CKD Events Research Articles

Cost-effectiveness of semaglutide in people with obesity and cardiovascular disease without diabetes

Aims The cardioprotective effects of semaglutide 2.4 mg reported in the SELECT cardiovascular (CV) outcomes trial (ClinicalTrials.gov NCT03574597) provide clinical benefit for subjects with overweight or obesity and established CV disease without type 2 diabetes (T2D). We assessed cost-effectiveness of semaglutide 2.4 mg in this population against the American College of Cardiology/American Heart Association value framework. Materials and methods A cohort-level Markov-state cost-effectiveness model using trial-derived data with outcomes from a healthcare sector perspective measured over a lifetime horizon was developed. Treatment costs were based on US list prices; scenario analyses used literature-reported estimated rebates. Healthcare costs and benefits were discounted at 3.0%. A simulated cohort of 100,000 subjects was aligned to the SELECT trial population baseline characteristics and time-on-treatment. Subjects received either semaglutide 2.4 mg or placebo in addition to standard of care (SoC). Modelled outcomes included clinical events (CV events, progression to T2D, chronic kidney disease [CKD]) and health economic measures, including direct costs and quality-adjusted life years (QALYs). Results Mean semaglutide 2.4 mg treatment duration was 2.79 years. Per 100,000 subjects, treatment avoided 2,791 non-fatal myocardial infarctions, 3,000 coronary revascularizations, 487 non-fatal strokes, and 115 CV deaths over the modeled lifetime horizon. Average per-subject lifetime treatment costs were $47,353; savings arose from avoided T2D ($14,431), CKD ($2,074), and CV events ($1,512). Semaglutide 2.4 mg was associated with increased lifetime costs ($29,767), additional QALYs gained (0.218) and an incremental cost-effectiveness ratio of $136,271/QALY at list price; a scenario using an empirically estimated 48% rebate predicted $32,219/QALY. Limitations The generalizability of observations from SELECT to a broader US population is unknown. Our model does not capture all outcomes nor costs that may be affected by weight loss. Modeling assumptions may present limitations. Conclusions Semaglutide 2.4 mg use as in SELECT is cost-effective at list price, using a $150,000/QALY willingness-to-pay threshold.

Plasma Ceramides and Risk of Cardiovascular Events in CKD

Plasma Ceramides and Risk of Cardiovascular Events in CKD

The Gut Microbial Metabolite Trimethylamine N -oxide, Incident CKD, and Kidney Function Decline.

Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline. We included 10,564 participants from two community-based, prospective cohorts with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 to assess incident CKD. TMAO was measured using targeted mass spectrometry at baseline and one follow-up visit. Creatinine and Cystatin C were measured up to 4 times during follow-up and used to compute eGFR. Incident CKD was defined as an eGFR decline ≥ 30% from baseline and a resulting eGFR<60 ml/min/1.73 m2. Time-varying Cox models assessed the association of serial TMAO measures with incident CKD, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors. Linear mixed models assessed the association with annualized eGFR change in 10,009 participants with at least one follow-up eGFR measure without exclusions for baseline eGFR levels. During a median follow-up of 9.4 years (interquartile range: 9.1-11.6 years), 979 incident CKD events occurred. Higher TMAO levels associated with higher risk of incident CKD (2nd to 5th vs. 1st quintile HR[95%CI]= 1.65 [1.22-2.23], 1.68 [1.26-2.25], 2.28 [1.72-3.02], and 2.24[1.68-2.98], respectively) and greater annualized eGFR decline ( 2nd to 5th vs. 1st quintile annualized eGFR change= -0.21 [-0.32, -0.09], -0.17 [-0.29, -0.05], -0.35 [-0.47, -0.22], and -0.43[-0.56, -0.30], respectively) with monotonic dose-response relationships. These associations were consistent across different racial/ethnic groups examined. The association with eGFR decline was similar to or larger than that seen for established CKD risk factors including diabetes, per 10 mmHg of higher systolic blood pressure, per 10 years of older age, and Black race. In community-based US adults, higher serial measures of plasma TMAO were associated with higher risk of incident CKD and greater annualized kidney function decline.

