Browsing by Subject "Glomerular Filtration Rate"

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    Association of Different Estimates of Renal Function With Cardiovascular Mortality and Bleeding in Atrial Fibrillation.
    (Journal of the American Heart Association, 2020-09) Hijazi, Ziad; Granger, Christopher B; Hohnloser, Stefan H; Westerbergh, Johan; Lindbäck, Johan; Alexander, John H; Keltai, Matyas; Parkhomenko, Alexander; López-Sendón, José L; Lopes, Renato D; Siegbahn, Agneta; Wallentin, Lars
    Background We compared different methods of estimated glomerular filtration rate (eGFR) and their association with cardiovascular death and major bleeding in 14 980 patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods and Results eGFR was calculated using equations based on creatinine (Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and/or cystatin C (CKD-EPICysC and CKD-EPICysC+Creatinine). These 5 eGFR equations, as well as the individual variables that are used in these equations, were assessed for correlation and discriminatory ability for cardiovascular death and major bleeding. The median age was 70.0 years, and 35.6% were women. The median eGFR was highest with Cockcroft-Gault (74.1 mL/min) and CKD-EPICysC (74.2 mL/min), and lowest with Modification of Diet in Renal Disease (66.5 mL/min). Correlation between methods ranged from 0.49 (Cockroft-Gault and CKD-EPICysC) to 0.99 (Modification of Diet in Renal Disease and CKD-EPI). Among the eGFR equations, those based on cystatin C yielded the highest C indices for cardiovascular death and major bleeding: 0.628 (CKD-EPICysC) and 0.612 (CKD-EPICysC+Creatinine), respectively. A model based on the variables within the different eGFR equations (age, sex, weight, creatinine, and cystatin C) yielded the highest discriminatory value for both outcomes, with a C index of 0.673 and 0.656, respectively. Conclusions In patients with atrial fibrillation on anticoagulation, correlation between eGFR calculated using different methods varied substantially. Cystatin C-based eGFRs seem to provide the most robust information for predicting death and bleeding. A model based on the individual variables within the eGFR equations, however, provided the highest discriminatory value. Our findings may help refine risk stratification in patients with atrial fibrillation and define how renal function should be determined in future atrial fibrillation studies. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00412984.
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    Benefit of Ezetimibe Added to Simvastatin in Reduced Kidney Function.
    (J Am Soc Nephrol, 2017-10) Stanifer, John W; Charytan, David M; White, Jennifer; Lokhnygina, Yuliya; Cannon, Christopher P; Roe, Matthew T; Blazing, Michael A
    Efficacy of statin-based therapies in reducing cardiovascular mortality in individuals with CKD seems to diminish as eGFR declines. The strongest evidence supporting the cardiovascular benefit of statins in individuals with CKD was shown with ezetimibe plus simvastatin versus placebo. However, whether combination therapy or statin alone resulted in cardiovascular benefit is uncertain. Therefore, we estimated GFR in 18,015 individuals from the IMPROVE-IT (ezetimibe plus simvastatin versus simvastatin alone in individuals with cardiovascular disease and creatinine clearance >30 ml/min) and examined post hoc the relationship of eGFR with end points across treatment arms. For the primary end point of cardiovascular death, major coronary event, or nonfatal stroke, the relative risk reduction of combination therapy compared with monotherapy differed by eGFR (P=0.04). The difference in treatment effect was observed at eGFR≤75 ml/min per 1.73 m2 and most apparent at levels ≤60 ml/min per 1.73 m2 Compared with individuals receiving monotherapy, individuals receiving combination therapy with a baseline eGFR of 60 ml/min per 1.73 m2 experienced a 12% risk reduction (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.82 to 0.95); those with a baseline eGFR of 45 ml/min per 1.73 m2 had a 13% risk reduction (HR, 0.87; 95% CI, 0.78 to 0.98). In stabilized individuals within 10 days of acute coronary syndrome, combination therapy seemed to be more effective than monotherapy in individuals with moderately reduced eGFR (30-60 ml/min per 1.73 m2). Further studies examining potential benefits of combination lipid-lowering therapy in individuals with CKD are needed.
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    Concordance With Screening and Treatment Guidelines for Chronic Kidney Disease in Type 2 Diabetes.
    (JAMA network open, 2024-06) Edmonston, Daniel; Lydon, Elizabeth; Mulder, Hillary; Chiswell, Karen; Lampron, Zachary; Marsolo, Keith; Goss, Ashley; Ayoub, Isabelle; Shah, Raj C; Chang, Alexander R; Ford, Daniel E; Jones, W Schuyler; Fonesca, Vivian; Machineni, Sriram; Fort, Daniel; Butler, Javed; Hunt, Kelly J; Pitlosh, Max; Rao, Ajaykumar; Ahmad, Faraz S; Gordon, Howard S; Hung, Adriana M; Hwang, Wenke; Bosworth, Hayden B; Pagidipati, Neha J

    Importance

    Chronic kidney disease (CKD) is an often-asymptomatic complication of type 2 diabetes (T2D) that requires annual screening to diagnose. Patient-level factors linked to inadequate screening and treatment can inform implementation strategies to facilitate guideline-recommended CKD care.

