 1.13-1.22, P = 1.76 × 10−16), other hypothyroidism (OR = 1.06, 95% CI: 1.04-1.07, P = 4.98 × 10−13), calculus of kidney and ureter (OR = 0.92, 95% CI: 0.89-0.94, P = 4.91 × 10−11), gout (OR = 1.07, 95% CI: 1.05-1.10, P = 2.34 × 10−8), chronic nephritic syndrome (OR = 1.21, 95% CI: 1.12-1.30, P = 3.20 × 10−7), Hypertensive renal disease (OR = 1.15, 95% CI: 1.09-1.21, P = 4.72 × 10−7), acute renal failure (OR = 1.04, 95% CI: 1.02-1.06, P = 4.58 × 10−6), glaucoma (OR = 0.95, 95% CI: 0.93-0.98, P = 2.16 × 10−5) and unspecified renal failure (OR = 1.10, 95% CI: 1.05-1.16, P = 2.70 × 10−5). Conclusion Genetically predicted deceased eGFR associated with a series of disease outcomes, providing evidence for prevention of following diseases in patients with kidney function impairment.

#559 Validation of the Kidney Failure Risk Equation (KFRE) in individuals with chronic kidney disease and multimorbidity

Abstract Background and Aims Increasing numbers of individuals with chronic kidney disease (CKD) experience multiple long-term conditions (multimorbidity). Clinical guidance recommends the use of validated risk prediction equations, such as the kidney failure risk equation (KFRE), to guide referral to specialist kidney care services. However, multimorbidity may impact the accuracy of creatinine-based eGFR and bias the prognostic utility of KFRE. Equations with alternative filtration markers, such as Cystatin C eGFR (eGFRcys) or the combined creatinine and Cystatin C eGFR (eGFRcrcys), may improve KFRE's risk stratification and discrimination of future kidney failure risks. This study aimed to validate the four-variable KFRE in individuals with CKD, with and without multimorbidity in a research-based cohort (UK Biobank) and a population-based cohort (Stockholm Creatinine Measurements project (SCREAM)). The study also assessed the performance of KFRE when using eGFRcr, eGFRcys and eGFRcrcys. Method Individuals from both cohorts were included if they had CKD, defined as eGFR&amp;lt;60 mL/min/1.73 m2 by any of the three eGFR equations (eGFRcr, eGFRcys and eGFRcrcys), and had available proteinuria measurement at time of testing or within the previous 12 months. Multimorbidity was defined as the presence of two or more long-term conditions in addition to CKD and was grouped into multimorbidity clusters based on previous research. The outcome was kidney failure, defined as the need for long-term dialysis or kidney transplantation. KFRE performance at 2- and 5-years was assessed using the area under the receiver operating characteristic curve and c-index for discrimination and calibration curves for calibration. Results We included 24 489 individuals from UK Biobank and 42 902 individuals from SCREAM (mean age 62.8 (SD 5.6) and 70.1 (SD14.1), 54% and 66% female, respectively). In UK biobank, 14 998 individuals had multimorbidity, of which 5 375 had cardiometabolic multimorbidity. In SCREAM, 30 147 had multimorbidity and 17 854 cardiometabolic multimorbidity. Overall, there were 252 and 312 kidney failure events and 1 108 and 1 471 death events in UK Biobank and 918 and 1 098 kidney failure events and 8 785 and 10 152 death events in SCREAM within 2- and 5-years respectively. Model performance was consistent across both cohorts. Discrimination power of KFRE was good in individuals with and without multimorbidity and across the 2-year and 5-year models (Table 1). Calibration plots revealed over-estimation of risk at 2-years in both cohorts and under-estimation of risk at 5-years in patients with multimorbidity in UK Biobank. There was no improvement in model performance when using eGFRcys or eGFRcrcys compared to eGFRCr. There was a higher cumulative incidence of both kidney failure and death in the multimorbidity group, with a prominent increase in risk of death over time compared to the no multimorbidity group. This was most evident in the SCREAM cohort (Fig. 1). Conclusion KFRE adequately predicts kidney failure in individuals with multimorbidity and either creatinine or cystatin C can be used. Given the high rates of mortality amongst people with multimorbidity, exploration of models that account for the competing risk of death is warranted.