Tubular and Glomerular Size by Cortex Depth as Predictor of Progressive CKD after Radical Nephrectomy for Tumor.

Glomerular size differs by cortex depth. Larger nephrons are prognostic of progressive kidney disease, but it is unknown whether this risk differs by cortex depth or by glomeruli versus proximal or distal tubule size. We studied the average minor axis diameter in oval proximal and distal tubules separately and by cortex depth in patients who had radical nephrectomy to remove a tumor from 2019 to 2020. In adjusted analyses, larger glomerular volume in the middle and deep cortex predicted progressive kidney disease. Wider proximal tubular diameter did not predict progressive kidney disease independent of glomerular volume. Wider distal tubular diameter showed a gradient of strength of prediction of progressive kidney disease in the more superficial cortex than in the deep cortex. Larger nephrons are prognostic of progressive kidney disease, but whether this risk differs by nephron segments or by depth in the cortex is unclear. We studied patients who underwent radical nephrectomy for a tumor between 2000 and 2019. Large wedge kidney sections were scanned into digital images. We estimated the diameters of proximal and distal tubules by the minor axis of oval tubular profiles and estimated glomerular volume with the Weibel-Gomez stereological model. Analyses were performed separately in the superficial, middle, and deep cortex. Cox proportional hazard models assessed the risk of progressive CKD (dialysis, kidney transplantation, sustained eGFR <10 ml/min per 1.73 m 2 , or a sustained 40% decline from the postnephrectomy baseline eGFR) with glomerular volume or tubule diameters. At each cortical depth, models were unadjusted, adjusted for glomerular volume or tubular diameter, and further adjusted for clinical characteristics (age, sex, body mass index, hypertension, diabetes, postnephrectomy baseline eGFR, and proteinuria). Among 1367 patients were 62 progressive CKD events during a median follow-up of 4.5 years. Glomerular volume predicted CKD outcomes at all depths, but only in the middle and deep cortex after adjusted analyses. Proximal tubular diameter also predicted progressive CKD at any depth but not after adjusted analyses. Distal tubular diameter showed a gradient of more strongly predicting progressive CKD in the superficial than deep cortex, even in adjusted analysis. Larger glomeruli are independent predictors of progressive CKD in the deeper cortex, whereas in the superficial cortex, wider distal tubular diameters are an independent predictor of progressive CKD.

Joint Modeling of Clinical and Biomarker Data in Acute Kidney Injury Defines Unique Subphenotypes with Differing Outcomes.

AKI is a heterogeneous syndrome. Current subphenotyping approaches have only used limited laboratory data to understand a much more complex condition. We focused on patients with AKI from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI). We used hierarchical clustering with Ward linkage on biomarkers of inflammation, injury, and repair/health. We then evaluated clinical differences between subphenotypes and examined their associations with cardiorenal events and death using Cox proportional hazard models. We included 748 patients with AKI: 543 (73%) of them had AKI stage 1, 112 (15%) had AKI stage 2, and 93 (12%) had AKI stage 3. The mean age (±SD) was 64 (13) years; 508 (68%) were men; and the median follow-up was 4.7 (Q1: 2.9, Q3: 5.7) years. Patients with AKI subphenotype 1 ( N =181) had the highest kidney injury molecule (KIM-1) and troponin T levels. Subphenotype 2 ( N =250) had the highest levels of uromodulin. AKI subphenotype 3 ( N =159) comprised patients with markedly high pro-brain natriuretic peptide and plasma tumor necrosis factor receptor-1 and -2 and low concentrations of KIM-1 and neutrophil gelatinase-associated lipocalin. Finally, patients with subphenotype 4 ( N =158) predominantly had sepsis-AKI and the highest levels of vascular/kidney inflammation (YKL-40, MCP-1) and injury (neutrophil gelatinase-associated lipocalin, KIM-1). AKI subphenotypes 3 and 4 were independently associated with a higher risk of death compared with subphenotype 2 and had adjusted hazard ratios of 2.9 (95% confidence interval, 1.8 to 4.6) and 1.6 (95% confidence interval, 1.01 to 2.6, P = 0.04), respectively. Subphenotype 3 was also independently associated with a three-fold risk of CKD and cardiovascular events. We discovered four AKI subphenotypes with differing clinical features and biomarker profiles that are associated with longitudinal clinical outcomes.