    Objective

    To identify risk factors for nonconcordance with guideline-recommended CKD screening and treatment in patients with T2D.

    Design, setting, and participants

    This retrospective cohort study was performed at 20 health care systems contributing data to the US National Patient-Centered Clinical Research Network. To evaluate concordance with CKD screening guidelines, adults with an outpatient clinician visit linked to T2D diagnosis between January 1, 2015, and December 31, 2020, and without known CKD were included. A separate analysis reviewed prescription of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in adults with CKD (estimated glomerular filtration rate [eGFR] of 30-90 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio [UACR] of 200-5000 mg/g) and an outpatient clinician visit for T2D between October 1, 2019, and December 31, 2020. Data were analyzed from July 8, 2022, through June 22, 2023.

    Exposures

    Demographics, lifestyle factors, comorbidities, medications, and laboratory results.

    Main outcomes and measures

    Screening required measurement of creatinine levels and UACR within 15 months of the index visit. Treatment reflected prescription of ACEIs or ARBs and SGLT2 inhibitors within 12 months before or 6 months following the index visit.

    Results

    Concordance with CKD screening guidelines was assessed in 316 234 adults (median age, 59 [IQR, 50-67] years), of whom 51.5% were women; 21.7%, Black; 10.3%, Hispanic; and 67.6%, White. Only 24.9% received creatinine and UACR screening, 56.5% received 1 screening measurement, and 18.6% received neither. Hispanic ethnicity was associated with lack of screening (relative risk [RR], 1.16 [95% CI, 1.14-1.18]). In contrast, heart failure, peripheral arterial disease, and hypertension were associated with a lower risk of nonconcordance. In 4215 patients with CKD and albuminuria, 3288 (78.0%) received an ACEI or ARB; 194 (4.6%), an SGLT2 inhibitor; and 885 (21.0%), neither therapy. Peripheral arterial disease and lower eGFR were associated with lack of CKD treatment, while diuretic or statin prescription and hypertension were associated with treatment.