#1329 Assessing eGFR performance against measured GFR stratifying for ethnicity and albumin: development of the AIM CKD UK study

Abstract Background and Aims Accurate measurement of kidney function using estimated glomerular filtration rate (eGFR) is essential for appropriate risk stratification of cardiovascular events, kidney failure and prescribing medications. The AIM CKD UK study (IRAS 320215) will assess the accuracy of current and novel creatinine-based eGFR equations compared to exogenous filtration marker derived measured GFR (mGFR) for people of different ethnicities in large national cohort. We performed a preliminary analysis from a single centre in AIM CKD UK to inform future data collection and assessed: Method All adults (≥18-years) who had paired mGFR and eGFR tests within 30 days between 2009-2022 were included. Patients with mGFR ≥150 ml/min/1.73 m2, incomplete datasets and previous amputations were excluded. Age, reported ethnicity, biological sex, referral specialty, height, weight, exogenous filtration marker, creatinine and albumin concentration were recorded. eGFR was calculated from creatinine, age and sex using five equations (Fig. 1). Each eGFR equation was compared to mGFR using median bias, precision, 30% accuracy (P30). Agreement was demonstrated with Bland-Altman plots. Results were stratified for time between eGFR-mGFR (≤7 days vs 8-30 days) and albumin concentration; low (&amp;lt;35 g/L) vs normal / high (≥35 g/L). Assessment of equation performance in different ethnicity was also stratified for the three largest ethnicity groups (White, Black and South Asian ethnicity). Data were analysed using software R V4.2.2. Results There were 2623 patients who met the inclusion criteria. Mean age was 54.8 ± 13.1 years, with 57.8% male (N = 1515). The majority of patients were White ethnicity (58.7%; N = 1539). Median mGFR was 77 mL/min/1.73 m2 (IQR 62–91 mL/min/1.73 m2). Median serum creatinine concentration was 74 umol/L (IQR 61–90 umol/L). The CKD-EPI 2009 equation, compared to mGFR, demonstrated a median bias of +12.8 mL/min/1.73 m2, percentage bias of 16.9% and P30 of 68.6%. The Lund-Malmo revised equation performed best with median bias of 2.1 mL/min/1.73 m2 (percentage bias 2.9%) and a P30 of 82.7%. Agreement, with ethnicity stratification is summarised in Table 1. The majority of patients (N = 2439; 93.0%) had paired mGFR-eGFR tests within 7-days. There was no significant difference between the median bias of each group (P = .749). 2610 (99.5%) patients had concurrent albumin tests performed; 183 (7.0%) of these patients had low albumin concentrations. Median bias was significantly higher in this group compared to normal/high albumin for each equation (e.g. Low vs Normal/high albumin median bias for CKD-EPI equation = 20.3 vs 12.5 mL/min/1.73 m2; P &amp;lt;. 001). Conclusion The LM revised and European Kidney Function Consortium equations perform best in this cohort. Limitations include selection bias and retrospective data. Future data analysis for the AIM CKD study can include paired samples within 30 days as there is no significant difference between 0-7 and 8-30 days. The impact of serum albumin on mGFR-eGFR association in a larger cohort stratified for confounding variables, such as liver disease, malignancy and body mass index is required.

Different cardiovascular risks associated with elevated creatinine-based eGFR and cystatin C-based eGFR

To compare the association of elevated estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcr) and cystatin C (eGFRcys) with the risk of cardiovascular diseases (CVD) and chronic kidney diseases (CKD). 372,060 participants free of CVD and CKD in the UK Biobank were included. Participants were categorized into low, normal and high eGFR groups according to the age- and sex-specific 5th and 95th percentiles of eGFR. The primary outcome was incident CVD, defined as a combination of ischemic heart disease, stroke, heart failure, and atrial fibrillation. Thresholds for high eGFR varied with age and sex, ranging from 96.5 to 116.0 mL/min/1.73 m2 and 100.3 to 120.1 mL/min/1.73 m2 for eGFRcr and eGFRcys, respectively. During a median follow-up of 12.4 years, 39,855 (10.7%) participants developed CVD. Compared with normal eGFR levels, high eGFRcr levels were associated with a higher risk of CVD (HR, 1.19; 95% CI: 1.14–1.25), while high eGFRcys levels were associated with a lower risk of CVD (HR, 0.90; 95% CI: 0.85–0.95). Compared to normal eGFR levels, both high eGFRcr and high eGFRcys levels were related to a lower risk of CKD. Elevated eGFRcr levels were associated with a higher risk of CVD, and elevated eGFRcys levels were associated with a lower risk of CVD.