FREQUENCY OF LEFT VENTRICULAR DIASTOLIC DYSFUCTION IN END STAGE RENAL DISEASE PATIENTS ON HEMODIALYSIS

INTRODUCTION:&#x0D; Cardiovascular diseases represent the main cause of morbidity and mortality in patients with chronic kidney disease (CKD. Left ventricular hypertrophy (LVH) represents a key&#x0D; feature to provide an accurate picture of systolic-diastolic left heart involvement in CKD&#x0D; patients.&#x0D; &#x0D; OBJECTIVE:&#x0D; &#x0D; To determine the frequency of left ventricular diastolic dysfunction in end stage renal disease patients on hemodialysis.&#x0D; &#x0D; Material and Methods: Descriptive Cross Sectional was conducted at Department of&#x0D; Nephrology, Institute of Kidney Diseases Peshawar from 11th July 2018 to 10th January&#x0D; &#x0D; All the patients were stabilized and after initial stabilization and treatment of these patients, written informed consent was obtained from them. Echocardiogram was&#x0D; &#x0D; performed by consultant cardiologist in order to look for the presence of LV dysfunction. LV systolic dysfunction considered depressed when left ventricular ejection fraction (LVEF) was found less than 45%. Clinical and electrocardiographic evidences of valvular heart disease, heart failure (EF&lt;50%) and myocardial ischemia were excluded from this study.&#x0D; &#x0D; RESULTS:&#x0D; &#x0D; As per frequencies and percentages for LVDD, 121 (87.68%) patients were recorded with&#x0D; LVDD.&#x0D; &#x0D; CONCLUSION:&#x0D; &#x0D; In this study, we concluded that LVDD is a typical feature of CKD-related cardiomyopathy as LVDD and myocardial fibrosis are associated with mortality risk and cardiovascular events in CKD and ESRD as demonstrated by higher rates of sudden cardiac death in these patients.

Renal functional and cardiovascular outcomes of partial nephrectomy versus radical nephrectomy for renal tumors: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the postoperative renal and cardiovascular outcomes of partial nephrectomy (PN) versus radical nephrectomy (RN) for the treatment of renal carcinoma. A systematic literature search was performed on scientific databases including Scopus, Web of Science, MEDLINE, and EMBASE from their inception to September 2021. Studies comparing renal and cardiovascular outcomes between PN and RN in patients with renal cancer were included. The generic inverse variance method with random-effects models was used to determine the pooled hazard ratios and odds ratio for each outcome. Quality Assessment for observational studies was guided by the New-Castle Ottawa Scale. Overall, a total of 31 studies (n=51,866) reported renal outcomes, while 11 studies (n= 101,678) reported cardiovascular outcomes. When compared to PN, RN had a higher rate of new-onset postoperative EGFR <60 mL/min/1.73 m2 (HR 3.39; CI 2.45 - 4.70; I2=93%; P=<0.00001) and EGFR <45 mL/min/1.73 m2 (HR 4.70; CI 2.26 - 9.79; I2=98%; P=<0.0001). No difference was observed in new-onset advanced kidney disease and end-stage renal disease. A 19% reduction in cardiovascular events was observed in the PN group (HR 0.81; CI 0.70 - 0.93, P=0.002). No protective effect of PN was observed in new-onset or worsening hypertension (HR 0.85; CI 0.64 - 1.14, P=0.28) nor myocardial infarction (HR 0.86; CI 0.71 - 1.04, P=0.13). PN was associated with a decreased risk of postoperative early-stage CKD and cardiovascular events compared with RN. However, no benefit of PN over RN was observed in advanced CKD, new-onset or worsening hypertension, myocardial infarction, and cardiovascular mortality.

