Lower eGFRcys Research Articles

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

Discrepancy between estimated glomerular filtration rate by creatinine versus cystatin C in different patient care settings

ObjectiveEstimated glomerular filtration rate (eGFR) calculated by cystatin C (cysC) has been recommended for broader adoption. This study assessed the discrepancy between eGFR calculated by cysC (eGFRcys) and creatinine (eGFRcr) in different patient care settings and explored potential contributing factors to such discrepancies. MethodsThis retrospective study included 2072 patients with paired cysC and creatinine results in different patient care settings. Delta eGFRcr-cys (eGFRcr − eGFRcys) was analyzed in relationship to patient care settings and the Elixhauser Comorbidity index. The 90-day survival in patients with different delta eGFR was assessed by Kaplan-Meier analysis, univariate and multivariate Cox proportional hazard models. In addition, discrepancy between eGFRcys and eGFRcr was analyzed in 50 ambulatory patients with systemic inflammation but normal kidney function. ResultsInpatients had higher cysC (median 1.91 mg/L), lower eGFRcys (median 31 mL/min/1.73 m2), and larger delta eGFRcr-cys (median 18 mL/min/1.73 m2) than outpatients (cysC median 1.53 mg/L, p < 0.0001, eGFRcys median 41 mL/min/1.73 m2, p < 0.0001, delta eGFRcr-cys median 4 mL/min/1.73 m2, p < 0.0001). Higher Elixhauser Comorbidity index correlated with lower eGFRcys and larger delta eGFRcr-cys, with median delta eGFRcr-cys 11 and 6 mL/min/1.73 m2 in patients with a Comorbidity index > 15 and ≤ 15, respectively (p < 0.0001). Increased delta eGFRcr-cys was associated with worse 90-day survival. Patients with systemic inflammation but normal kidney function had lower eGFRcys (median 77.5 mL/min/1.73 m2) than eGFRcr (median 97 mL/min/1.73 m2, p < 0.001), with red blood cell abnormalities as associated factors. ConclusionInflammation and comorbidities are associated with decreased eGFRcys and large discrepancies between eGFRcr and eGFRcys independent of kidney function and are most apparent in inpatients. Creatinine-cysC combined eGFR reduces this discrepancy and should be broadly adopted.

Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity

Cystatin C-based estimated glomerular filtration rate (eGFRcys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFRcr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFRcys with kidney and cardiovascular outcomes. Cohort study. 27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study. eGFRcys, eGFRcr, waist circumference, and body mass index (BMI). All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF). Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFRcys with risks of 4 clinical outcomes. Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFRcys<60mL/min/1.73m2. The baseline prevalence of abdominal obesity (waist circumference≥88cm for women or≥102cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15mL/min/1.73m2 lower eGFRcys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI<24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI≥35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFRcys with mortality, kidney failure, incident ASCVD, or incident HF (all Pinteraction>0.05). Included only Black and White persons in the United States. Obesity did not modify the association of eGFRcys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes. Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C-based eGFR (eGFRcys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFRcys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFRcys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.

Discordances Between Creatinine- and Cystatin C–Based Estimated GFR and Adverse Clinical Outcomes in Routine Clinical Practice