    Conclusions and relevance

    In this cohort study of patients with T2D, fewer than one-quarter received recommended CKD screening. In patients with CKD and albuminuria, 21.0% did not receive an SGLT2 inhibitor or an ACEI or an ARB, despite compelling indications. Patient-level factors may inform implementation strategies to improve CKD screening and treatment in people with T2D.
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    Creatinine- versus cystatin C-based renal function assessment in the Northern Manhattan Study.
    (PloS one, 2018-01) Husain, S Ali; Willey, Joshua Z; Park Moon, Yeseon; Elkind, Mitchell SV; Sacco, Ralph L; Wolf, Myles; Cheung, Ken; Wright, Clinton B; Mohan, Sumit
    BACKGROUND:Accurate glomerular filtration rate estimation informs drug dosing and risk stratification. Body composition heterogeneity influences creatinine production and the precision of creatinine-based estimated glomerular filtration rate (eGFRcr) in the elderly. We compared chronic kidney disease (CKD) categorization using eGFRcr and cystatin C-based estimated GFR (eGFRcys) in an elderly, racially/ethnically diverse cohort to determine their concordance. METHODS:The Northern Manhattan Study (NOMAS) is a predominantly elderly, multi-ethnic cohort with a primary aim to study cardiovascular disease epidemiology. We included participants with concurrently measured creatinine and cystatin C. eGFRcr was calculated using the CKD-EPI 2009 equation. eGFRcys was calculated using the CKD-EPI 2012 equation. Logistic regression was used to estimate odds ratios and 95% confidence intervals of factors associated with reclassification from eGFRcr≥60ml/min/1.73m2 to eGFRcys<60ml/min/1.73m2. RESULTS:Participants (n = 2988, mean age 69±10yrs) were predominantly Hispanic, female, and overweight/obese. eGFRcys was lower than eGFRcr by mean 23mL/min/1.73m2. 51% of participants' CKD status was discordant, and only 28% maintained the same CKD stage by both measures. Most participants (78%) had eGFRcr≥60mL/min/1.73m2; among these, 64% had eGFRcys<60mL/min/1.73m2. Among participants with eGFRcr≥60mL/min/1.73m2, eGFRcys-based reclassification was more likely in those with age >65 years, obesity, current smoking, white race, and female sex. CONCLUSIONS:In a large, multiethnic, elderly cohort, we found a highly discrepant prevalence of CKD with eGFRcys versus eGFRcr. Determining the optimal method to estimate GFR in elderly populations needs urgent further study to improve risk stratification and drug dosing.
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    Earlier onset and greater severity of disordered mineral metabolism in diabetic patients with chronic kidney disease.
    (Diabetes care, 2012-05) Wahl, Patricia; Xie, Huiliang; Scialla, Julia; Anderson, Cheryl AM; Bellovich, Keith; Brecklin, Carolyn; Chen, Jing; Feldman, Harold; Gutierrez, Orlando M; Lash, Jim; Leonard, Mary B; Negrea, Lavinia; Rosas, Sylvia E; Anderson, Amanda Hyre; Townsend, Raymond R; Wolf, Myles; Isakova, Tamara; Chronic Renal Insufficiency Cohort Study Group
    Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status.Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30-39 vs. 20-29, P < 0.001; FGF23: eGFR 50-59 vs. 40-49, P < 0.001).Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.
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    Effect of primary care physicians' use of estimated glomerular filtration rate on the timing of their subspecialty referral decisions.
    (BMC Nephrol, 2011-01-14) Greer, Raquel C; Powe, Neil R; Jaar, Bernard G; Troll, Misty U; Boulware, L Ebony
    BACKGROUND: Primary care providers' suboptimal recognition of the severity of chronic kidney disease (CKD) may contribute to untimely referrals of patients with CKD to subspecialty care. It is unknown whether U.S. primary care physicians' use of estimated glomerular filtration rate (eGFR) rather than serum creatinine to estimate CKD severity could improve the timeliness of their subspecialty referral decisions. METHODS: We conducted a cross-sectional study of 154 United States primary care physicians to assess the effect of use of eGFR (versus creatinine) on the timing of their subspecialty referrals. Primary care physicians completed a questionnaire featuring questions regarding a hypothetical White or African American patient with progressing CKD. We asked primary care physicians to identify the serum creatinine and eGFR levels at which they would recommend patients like the hypothetical patient be referred for subspecialty evaluation. We assessed significant improvement in the timing [from eGFR < 30 to ≥ 30 mL/min/1.73m(2)) of their recommended referrals based on their use of creatinine versus eGFR. RESULTS: Primary care physicians recommended subspecialty referrals later (CKD more advanced) when using creatinine versus eGFR to assess kidney function [median eGFR 32 versus 55 mL/min/1.73m(2), p < 0.001]. Forty percent of primary care physicians significantly improved the timing of their referrals when basing their recommendations on eGFR. Improved timing occurred more frequently among primary care physicians practicing in academic (versus non-academic) practices or presented with White (versus African American) hypothetical patients [adjusted percentage(95% CI): 70% (45-87) versus 37% (reference) and 57% (39-73) versus 25% (reference), respectively, both p ≤ 0.01). CONCLUSIONS: Primary care physicians recommended subspecialty referrals earlier when using eGFR (versus creatinine) to assess kidney function. Enhanced use of eGFR by primary care physicians' could lead to more timely subspecialty care and improved clinical outcomes for patients with CKD.
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    Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial.
    (Diabetes care, 2020-08) Perkovic, Vlado; Toto, Robert; Cooper, Mark E; Mann, Johannes FE; Rosenstock, Julio; McGuire, Darren K; Kahn, Steven E; Marx, Nikolaus; Alexander, John H; Zinman, Bernard; Pfarr, Egon; Schnaidt, Sven; Meinicke, Thomas; von Eynatten, Maximillian; George, Jyothis T; Johansen, Odd Erik; Wanner, Christoph; CARMELINA investigators

    Objective

    Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m2) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532).

    Research design and methods

    Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia.

    Results

    A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories.