JS-HR-2: HYPERTENSION MANAGEMENT IN CKD: UPDATE FOR BETTER CARDIO-RENAL OUTCOMES

Hypertension in CKD patients is a risk factor for end-stage renal disease, cardiovascular events, and mortality. Thus, the prevention and appropriate management of hypertension in these patients are essential strategies for better cardio-renal outcomes. Recently, novel risk factors for hypertension have been reported. Circulating fibroblast growth factor 21, an endocrine hormone mainly secreted by the liver, is associated with elevated blood pressure (BP) and/or aortic stiffness with renal dysfunction. Furthermore, several promising prognostic markers for cardio-renal outcomes have been suggested. A higher urinary sodium-to-potassium ratio was independently associated with poor renal outcomes in CKD patients. Higher albumin-to-creatinine ratios significantly increased the risk of first stroke or first ischemic stroke. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and mineralocorticoid receptor (MR) blockers are promising treatment options for better cardio-renal outcomes. The clinical use of SGLT2is has recently expanded to non-diabetic patients with CKD and heart failure as well as diabetic patients. SGLT2is have an antihypertensive effect, and the degree of BP change in patients undergoing SGLT2i therapy depends on the baseline BP; a larger reduction is observed in patients with higher baseline BP, and a minor reduction or slight increase is observed in patients with lower baseline BP. These BP regulation mechanisms may partially depend on body fluid homeostasis by SGLT2is. SGLT2is ameliorate fluid retention through osmotic diuresis and natriuresis, but are also associated with a low rate of hypovolemia, which is evident by the compensatory upregulation of renin and vasopressin levels. These fluid homeostatic mechanisms exerted by SGLT2is may contribute to the stabilization of BP and better cardio-renal outcomes. MR blockers are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR antagonist, finerenone, has been launched as a treatment for CKD with type 2 diabetes. In the FIDELIO-DKD study, finerenone significantly reduced the risk of kidney and cardiovascular events in CKD and type 2 diabetes.

Gender-Specific Risk of Atheromatous and Non-Atheromatous Cardiovascular Events in CKD

Gender-Specific Risk of Atheromatous and Non-Atheromatous Cardiovascular Events in CKD

Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies.

Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment. We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria. Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis >50% in discriminating risk of ESKD or progressive CKD. Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.

Association of combined fractional excretion of phosphate and FGF23 with heart failure and cardiovascular events in moderate and advanced renal disease.

High levels of FGF23 associate with adverse events in CKD. The urinary fractional excretion of phosphate (FePi) might modify this association, although data are limited in moderate and advanced CKD. We investigated the association of combined FePi and serum FGF23 with incident heart failure, cardiovascular events and mortality in patients withCKD stages2-4. Patients from the Chronic Renal Insufficiency Cohort were divided into four groups according to the median of FePi and FGF23: low-FePi/low-FGF23, reference group; high-FePi/low-FGF23; low-FePi/high-FGF23; high-FePi/high-FGF23. Primary outcomes were: the composite of cardiovascular death or hospitalization for heart failure; cardiovascular death; hospitalization for heart failure; and death from any cause. Survival analysis and adjusted regression analyses were performed. We analyzed 3684 patients with a mean age of 58 ± 11years of whom 45% were male. Mean eGFR was 44 ± 15ml/min/1.73m2. The median time of follow-up was 12 (IQR 7-13) years. The risk of the composite of cardiovascular death or hospitalization for heart failure was increased in the low-FePi/high-FGF23 group (HR 1.35; 95%CI 1.09-1.67) and in the high-FePi/high-FGF23 group (HR 1.50; 95%CI 1.20-1.86), compared to the low-FePi/low-FGF23 group. Cardiovascular death and hospitalization for heart failure were also increased in both groups with high FGF23. Death from any cause was increased in the low-FePi/high-FGF23 group (HR 1.56 (95%CI 1.30-1.89) and in the high-FePi/high-FGF23 (HR 1.57 (95%CI 1.29-1.90)). High FGF23 was associated with heart failure and cardiovascular death in patients with low FePi and high FePi with moderate to advanced CKD. This contrasts with reports in mild CKD.