Cystatin C is recommended for measuring estimated glomerular filtration rate (eGFR) when estimates based on creatinine (eGFRcr) are not thought to be accurate enough for clinical decision making. While global adoption is slow, routine cystatin C testing in Sweden has been available for over a decade, providing real-world evidence about the magnitude of differences between eGFRcys and eGFRcr and their association with clinical outcomes. Observational study. 158,601 adults (48% women; mean age 62 years, eGFRcr 80, and eGFRcys 73mL/min/1.73/m2) undergoing testing for creatinine and cystatin C on the same day in connection with a health care encounter during 2010-2018 in Stockholm, Sweden. Percentage difference of eGFRcys minus eGFRcr (eGFRdiff). Kidney failure with replacement therapy (KFRT), acute kidney injury (AKI), atherosclerotic cardiovascular disease (ASCVD), heart failure, and death. Multivariable Cox proportional hazards regression. Discordances between eGFRcr and eGFRcys were common, with eGFRcys being lower than eGFRcr (negative eGFRdiff) in most cases (65%). Patients with larger negative eGFRdiff were older, more often female, with higher eGFRcr and albuminuria, and more comorbid conditions. Compared with patients with similar eGFRcys and eGFRcr, the lowest quartile (eGFRcys > 27% lower than eGFRcr) had the higher HR of all study outcomes: AKI, 2.6 (95% CI, 2.4-2.9); KFRT, 1.4 (95% CI, 1.2-1.6); ASCVD, 1.4 (95% CI, 1.3-1.5); heart failure, 2.0 (95% CI, 1.9-2.2); and all-cause death, 2.6 (95% CI, 2.5-2.7). Conversely, patients in the highest quartile (positive eGFRdiff) were at lower risk. Observational study, lack of information on indications for cystatin C testing. Cystatin C testing in routine care shows that many patients have a lower eGFRcys than eGFRcr, and these patients have a higher risk of multiple adverse outcomes. Clinicians require guidance when there are discrepancies between the estimated glomerular filtration rate based on creatinine (eGFRcr) and based on cystatin C (eGFRcys) in the same individual. Routine cystatin C testing in Sweden for over a decade permits exploration of how common and large these discrepancies are, and their associations with adverse clinical outcomes. In this observational study, we found that discordances between eGFRcys and eGFRcr are common, and 1 in 4 patients tested had an eGFRcys > 28% lower than their eGFRcr. We also show that an eGFRcys that is lower than the eGFRcr consistently identifies patients at higher risk of adverse outcomes, including cardiovascular events, kidney replacement therapy, acute kidney injury, and death.

GFR estimated with creatinine rather than cystatin C is more reflective of the true risk of adverse outcomes with low GFR in kidney transplant recipients.

Serum cystatin C-based estimated glomerular filtration rate (eGFRcys) generally associates with clinical outcomes better than serum creatinine-based eGFR (eGFRcr) despite similar precision in estimating measured GFR (mGFR). We sought to determine whether the risk of adverse outcomes with eGFRcr or eGFRcys was via GFR alone or also via non-GFR determinants among kidney transplant recipients. Consecutive adult kidney transplant recipients underwent a standardized GFR assessment during a routine follow-up clinic visit between 2011 and 2013. Patients were followed for graft failure or the composite outcome of cardiovascular (CV) events or mortality through 2020. The risk of these events by baseline mGFR, eGFRcr and eGFRcys was assessed unadjusted, adjusted for mGFR and adjusted for CV risk factors. There were 1135 recipients with a mean baseline mGFR of 55.6, eGFRcr of 54.8 and eGFRcys of 46.8ml/min/1.73m2 and a median follow-up of 6years. Each 10ml/min/1.73m2 decrease in mGFR, eGFRcr or eGFRcys associated with graft failure [hazard ratio (HR) 1.79, 1.68 and 2.07, respectively; P<.001 for all) and CV events or mortality outcome (HR 1.28, 1.19 and 1.43, respectively; P<.001 for all). After adjusting for mGFR, eGFRcys associated with graft failure (HR 1.57, P<.001) and CV events or mortality (HR 1.49, P<.001), but eGFRcr did not associate with either. After further adjusting for CV risk factors, risk of these outcomes with lower eGFRcys was attenuated. eGFRcr better represents the true relationship between GFR and outcomes after kidney transplantation because it has less non-GFR residual association. Cystatin C is better interpreted as a nonspecific prognostic biomarker than is eGFR in the kidney transplant setting.

Cystatin C-based eGFR predicts cardiovascular disease in patients with overweight/obesity and hyperglycemia.