    Conclusions

    Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c and no difference in AEs were observed.
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    Impact of renal dysfunction on acute coronary syndrome evaluation in observation unit patients.
    (Am J Emerg Med, 2010-07) Limkakeng, Alexander T; Chandra, Abhinav
    OBJECTIVES: The impact of renal disease on risk stratification of patients at low risk for potential acute coronary syndrome has not been well defined. The objective of this study was to document the prevalence of renal dysfunction and assess the association between renal impairment and abnormal cardiac evaluation in observation unit (OU) patients. METHODS: Retrospective cohort study at an academic medical center OU. Data were abstracted using predetermined definitions of data outcomes by trained abstractors. Patients had symptoms consistent with acute coronary syndrome and did not have obvious evidence of acute MI or ischemia on electrocardiogram, unstable vital signs, abnormal cardiac markers, serious arrhythmias, or uncontrollable chest pain. Observation patients received serial cardiac markers and electrocardiograms, with the majority receiving stress testing at treating physician discretion. Patients were stratified by glomerular filtration rates (GFR) at cut-off points of less than 60 and less than 90 mL/min per 1.73 m(2). Odds ratios were calculated for stress test findings of inducible ischemia or hospital admission. RESULTS: Five hundred and twenty-nine out of 545 patients had complete data and were enrolled. Sixty-nine (13%) patients had a GFR of less than 60 and 300 (56%) patients had a GFR of less than 90. An abnormal cardiac evaluation was found in 64 (12%) patients, of whom 31 (49%) had some renal impairment. The odds ratio of an abnormal cardiac evaluation with a GFR of less than 90 is 1.65 (95% confidence interval, 0.95-2.88) and 1.65 (95% confidence interval, 0.83-3.28) for GFR less than 60. CONCLUSIONS: Renal dysfunction is common in OU patients. In these patients, renal dysfunction did not confer higher risk for abnormal cardiac evaluation.
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    In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
    (PLoS Genet, 2015-07) Anderson, Blair R; Howell, David N; Soldano, Karen; Garrett, Melanie E; Katsanis, Nicholas; Telen, Marilyn J; Davis, Erica E; Ashley-Koch, Allison E
    African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.
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    Kidney and Cardiovascular Effectiveness of Empagliflozin Compared With Dipeptidyl Peptidase-4 Inhibitors in Patients With Type 2 Diabetes.
    (The American journal of cardiology, 2024-06) Edmonston, Daniel; Mulder, Hillary; Lydon, Elizabeth; Chiswell, Karen; Lampron, Zachary; Shay, Christina; Marsolo, Keith; Jones, William Schuyler; Butler, Javed; Shah, Raj C; Chamberlain, Alanna M; Ford, Daniel E; Gordon, Howard S; Hwang, Wenke; Chang, Alexander; Rao, Ajaykumar; Bosworth, Hayden B; Pagidipati, Neha
    Placebo-controlled trials of sodium-glucose co-transporter-2 inhibitors demonstrate kidney and cardiovascular benefits for patients with type 2 diabetes and chronic kidney disease (CKD). We used real-world data to compare the kidney and cardiovascular effectiveness of empagliflozin to dipeptidyl peptidase-4 inhibitors (DPP4is), a commonly prescribed antiglycemic medication, in a diverse population with and without CKD. Using electronic health record data from 20 large US health systems, we leveraged propensity overlap weighting to compare the outcomes for empagliflozin and DPP4i initiators with type 2 diabetes between 2016 and 2020. The primary composite kidney outcome included 40% estimated glomerular filtration rate decrease, incident end-stage kidney disease, or all-cause mortality through 2 years or censoring. We also assessed cardiovascular and safety outcomes. Of 62,197 new users, 20,279 initiated empagliflozin and 41,918 initiated DPP4i. Over a median follow-up of 1.1 years, empagliflozin prescription was associated with a lower risk of the primary outcome (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65 to 0.87) than DPP4is. The risks for mortality (HR 0.76, 95% CI 0.62 to 0.92) and a cardiovascular composite of stroke, myocardial infarction, or all-cause mortality (HR 0.81, 95% CI 0.70 to 0.95) were also lower for empagliflozin initiators. No difference in heart failure hospitalization risk between groups was observed. Genital mycotic infections were more common in patients prescribed empagliflozin (HR 1.72, 95% CI 1.58 to 1.88). Empagliflozin was associated with a lower risk of the primary outcome in patients with CKD (HR 0.68, 95% CI 0.53 to 0.88) and those without CKD (HR 0.79, 95% CI 0.67 to 0.94). In conclusion, the initiation of empagliflozin was associated with a significantly lower risk of kidney and cardiovascular outcomes than DPP4is over a median of just over 1 year. The association with a lower risk for clinical outcomes was apparent even for patients without known CKD at baseline.
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    Kidney and Cardiovascular Effectiveness of SGLT2 Inhibitors vs GLP-1 Receptor Agonists in Type 2 Diabetes.
    (Journal of the American College of Cardiology, 2024-08) Edmonston, Daniel; Mulder, Hillary; Lydon, Elizabeth; Chiswell, Karen; Lampron, Zachary; Shay, Christina; Marsolo, Keith; Shah, Raj C; Jones, W Schuyler; Gordon, Howard; Hwang, Wenke; Ayoub, Isabella; Ford, Daniel; Chamberlain, Alanna; Rao, Ajaykumar; Fonseca, Vivian; Chang, Alexander; Ahmad, Faraz; Hung, Adriana; Hunt, Kelly; Butler, Javed; Bosworth, Hayden B; Pagidipati, Neha

    Background

    Emerging data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve kidney outcomes for people with type 2 diabetes (T2D). Direct comparisons of the kidney and cardiovascular effectiveness of GLP-1 RA with sodium-glucose cotransporter 2 inhibitors (SGLT2i), a first-line therapy for this population, are needed.