CYSTATIN C BASED EGFR IS SUPERIOR FOR THE ASSESSMENT OF CARDIOVASCULAR RISK IN PRETERM CHILDREN

Objective: Preterm birth is a risk factor for hypertension (HTN), chronic kidney disease (CKD) and adverse cardiovascular (CV) outcomes. The aims of the study were to evaluate the utility of eGFR based on cystatin C (Cys C) compared to creatinine in regard to associations with office blood pressure (BP) and central systolic BP (cSBP). Design and method: This case-control study included 52 children and adolescents born prematurely (ex-preterms) and 26 at full term (controls) matched for age in 2:1 ratio. All participants underwent office BP and cSBP measurement and laboratory evaluation including assessment of CysC values at the same visit. Results: Mean age of the population was 10.74±3.55 years. There were no significant differences in BP levels, eGFR(creatinine) and eGFR(CysC) between ex-preterm and control group. CysC levels were similar between the ex-preterm and the control group. CysC significantly correlated with cSBP z score (r=0.32, p=0.02, Spearman test). This association remained significant after adjustment for age, sex and BMI z score in the ex-preterm group (B=1.003, 95%CI 1.001-0.005, p=0.006). 42% (n=22) of the ex-preterm children presented cSBP levels greater than the 95th percentile. eGFR(CysC) presented positive association with office DBP (r=-0.37, p= 0.006, Spearman test) and cSBP z score (r= -0.32, p=0.022, Spearman test) in the ex-preterm group, but not in the control group (Figure). eGFR(creatinine) did not associate with BP parameters. eGFR(creatinine) overestimated eGFR levels in ex-preterm group (mean difference 20.56±22.66, p &lt;0.001). Two (3%) and 17(32.6%) ex preterm children had GFR &lt; 90 ml/min/1.73m2 by creatinine-based eGFR compared by eGFR(CysC). Conclusions: eGFR(CysC) presents apositive association with cSBP and thus, may better classify future cardiovascular risk in ex-preterm children. cSBP elevation and its association with CysC maybe a target for future studies to elucidate the role of central hemodynamic alterations in the development of HTN and CV disease in the ex-preterm individuals.

Predictive effect of estimated glomerular filtrate rate by creatinine or cystatin C on mortality in patients with coronary artery disease

Background Renal dysfunction leads to poor prognosis of patients with coronary artery disease (CAD). Current studies have reported the prognosis or mortality of various diseases using different estimated glomerular filtrate rate (eGFR) formulas, while the performance of these equations is unclear in CAD patients. We aim to evaluate the predict effect of creatinine-based eGFR (eGFRcr), cystatin C-based eGFR (eGFRcys), and both creatinine and cystatin C-based eGFR (eGFRcr-cys) in CAD patients. Methods A total of 23,178 patients with CAD were included from CIN-II cohort study. The association of eGFRcr, eGFRcys and eGFRcr-cys with cardiovascular and all-cause mortality was detected by Cox regression analysis. The predictive effect of eGFRcr, eGFRcys and eGFRcr-cys on mortality was assessed. Results During a median follow up of 4.3 years, totally 2051 patients (8.8%) experience all-cause mortality, of which 1427 patients (6.2%) died of cardiovascular disease. For the detection of cardiovascular mortality among CAD patients, eGFRcr-cys had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.730, which was significantly better than eGFRcr (AUC = 0.707, p < 0.001) and eGFRcys (AUC = 0.719, p < 0.001). Similar results were observed in all-cause mortality. Restricted cubic spline showed a U-shaped association between eGFRcr and all outcomes in patients with both reduced and supranormal eGFR levels, while a L-shaped association in eGFRcys and eGFRcr-cys. Conclusions Estimated GFR based on both creatinine and cystatin C has highest predictive effect for cardiovascular and all-cause mortality among CAD patients. Meanwhile, supranormal eGFRcr may indicate a higher risk of mortality.

The 10-Year Effects of Intensive Lifestyle Intervention on Kidney Outcomes

Limited data exist on longitudinal kidney outcomes after nonsurgical obesity treatments. We investigated the effects of intensive lifestyle intervention on kidney function over 10 years. Post hoc analysis of Action for Health in Diabetes (Look AHEAD) randomized controlled trial. We studied 4,901 individuals with type 2 diabetes and body mass index of≥25kg/m2 enrolled in Look AHEAD (2001-2015). The original Look AHEAD trial excluded individuals with 4+urine dipstick protein, serum creatinine level of>1.4mg/dL (women), 1.5mg/dL (men), or dialysis dependence. Intensive lifestyle intervention versus diabetes support and education (ie, usual care). Primary outcome was estimated glomerular filtration rate (eGFR, mL/min/1.73m2) slope. Secondary outcomes were mean eGFR, slope, and mean urine albumin to creatinine ratio (UACR, mg/mg). Linear mixed-effects models with random slopes and intercepts to evaluate the association between randomization arms and within-individual repeated measures of eGFR and UACR. We tested for effect modification by baseline eGFR. At baseline, mean eGFR was 89, and 83% had a normal UACR. Over 10 years, there was no difference in eGFR slope (+0.064 per year; 95% CI: -0.036 to 0.16; P=0.21) between arms. Slope or mean UACR did not differ between arms. Baseline eGFR, categorized as eGFR of<80, 80-100, or>100, did not modify the intervention's effect on eGFR slope or mean. Loss of muscle may confound creatinine-based eGFR. In patients with type 2 diabetes and preserved kidney function, intensive lifestyle intervention did not change eGFR slope over 10 years. Among participants with baseline eGFR<80, lifestyle intervention had a slightly higher longitudinal mean eGFR than usual care. Further studies evaluating the effects of intensive lifestyle intervention in people with kidney disease are needed.