11-LB: A Prediction Model on Incident CKD among Individuals with T2D in the United States

CKD is highly prevalent and costly in individuals with diabetes. Clinicians need to have a tool for early identification and prediction of incident CKD in individuals with diabetes. This study aimed to predict incident CKD among individuals with diabetes. A time-varying Cox model was derived from the ACCORD clinical trial data to predict the risk of incident CKD, defined as eGFR&amp;lt;60 mL/min/1.73 m2 or UACR&amp;gt;30 mg/g lasting for 3 months. A list of candidate variables was chosen based on literature reviews and experts’ consultation, including demographic characteristics, physical exam, laboratory, medical history, drug use, and healthcare utilization. Predictors were selected from candidate variables using a stepwise algorithm. Data were split into training and validation set. Model performance was evaluated by Brier score (BS) and C statistics. Confidence intervals (CI) was calculated using a bootstrap method. Decomposition analysis was conducted to assess the predictor contribution. External validation was performed on patient-level data of HARMONY Outcome clinical trial. A total of 6,006 diabetes patients free of CKD at baseline were used for model development, with a median follow-up of 3 years and 2,257 new onset CKD events. The CKD risk model identified age at T2D diagnosed, smoking status, BMI, HDL, VLDL, ALT, eGFR, UACR, hypoglycemia event, retinopathy event, CHF event, CHD history, antihyperlipidemic drug use, antihypertensive drug use, and hospitalization. The model demonstrated good discrimination (C-statistics 0.828 [95% CI 0.812-0.845]) and calibration (BS 0.0552 [95% CI 0.0474-0.0593]) performance. UACR, eGFR, and CHF event were the top 3 factors that contributed most to the prediction. A total of 8,221 patients free of CKD was selected from HARMONY Outcome trial with 1,288 CKD events and median follow-up of 2 years. The model demonstrated acceptable discrimination (C-statistics: 0.772 [95% CI 0.767-0.805]) and calibration (BS: 0.0504 [95% CI 0.0477-0.0531]) in external data. A risk prediction of incident CKD among T2D patients was developed and validated for use in decision support of CKD prevention. Disclosure Y. Lin: None. H. Shao: Board Member; BRAVO4HEALTH, LLC. A. H. Anderson: None. V. Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. V. Batuman: None. L. Shi: None.

MO566: Relationship Between Cholesterol Intake and Development of Chronic Kidney Disease: A Community-Based Prospective Cohort Study

Abstract BACKGROUND AND AIMS Globally, the incidence and prevalence of CKD have been increased. Also, CKD DALYs and death due to CKD have been increased (DALYs: The disability-adjusted life-year).[1] CKD puts a lot of mental and economic burden on an individual’s life and lowers the quality of life.[2] As CKD progress, kidney-specific risk factor for cardiovascular events and disease are increased.[3] Dyslipidemia is generally known to be associated with the development and progression of chronic kidney disease.[4] However, it is unclear whether limiting cholesterol intake helps prevent CKD. Recent studies have reported that there is no association between cholesterol intake and cardiovascular disease.[5] The aim of our study is to analyze the relationship between cholesterol intake and the development of CKD in a general population. METHOD We included 9226 subjects without CKD from the Korean Genome and Epidemiology Study. The amount of daily cholesterol intake was assessed by food frequency questionnaire. The primary outcome was the development of CKD, which was defined as an estimated glomerular filtration rate (eGFR) of &amp;lt; 60 mL/min/1.73 m2 and/or proteinuria (≥1+). RESULTS The mean age was 55.7 ± 8.8 years and 39.6% of subjects were men. The cholesterol intake was only significantly correlated with serum HDL cholesterol but not with total and non-HDL cholesterol. Moreover, this significant relationship was disappeared after adjusting for daily fat intake. During median follow-up duration of 11.4 years, 778 (8.5%) CKD events occurred. In multivariable Cox analysis, serum total cholesterol was significantly associated with incident CKD (hazard ratio [HR] 1.005, 95% confidence interval [CI]: 1.003–1.007; P &amp;lt; 0.001). However, cholesterol intake was not associated with incident CKD both in subjects with dyslipidemia (HR: 1.001; 95% CI: 1.000–1.002; P = 0.205) and without dyslipidemia (HR: 0.999; 95% CI: 0.997–1.000; P = 0.134). CONCLUSION Cholesterol intake was not correlated with serum cholesterol levels with considering fat intake. In addition, cholesterol intake was not associated with increased risk of CKD in the general population. Therefore, it may not be necessary to limit cholesterol intake to prevent CKD in this population.