    Objectives

    The authors compared kidney and cardiovascular outcomes for new users of SGLT2i and GLP-1 RAs with T2D.

    Methods

    Using propensity score overlap weighting, we analyzed electronic health record data from 20 U.S. health systems contributing to PCORnet between 2015 and 2020. The primary kidney outcome was a composite of sustained 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease, or all-cause mortality over 2 years or until censoring. In addition, we examined cardiovascular and safety outcomes.

    Results

    The weighted study cohort included 35,004 SGLT2i and 47,268 GLP-1 RA initiators. Over a median of 1.2 years, the primary outcome did not differ between treatments (HR: 0.91; 95% CI: 0.81-1.02), although SGLT2i were associated with a lower risk of 40% eGFR decline (HR: 0.77; 95% CI: 0.65-0.91). Risks of mortality (HR: 1.08; 95% CI: 0.92-1.27), a composite of stroke, myocardial infarction, or death (HR: 1.03; 95% CI: 0.93-1.14), and heart failure hospitalization (HR: 0.95; 95% CI: 0.80-1.13) did not differ. Genital mycotic infections were more common for SGLT2i initiators, but other safety outcomes did not differ. The results were similar regardless of chronic kidney disease status.

    Conclusions

    SGLT2i and GLP-1 RAs led to similar kidney and cardiovascular outcomes in people with T2D, though SGLT2i initiation was associated with a lower risk of 40% eGFR decline. (Evaluating Comparative Effectiveness of Empagliflozin in Type 2 Diabetes Population With and Without Chronic Kidney Disease; NCT05465317).
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    Patterns of care quality and prognosis among hospitalized ischemic stroke patients with chronic kidney disease.
    (J Am Heart Assoc, 2014-06-05) Ovbiagele, Bruce; Schwamm, Lee H; Smith, Eric E; Grau-Sepulveda, Maria V; Saver, Jeffrey L; Bhatt, Deepak L; Hernandez, Adrian F; Peterson, Eric D; Fonarow, Gregg C
    BACKGROUND: Relatively little is known about the quality of care and outcomes for hospitalized ischemic stroke patients with chronic kidney disease (CKD). We examined quality of care and in-hospital prognoses among patients with CKD in the Get With The Guidelines-Stroke (GWTG-Stroke) program METHODS AND RESULTS: We analyzed 679 827 patients hospitalized with ischemic stroke from 1564 US centers participating in the GWTG-Stroke program between January 2009 and December 2012. Use of 7 predefined ischemic stroke performance measures, composite "defect-free" care compliance, and in-hospital mortality were examined based on glomerular filtration rate (GFR) categorized as a dichotomous (+CKD as <60) or rank-ordered variable: normal (≥ 90), mild (≥ 60 to <90), moderate (≥ 30 to <60), severe (≥ 15 to <30), and kidney failure (<15 or dialysis). There were 236 662 (35%) ischemic stroke patients with CKD. Patients with severe renal dysfunction or failure were significantly less likely to receive guideline-based therapies. Compared with patients with normal kidney function (≥ 90), those with CKD (adjusted OR 0.91 [95% CI: 0.89 to 0.92]), moderate dysfunction (adjusted OR 0.94 [95% CI: 0.92 to 0.97]), severe dysfunction (adjusted OR 0.80 [95% CI: 0.77 to 0.84]), or failure (adjusted OR 0.72 [95% CI: 0.68 to 0.0.76]), were less likely to receive 100% defect-free care measure compliance. Inpatient mortality was higher for patients with CKD (adjusted odds ratio 1.44 [95% CI: 1.40 to 1.47]), and progressively rose with more severe renal dysfunction. CONCLUSIONS: Despite higher in-hospital mortality rates, ischemic stroke patients with CKD, especially those with greater severity of renal dysfunction, were less likely to receive important guideline-recommended therapies.
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    Persistent high serum bicarbonate and the risk of heart failure in patients with chronic kidney disease (CKD): A report from the Chronic Renal Insufficiency Cohort (CRIC) study.
    (Journal of the American Heart Association, 2015-04-20) Dobre, Mirela; Yang, Wei; Pan, Qiang; Appel, Lawrence; Bellovich, Keith; Chen, Jing; Feldman, Harold; Fischer, Michael J; Ham, LL; Hostetter, Thomas; Jaar, Bernard G; Kallem, Radhakrishna R; Rosas, Sylvia E; Scialla, Julia J; Wolf, Myles; Rahman, Mahboob; CRIC Study Investigators
    Serum bicarbonate varies over time in chronic kidney disease (CKD) patients, and this variability may portend poor cardiovascular outcomes. The aim of this study was to conduct a time-updated longitudinal analysis to evaluate the association of serum bicarbonate with long-term clinical outcomes: heart failure, atherosclerotic events, renal events (halving of estimated glomerular filtration rate [eGFR] or end-stage renal disease), and mortality.Serum bicarbonate was measured annually, in 3586 participants with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. Marginal structural models were created to allow for integration of all available bicarbonate measurements and proper adjustment for time-dependent confounding. During the 6 years follow-up, 512 participants developed congestive heart failure (26/1000 person-years) and 749 developed renal events (37/1000 person-years). The risk of heart failure and death was significantly higher for participants who maintained serum bicarbonate >26 mmol/L for the entire duration of follow-up (hazard ratio [HR] 1.66; 95% confidence interval [CI], 1.23 to 2.23, and HR 1.36, 95% CI 1.02 to 1.82, respectively) compared with participants who kept their bicarbonate 22 to 26 mmol/L, after adjusting for demographics, co-morbidities, medications including diuretics, eGFR, and proteinuria. Participants who maintained serum bicarbonate <22 mmol/L had almost a 2-fold increased risk of renal disease progression (HR 1.97; 95% CI, 1.50 to 2.57) compared with participants with bicarbonate 22 to 26 mmol/L.In this large CKD cohort, persistent serum bicarbonate >26 mmol/L was associated with increased risk of heart failure events and mortality. Further studies are needed to determine the optimal range of serum bicarbonate in CKD to prevent adverse clinical outcomes.
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    Racial Differences in the Effectiveness of a Multifactorial Telehealth Intervention to Slow Diabetic Kidney Disease.
    (Medical care, 2020-11) Kobe, Elizabeth A; Diamantidis, Clarissa J; Bosworth, Hayden B; Davenport, Clemontina A; Oakes, Megan; Alexopoulos, Anastasia-Stefania; Pendergast, Jane; Patel, Uptal D; Crowley, Matthew J