Although many clinical parameters have been identified as predictors for cardiovascular disease (CVD) development in the general population, the accurate predictor for CVD in patients with obesity is still unknown. The study aimed to explore an additional risk factor and predictor for CVD in patients with overweight/obesity considering the interaction of obesity-related pathophysiology. The Japan Obesity and Metabolic Syndrome study, a multicenter prospective study, enrolled 787 outpatients, of which 318 eligible patients were analyzed. Patients with fasting plasma glucose (FPG) levels ≥6.11 and<6.11mmol/L were considered to have high FPG (HFPG) and normal FPG (NFPG), respectively. Thirty-six patients who developed CVD during the 5years follow-up were assigned to the CVD group. Cox's proportional hazards model revealed no significant association between CVD and cystatin C-based estimated glomerular filtration rate (eGFRcys) or creatinine-based eGFR (eGFRcr) in the NFPG group. In the HFPG group, lower eGFRcys, but not eGFRcr, was significantly associated with CVD development. A generalized linear mixed model demonstrated greater reduction in eGFRcys levels over time with HFPG than with NFPG. Although the CVD group showed gradual reduction in eGFRcys levels, the non-CVD group-matched using propensity scores-did not show a decline in eGFRcys levels. Lower eGFRcys levels may be more accurate than eGFRcr in predicting CVD development in patients with overweight/obesity and hyperglycemia. Furthermore, eGFRcys reduction over time is associated with CVD development. UMIN000000559.

Bidirectional Association Between Kidney Function and Atrial Fibrillation: A Population-Based Cohort Study.

BackgroundConsensus lacks concerning a bidirectional association between kidney function and atrial fibrillation (AF), but this is crucial information for prevention/treatment efforts for both chronic kidney disease and AF. Therefore, we investigated the bidirectional association between kidney function and AF.Methods and ResultsThis study was a prospective cohort study including 9228 participants (mean age, 64.9 years; 57.2% women) with information on kidney function (estimated glomerular filtration rate [eGFR] based on serum creatinine [eGFRcreat], cystatin C [eGFRcys], or both [eGFRcreat‐cys], and urine albumin‐to‐creatinine ratio) and AF. Reduced kidney function was defined as eGFRcreat <60 mL/min per 1.73 m2. Cox proportional‐hazards, logistic regression, linear mixed, and joint models were used to investigate the association of kidney function with AF and vice versa. During follow‐up (median of 8.0 years), 780 events of incident AF occurred. Lower eGFRcys and eGFRcreat‐cys were associated with increased AF risk (hazard ratio [HR], 1.08 [95% CI, 1.03–1.14] and HR, 1.07 [95% CI, 1.01–1.14], respectively, per 10 mL/min per 1.73 m2 eGFR decrease). For eGFRcys and eGFRcreat‐cys, 10‐year cumulative incidence of AF was 16% (eGFR <60) and 6% (eGFR ≥60). Prevalent AF (versus no prevalent AF) was associated with 2.85 mL/min per 1.73 m2 lower eGFRcreat and with a faster decline of eGFRcreat with age. Prevalent AF was associated with a 1.3‐fold increased risk of incident reduced kidney function.ConclusionsKidney function, especially eGFRcys, and AF are bidirectionally associated. There are currently no targeted prevention efforts for AF in patients with mild chronic kidney disease and vice versa. Our results could provide the first step to improve prediction/prevention of both conditions.

Kidney function and the risk of sudden cardiac death in the general population.

ABSTRACTBackgroundChronic kidney disease increases sudden cardiac death (SCD) risk, but the association between kidney function and SCD in a general population is largely unknown. Therefore, we investigated the association between kidney function and SCD in a general middle-aged and elderly population.MethodsWe included individuals aged ≥45 years from a prospective population-based cohort study. The association between kidney function assessments [estimated glomerular filtration rate based on serum creatinine (eGFRcreat), cystatin C (eGFRcys) or both (eGFRcreat-cys)] and SCD was investigated using Cox proportional-hazards and joint models. Absolute 10-year risks were computed using competing risk analyses. Mediation analyses were performed using a four-way decomposition method.ResultsWe included 9687 participants (median follow-up 8.9 years; mean age 65.3 years; 56.7% women; 243 SCD cases). Lower eGFRcys and eGFRcreat-cys were associated with increased SCD risk [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.12–1.34 and HR 1.17, 95% CI 1.06–1.29, per 10 mL/min/1.73 m2 eGFR decrease]. A significant trend (P = 0.001) across eGFRcys categories was found, with an HR of 2.11 (95% CI 1.19–3.74) for eGFRcys <60 compared with eGFRcys >90 mL/min/1.73 m2. Comparing eGFRcys of 90 to 60 mL/min/1.73 m2, absolute 10-year risk increased from 1.0% to 2.5%. Identified subgroups at increased risk included older participants and participants with atrial fibrillation. The associations were not mediated by coronary heart disease, hypertension or diabetes.ConclusionsReduced kidney function is associated with increased SCD risk in the general population, especially with eGFRcys. eGFRcys could be added to prediction models and screening programmes for SCD prevention.

Abstract P330: Chronic Kidney Disease is Associated With Short-Term Risk of Hospitalization Among Older Adults

Background: Chronic kidney disease (CKD) is now staged by estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR). Risks of cardiovascular disease, dialysis, and mortality are well described, but risks of hospitalization at older age have not been explored to the same depths. Hypothesis: CKD stages will be associated with risk of all-cause hospitalizations. Methods: The analysis was conducted on 5669 white and African-American participants of the ARIC Visit 5 (2011-2013) cohort (mean age, 76 y; female, 57%; African-American, 23%). CKD was staged according to KDIGO 2012 criteria with eGFR from serum cystatin C (eGFRcys) and ACR. The primary outcome of all-cause hospitalization risk was analyzed by using negative binomial regression to estimate incidence rate ratios (IRR), adjusted for demographics, behaviors, and comorbidities. Results: Over a median follow-up period of 3.5 years (by December 31 st , 2015), 6124 hospitalizations occurred over 19788 person-years (Crude Incidence Rate, 309 per 1000 person-years). Risk of hospitalization increased markedly with lower eGFRcys and higher albuminuria ( Table 1 ). Other baseline comorbidities were also associated with hospitalization risk (IRR [95% CI] for heart failure, coronary heart disease (CHD), stroke, cancer were 1.7 [1.4-2.0], 1.5 [1.3-1.7], 1.3 [1.1-1.6], and 1.2 [0.9-1.5]). Conclusions: Among older adults, both low eGFR and high ACR are strongly related to risk of hospitalization. These findings provide insight for risk stratification and prevention of CKD at older ages. Table 1. Risk of hospitalization by CKD stages defined by eGFR and ACR

Association of cystatin C- and creatinine-based eGFR with osteoporotic fracture in Japanese postmenopausal women with osteoporosis: sarcopenia as risk for fracture.

Coexistence of chronic kidney disease (CKD) is regarded as a risk for osteoporotic fracture particularly in postmenopausal women, not only because of increased parathyroid hormone level but also uremic sarcopenia. We examined the relationships of cystatin C-based glomerular filtration rate (eGFRcys) and creatinine-based GFR (eGFRcr), as well as their ratio with occurrence of osteoporotic fracture in postmenopausal osteoporotic women. This cross-sectional study included 555 postmenopausal women with osteoporosis. eGFRcr and eGFRcys were simultaneously measured, while occurrence of osteoporotic fracture was obtained by a medical chart review. Patients with osteoporotic fractures (n=211) exhibited significantly lower levels of physical activity, eGFRcr, eGFRcys, and eGFRcys/eGFRcr ratios, while a higher percentage was CKD stage 3 or more, estimated by eGFRcr or eGFRcys (CKDcys), than those without (n=344). Lower eGFRcys, but not lower eGFRcr, was independently associated with osteoporotic fracture in the entire cohort and that association was retained in CKDcys patients. Of great interest, higher eGFRcr was associated with osteoporotic fracture independent of eGFRcys in CKDcys patients. Furthermore, lower eGFRcys/eGFRcr ratio was independently associated with osteoporotic fracture in both CKDcys patients and the entire cohort. eGFRcys reduction might be associated with osteoporotic fracture in postmenopausal osteoporotic women, indicating the involvement of renal osteopathy in its occurrence. Furthermore, the association of higher, but not lower, eGFRcr with osteoporotic fracture in CKDcys cases might be explained by underestimation of renal dysfunction by eGFRcr resulting from decreased muscle mass and quality in those patients.