    Background

    African Americans are significantly more likely than non-African Americans to have diabetes, chronic kidney disease, and uncontrolled hypertension, increasing their risk for kidney function decline.

    Objective

    The objective of this study was to compare how African Americans and non-African Americans with diabetes responded to a multifactorial telehealth intervention designed to slow kidney function decline.

    Research design

    Secondary analysis of a randomized trial. Primary care patients (N=281, 56% African American) were allocated to either: (1) a multifactorial, pharmacist-delivered phone-based telehealth intervention focused on behavioral and medication management of diabetic kidney disease; or (2) an education control.

    Measures

    The primary study outcome was change in estimated glomerular filtration rate (eGFR). Linear mixed models were used to explore the moderating effect of race on the relationship between study arm and eGFR decline over time; the mean annual rate of eGFR decline was estimated by race and study arm.

    Results

    Findings demonstrated a differential intervention effect on kidney function over time by race (Pinteraction=0.005). Among African Americans, the intervention arm had significantly greater preservation of eGFR over time than the control arm (difference in the annual rate of eGFR decline=1.5 mL/min/1.73 m; 95% confidence interval: 0.04, 3.02). For non-African Americans, the intervention arm had a faster decline in eGFR over time than the control arm (difference in the annual rate of eGFR decline=-1.7 mL/min/1.73 m; 95% confidence interval: -3.3, -0.02).