Marijuana Use and Estimated Glomerular Filtration Rate in Young Adults.

Marijuana use has become more widely accepted in the United States and has been legalized in many areas. Although it is biologically plausible that marijuana could affect kidney function, epidemiologic data are lacking. We conducted a cohort study among young adults with preserved eGFR (i.e., eGFR≥60 ml/min per 1.73 m2) using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. At scheduled examinations occurring every 5 years and starting at study year 10 (calendar years, 1995-1996), cystatin C was collected over a 10-year period, and urine albumin-to-creatinine ratio was collected over a 15-year period. We investigated the cross-sectional association between current and cumulative marijuana use (in marijuana-years; one marijuana-year equals 365 days of marijuana use) and eGFR by cystatin C (eGFRcys) at year 10. In longitudinal analyses, we investigated the association between cumulative marijuana use and eGFRcys change and rapid (≥3%/year) eGFRcys decline over two 5-year intervals and prevalent albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) over a 15-year period. Past or current marijuana use was reported by 83% (3131 of 3765) of the cohort, and the mean eGFRcys was 111 ml/min per 1.73 m2 at year 10. Over the following 10 years, 504 had rapid eGFRcys decline, and over the following 15 years, 426 had prevalent albuminuria. Compared with no use, daily current use and ≥5 marijuana-years of cumulative use were associated with lower eGFRcys at year 10: -4.5% (95% confidence interval, -8.1 to -0.7%; P=0.02) and -3.0% (95% confidence interval, -5.6 to -0.4%; P=0.03), respectively. Marijuana use was not significantly associated with eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria. Although we identified a modest cross-sectional association between higher marijuana exposure and lower eGFRcys among young adults with preserved eGFR, our findings were largely null and did not demonstrate a longitudinal association between marijuana use and eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_24_CJASNPodcast_17_10.mp3.

Abstract MP28: Filtration Markers, Cardiovascular Disease and All-cause Mortality in Kidney Transplant Recipients: The FAVORIT Trial

Background: Cardiovascular disease (CVD) is common in kidney transplant recipients (KTRs). The level of kidney function (glomerular filtration rate [GFR]) estimated from serum creatinine has been shown to be independently associated with CVD outcomes in a wide range of populations, including KTRs. In other populations, CVD outcomes are more strongly associated with the alternative filtration markers serum cystatin C and beta-2-microglobulin (B2M) than creatinine, but this has not been evaluated in KTRs. Methods: We performed a case-cohort study of participants of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a randomized, double blind clinical trial of homocysteine lowering with B vitamins in KTRs. Study participants were enrolled from 2002-07 from centers in the US, Canada &amp; Brazil; we studied a 15% random subcohort of eligible baseline participants (N=508; mean age 52 years, 38% women) and all additional eligible adjudicated CVD (CVD death, myocardial infarction, resuscitated sudden death, stroke, N=211) and all-cause mortality (N=314) events that occurred through June 2009. Filtration markers measured at baseline were expressed as estimated GFR using established CKD-EPI equations (eGFRcr, eGFRcys &amp; eGFRB2M). Associations of eGFRcr, eGFRcys &amp; eGFRB2M with CVD and mortality were evaluated with weighted Cox proportional hazard regression to account for the case-cohort design. Results: In multivariable adjusted models eGFRcr was not significantly associated with CVD or all-cause mortality. In contrast, both lower eGFRcys and eGFRB2M were associated with increased risk of CVD and all-cause mortality (Figure). Findings were similar when eGFR was treated as a continuous variable. Conclusion: Similar to non-transplant cohorts, cystatin C and B2M have stronger risk associations for CVD and all-cause mortality compared to creatinine in KTRs. These findings likely reflect differences in their non-GFR determinants; future work is needed to evaluate non-GFR determinants in KTRs.

Kidney function and microstructural integrity of brain white matter.

To investigate the association of kidney function with white matter microstructural integrity. We included 2,726 participants with a mean age of 56.6 years (45% men) from the population-based Rotterdam Study. Albumin-to-creatinine ratio, and estimated glomerular filtration rate (eGFR), using serum cystatin C (eGFRcys) and creatinine (eGFRcr), were measured to evaluate kidney function. Diffusion-MRI was used to assess microstructural integrity of the normal-appearing white matter. Multiple linear regression models, adjusted for macrostructural MRI markers and cardiovascular risk factors, were used to model the association of kidney function with white matter microstructure. Participants had average eGFRcr of 86.1 mL/min/1.73 m(2), average eGFRcys of 86.2 mL/min/1.73 m(2), and median albumin-to-creatinine ratio of 3.4 mg/g. Lower eGFRcys was associated with worse global white matter microstructural integrity, reflected as lower fractional anisotropy (standardized difference per SD: -0.053, 95% confidence interval [CI]: -0.092, -0.014) and higher mean diffusivity (0.036, 95% CI: 0.001, 0.070). Similarly, higher albumin-to-creatinine ratio was associated with lower fractional anisotropy (-0.044, 95% CI: -0.078, -0.011). There was no linear association between eGFRcr and white matter integrity. Subgroup analyses showed attenuation of the associations after excluding subjects with hypertension. The associations with global diffusion tensor imaging measures did not seem to be driven by particular tracts, but rather spread across multiple tracts in various brain regions. Reduced kidney function is associated with worse white matter microstructural integrity. Our findings highlight the importance for clinicians to consider concomitant macro- and microstructural changes of the brain in patients with impaired kidney function.

Cystatin C- and creatinine-based estimated glomerular filtration rate, vascular disease, and mortality in persons with diabetes in the U.S.

OBJECTIVESerum cystatin C is an alternative to serum creatinine for estimating glomerular filtration rate (GFR), since cystatin C is less influenced by age and muscle mass. Among persons with diabetes, we compared the performance of GFR estimated using cystatin C (eGFRcys) with that using creatinine (eGFRcr) for the identification of reduced kidney function and its association with diabetes complications.RESEARCH DESIGN AND METHODSWe analyzed data from adult participants from the 1999–2002 National Health and Nutrition Examination Survey with available cystatin C (N = 4,457). Kidney function was dichotomized as preserved (eGFR ≥60 mL/min/1.73 m2) or reduced (eGFR <60 mL/min/1.73 m2) using the 2012 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C and the 2009 CKD-EPI creatinine equations.RESULTSAmong 778 persons with diabetes, the prevalence of reduced kidney function was 16.5% using eGFRcr and 22.0% using eGFRcys. More persons with diabetes were reclassified from preserved kidney function by eGFRcr to reduced kidney function by eGFRcys than persons without diabetes (odds ratio 3.1 [95% CI 1.9–4.9], P < 0.001). The associations between lower eGFR and higher prevalence of albuminuria, retinopathy, peripheral arterial disease, and coronary artery disease were robust regardless of filtration marker. Similarly, the risk of all-cause mortality increased with lower eGFRcr and eGFRcys. Only lower eGFRcys was significantly associated with cardiovascular mortality.CONCLUSIONSMore persons with diabetes had reduced kidney function by eGFRcys than by eGFRcr, and lower eGFRcys was strongly associated with diabetes complications. Whether eGFRcys is superior to eGFRcr in approximating true kidney function in a diabetic population requires additional study.

Low birth weight, later renal function, and the roles of adulthood blood pressure, diabetes, and obesity in a British birth cohort

Low birth weight has been shown to be associated with later renal function, but it is unclear to what extent this is explained by other established kidney disease risk factors. Here we investigate the roles of diabetes, hypertension, and obesity using data from the Medical Research Council National Survey of Health and Development, a socially stratified sample of 5362 children born in March 1946 in England, Scotland, and Wales, and followed since. The birth weight of 2192 study members with complete data was related to three markers of renal function at age 60–64 (estimated glomerular filtration rate (eGFR) calculated using cystatin C (eGFRcys), eGFR calculated using creatinine and cystatin C (eGFRcr-cys), and the urine albumin–creatinine ratio) using linear regression. Each 1 kg lower birth weight was associated with a 2.25 ml/min per 1.73 m2 (95% confidence interval 0.80–3.71) lower eGFRcys and a 2.13 ml/min per 1.73 m2 (0.69–3.58) lower eGFRcr-cys. There was no evidence of an association with urine albumin–creatinine ratio. These associations with eGFR were not confounded by socioeconomic position and were not explained by diabetes or hypertension, but there was some evidence that they were stronger in study members who were overweight in adulthood. Thus, our findings highlight the role of lower birth weight in renal disease and suggest that in those born with lower birth weight particular emphasis should be placed on avoiding becoming overweight.

Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women.

Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine. Retrospective cohort analysis. Cystatin C and creatinine were measured from specimens taken and stored during the 1999-2000 examination among 908 HIV-infected participants in the Women's Interagency HIV study (WIHS). Mean follow-up was 10.2 years. Predictors of differential glomerular filtration rate (GFR) estimates were evaluated with multivariable linear regression. The associations of baseline categories (<60, 60-90, and >90 ml/min per 1.73 m) of creatinine estimated GFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging. CKD risk factors were associated with lower eGFRcys and eGFRcr-cys values compared with eGFRcr. Relative to eGFR more than 90, the eGFR less than 60 category by eGFRcys (Adjusted hazard ratio: 2.56; 95% confidence interval: 1.63-4.02), eGFRcr-cys (3.11; 1.94-5.00), and eGFRcr (2.34; 1.44-3.79) was associated with increased mortality risk. However, the eGFR 60-90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28-2.53) and eGFRcr-cys (1.91; 1.38-2.66) but not eGFRcr (1.20; 0.85-1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (P < 0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (P < 0.001). The addition of cystatin C may improve mortality risk prediction by stages of kidney function relative to creatinine. CKD risk factors are associated with an overestimate of GFR by serum creatinine relative to cystatin C.

Association of a Cystatin C Gene Variant With Cystatin C Levels, CKD, and Risk of Incident Cardiovascular Disease and Mortality

Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality. Observational. 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies. We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305. We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis. In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD. rs13038305 explains only a small proportion of cystatin C variation. Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

A Prospective Study of Frailty in Nephrology-Referred Patients With CKD

Frailty is a construct developed to characterize a state of reduced functional capacity in older adults. However, there are limited data describing the prevalence or consequences of frailty in middle-aged patients with chronic kidney disease (CKD). Observational study. 336 non-dialysis-dependent patients with stages 1-4 CKD with estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m(2) (by the CKD-EPI [CKD Epidemiology Collaboration] serum creatinine-based equation) or evidence of microalbuminuria enrolled in the Seattle Kidney Study, a clinic-based cohort study. Findings were compared with community-dwelling older adults in the Cardiovascular Health Study. Prevalence and determinants of frailty in addition to its association with the combined outcome of all-cause mortality or renal replacement therapy. We defined frailty according to established criteria as 3 or more of the following characteristics: slow gait, weakness, unintentional weight loss, exhaustion, and low physical activity. We estimated kidney function using serum cystatin C concentrations (eGFR(cys)) to minimize confounding due to relationships of serum creatinine levels with muscle mass and frailty. The mean age of the study population was 59 years and mean eGFR(cys) was 51 mL/min/1.73 m(2). The prevalence of frailty (14.0%) was twice that of the much older non-CKD reference population (P < 0.01). The most common frailty components were physical inactivity and exhaustion. After adjustment including diabetes, eGFR(cys) categories of <30 and 30-44 mL/min/1.73 m(2) were associated with a 2.8- (95% CI, 1.3-6.3) and 2.1 (95% CI, 1.0-4.7)-fold greater prevalence of frailty compared with GFR(cys) ≥60 mL/min/1.73 m(2). There were 63 events during a median 987 days of follow-up. After adjustment, the frailty phenotype was associated with an estimated 2.5 (95% CI, 1.4-4.4)-fold greater risk of death or dialysis therapy. Cross-sectional study design obscures inference regarding temporal relationships between CKD and frailty. Frailty is relatively common in middle-aged patients with CKD and is associated with lower eGFR(cys) and increased risk of death or dialysis therapy.