    Conclusion

    A multifactorial, pharmacist-delivered telehealth intervention for diabetic kidney disease may be more effective for slowing eGFR decline among African Americans than non-African Americans.
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    Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.
    (Cardiovascular diabetology, 2018-03-14) Rosenstock, Julio; Perkovic, Vlado; Alexander, John H; Cooper, Mark E; Marx, Nikolaus; Pencina, Michael J; Toto, Robert D; Wanner, Christoph; Zinman, Bernard; Baanstra, David; Pfarr, Egon; Mattheus, Michaela; Broedl, Uli C; Woerle, Hans-Juergen; George, Jyothis T; von Eynatten, Maximilian; McGuire, Darren K; CARMELINA® investigators
    BACKGROUND:Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. METHODS:CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. RESULTS:Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. CONCLUSIONS:CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.
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    Renal Dysfunction and In-Hospital Outcomes in Patients With Acute Ischemic Stroke After Intravenous Thrombolytic Therapy.
    (Journal of the American Heart Association, 2019-10-09) Rao, Zhen-Zhen; Gu, Hong-Qiu; Wang, Xian-Wei; Xie, Xue-Wei; Yang, Xin; Wang, Chun-Juan; Zhao, Xingquan; Xian, Ying; Wang, Yi-Long; Li, Zi-Xiao; Xiao, Rui-Ping; Wang, Yong-Jun; Chinese Stroke Center Alliance investigators
    Background The impact of estimated glomerular filtration rate (eGFR) on clinical short-term outcomes after stroke thrombolysis with tissue plasminogen activator remains controversial. Methods and Results We analyzed 18 320 ischemic stroke patients who received intravenous tissue plasminogen activator at participating hospitals in the Chinese Stroke Center Alliance between June 2015 and November 2017. Multivariate logistic regression models were used to evaluate associations between eGFR (<45, 45-59, 60-89, and ≥90 mL/min per 1.73 m2) and in-hospital mortality and symptomatic intracerebral hemorrhage, adjusting for patient and hospital characteristics and the hospital clustering effect. Of the 18 320 patients receiving tissue plasminogen activator, 601 (3.3%) had an eGFR <45, 625 (3.4%) had an eGFR 45 to 59, 3679 (20.1%) had an eGFR 60 to 89, and 13 415 (73.2%) had an eGFR ≥90. As compared with eGFR ≥90, eGFR values <45 (6.7% versus 0.9%, adjusted odds ratio, 3.59; 95% CI, 2.18-5.91), 45 to 59 (4.0% versus 0.9%, adjusted odds ratio, 2.00; 95% CI, 1.18-3.38), and 60 to 89 (2.5% versus 0.9%, adjusted odds ratio, 1.67; 95% CI, 1.20-2.34) were independently associated with increased odds of in-hospital mortality. However, there was no statistically significant association between eGFR and symptomatic intracerebral hemorrhage. Conclusions eGFR was associated with an increased risk of in-hospital mortality in acute ischemic stroke patients after treatment with tissue plasminogen activator. eGFR is an important predictor of poststroke short-term death but not of symptomatic intracerebral hemorrhage.
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    Risk Factors for Heart Failure in Patients With Chronic Kidney Disease: The CRIC (Chronic Renal Insufficiency Cohort) Study.
    (Journal of the American Heart Association, 2017-05-17) He, Jiang; Shlipak, Michael; Anderson, Amanda; Roy, Jason A; Feldman, Harold I; Kallem, Radhakrishna Reddy; Kanthety, Radhika; Kusek, John W; Ojo, Akinlolu; Rahman, Mahboob; Ricardo, Ana C; Soliman, Elsayed Z; Wolf, Myles; Zhang, Xiaoming; Raj, Dominic; Hamm, Lee; CRIC (Chronic Renal Insufficiency Cohort) Investigators
    BACKGROUND:Heart failure is common in patients with chronic kidney disease. We studied risk factors for incident heart failure among 3557 participants in the CRIC (Chronic Renal Insufficiency Cohort) Study. METHODS AND RESULTS:Kidney function was assessed by estimated glomerular filtration rate (eGFR) using serum creatinine, cystatin C, or both, and 24-hour urine albumin excretion. During an average of 6.3 years of follow-up, 452 participants developed incident heart failure. After adjustment for age, sex, race, and clinical site, hazard ratio (95% CI) for heart failure associated with 1 SD lower creatinine-based eGFR was 1.67 (1.49, 1.89), 1 SD lower cystatin C-based-eGFR was 2.43 (2.10, 2.80), and 1 SD higher log-albuminuria was 1.65 (1.53, 1.78), all P<0.001. When all 3 kidney function measures were simultaneously included in the model, lower cystatin C-based eGFR and higher log-albuminuria remained significantly and directly associated with incidence of heart failure. After adjusting for eGFR, albuminuria, and other traditional cardiovascular risk factors, anemia (1.37, 95% CI 1.09, 1.72, P=0.006), insulin resistance (1.16, 95% CI 1.04, 1.28, P=0.006), hemoglobin A1c (1.27, 95% CI 1.14, 1.41, P<0.001), interleukin-6 (1.15, 95% CI 1.05, 1.25, P=0.002), and tumor necrosis factor-α (1.10, 95% CI 1.00, 1.21, P=0.05) were all significantly and directly associated with incidence of heart failure. CONCLUSIONS:Our study indicates that cystatin C-based eGFR and albuminuria are better predictors for risk of heart failure compared to creatinine-based eGFR. Furthermore, anemia, insulin resistance, inflammation, and poor glycemic control are independent risk factors for the development of heart failure among patients with chronic kidney disease.
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    The comparison of the commonly used surrogates for baseline renal function in acute kidney injury diagnosis and staging.
    (BMC nephrology, 2016-01) Thongprayoon, Charat; Cheungpasitporn, Wisit; Harrison, Andrew M; Kittanamongkolchai, Wonngarm; Ungprasert, Patompong; Srivali, Narat; Akhoundi, Abbasali; Kashani, Kianoush B

    Background

    Baseline serum creatinine (SCr) level is frequently not measured in clinical practice. The aim of this study was to investigate the effect of various methods of baseline SCr determination measurement on accuracy of acute kidney injury (AKI) diagnosis in critically ill patients.

    Methods

    This was a retrospective cohort study. All adult intensive care unit (ICU) patients admitted at a tertiary referral hospital from January 1, 2011 through December 31, 2011, with at least one measured SCr value during ICU stay, were included in this study. The baseline SCr was considered either an admission SCr (SCrADM) or an estimated SCr, using MDRD formula, based on an assumed glomerular filtration rate (GFR) of 75 ml/min/1.73 m(2) (SCrGFR-75). Determination of AKI was based on the KDIGO SCr criterion. Propensity score to predict the likelihood of missing SCr was used to generate a simulated cohort of 3566 patients with baseline outpatient SCr, who had similar characteristics with patients whose outpatient SCr was not available.

    Results

    Of 7772 patients, 3504 (45.1 %) did not have baseline outpatient SCr. Among patients without baseline outpatient SCr, AKI was detected in 571 (16.3 %) using the SCrADM and 997 (28.4 %) using SCrGFR-75 (p < .001). Compared with non-AKI patients, patients who met AKI only by SCrADM, but not SCrGFR-75, were significantly associated with 60-day mortality (OR 2.90; 95 % CI 1.66-4.87), whereas patients who met AKI only by SCrGFR-75, but not SCrADM, had a non-significant increase in 60-day mortality risk (OR 1.33; 95 % CI 0.94-1.88). In a simulated cohort of patients with baseline outpatient SCr, SCrGFR-75 yielded a higher sensitivity (77.2 vs. 50.5 %) and lower specificity (87.8 vs. 94.8 %) for the AKI diagnosis in comparison with SCrADM.

    Conclusions

    When baseline outpatient SCr was not available, using SCrGFR-75 as surrogate for baseline SCr was found to be more sensitive but less specific for AKI diagnosis compared with using SCrADM. This resulted in higher incidence of AKI with larger likelihood of false-positive cases.
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    Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease.
    (Metabolomics : Official journal of the Metabolomic Society, 2021-12) Lunyera, Joseph; Diamantidis, Clarissa J; Bosworth, Hayden B; Patel, Uptal D; Bain, James; Muehlbauer, Michael J; Ilkayeva, Olga; Nguyen, Maggie; Sharma, Binu; Ma, Jennie Z; Shah, Svati H; Scialla, Julia J

    Introduction

    Urine tricarboxylic acid (TCA) cycle organic anions (OAs) are elevated in diabetes and may be biomarkers for diabetic kidney disease (DKD) progression.

    Objectives

    We assessed associations of 10 urine TCA cycle OAs with estimated glomerular filtration rate (eGFR) and eGFR slope.

    Methods

    This study is ancillary to the Simultaneous Risk Factor Control Using Telehealth to SlOw Progression of Diabetic Kidney Disease (STOP-DKD) Trial-a randomized trial of pharmacist-led medication and behavior management in 281 patients with early to moderate DKD at Duke from 2014 to 2015. We used linear mixed models to assess associations of urine TCA cycle OAs with outcomes and modelled TCA cycle OAs as: (1) the average of z-scores for each OA; and (2) principal component (PC) scores derived by principal component analysis (PCA). Untargeted urine metabolomics were added for additional discovery.

    Results

    Among 132 participants with 24 h urine samples (50% men; 58% Black; mean age 64 years [SD 9]; mean eGFR 74 ml/min/1.73m2 [SD 21] and median urine albumin-to-creatinine [UACR] 20 mg/g [IQR 8-95]), PCA identified 3 OA metabolite PCs. Malate, fumarate, pyruvate, α-ketoglutarate, lactate, succinate and citrate/isocitrate loaded positively on PC1; methylsuccinate, ethylmalonate and succinate loaded positively on PC2; and methylmalonate, ethylmalonate and citrate/isocitrate loaded negatively on PC3. Over a median follow-up of 1.8 years (IQR, 1.2 to 2.2), higher average OA z-score was strongly associated with higher eGFR after covariate adjustment (p = 0.01), but not with eGFR slope (p = 0.9). Higher PC3, but not other PCs, was associated with lower eGFR (p < 0.001). Conditional random forests and smooth clipped absolute deviation models confirmed methylmalonate, citrate/isocitrate, and ethylmalonate, and added lactate as top ranked metabolites in models of baseline eGFR (R-squared 0.32 and 0.33, respectively). Untargeted urine metabolites confirmed association of urine TCA cycle OAs with kidney function.

    Conclusion

    Thus, lower urine TCA cycle OAs, most notably lower methylmalonate, ethylmalonate and citrate/isocitrate, are potential indicators of kidney impairment in early stage DKD.