Framingham Risk Score and ACC/AHA Pooled Cohort Equation for Prediction of Atherosclerotic Cardiovascular Events in CKD

Framingham Risk Score and ACC/AHA Pooled Cohort Equation for Prediction of Atherosclerotic Cardiovascular Events in CKD

A Higher Foci Density of Interstitial Fibrosis and Tubular Atrophy Predicts Progressive CKD after a Radical Nephrectomy for Tumor.

Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000-2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm2 cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6-12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics. Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m2), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

Chronic kidney disease, atherosclerotic plaque characteristics on carotid magnetic resonance imaging, and cardiovascular outcomes

BackgroundIt is unclear whether faster progression of atherosclerosis explains the higher risk of cardiovascular events in CKD. The objectives of this study were to 1. Characterize the associations of CKD with presence and morphology of atherosclerotic plaques on carotid magnetic resonance imaging (MRI) and 2. Examine the associations of baseline CKD and carotid atherosclerotic plaques with subsequent cardiovascular events.MethodsIn a subgroup (N = 465) of Systolic Blood Pressure Intervention Trial.(SPRINT) participants, we measured carotid plaque presence and morphology at baseline and after 30-months with MRI. We examined the associations of CKD (baseline eGFR < 60 ml/min/1.73m2) with progression of carotid plaques and the SPRINT cardiovascular endpoint.ResultsOne hundred and ninety six (42%) participants had CKD. Baseline eGFR in the non-CKD and CKD subgroups were 77 ± 14 and 49 ± 8 ml/min/1.73 m2, respectively. Lipid rich necrotic-core plaque was present in 137 (29.5%) participants. In 323 participants with both baseline and follow-up MRI measurements of maximum wall thickness, CKD was not associated with progression of maximum wall thickness (OR 0.62, 95% CI 0.36 to 1.07, p = 0.082). In 96 participants with necrotic core plaque at baseline and with a valid follow-up MRI, CKD was associated with lower odds of progression of necrotic core plaque (OR 0.41, 95% CI 0.17 to 0.95, p = 0.039). There were 28 cardiovascular events over 1764 person-years of follow-up. In separate Cox models, necrotic core plaque (HR 2.59, 95% CI 1.15 to 5.85) but not plaque defined by maximum wall thickness or presence of a plaque component (HR 1.79, 95% CI 0.73 to 4.43) was associated with cardiovascular events. Independent of necrotic core plaque, CKD (HR 3.35, 95% CI 1.40 to 7.99) was associated with cardiovascular events.ConclusionsPresence of necrotic core in carotid plaque rather than the presence of plaque per se was associated with increased risk of cardiovascular events. We did not find CKD to be associated with faster progression of necrotic core plaques, although both were independently associated with cardiovascular events. Thus, CKD may contribute to cardiovascular disease principally via mechanisms other than atherosclerosis such as arterial media calcification or stiffening.Trial RegistrationNCT01475747, registered on November 21, 2011.

Larger Nephron Size and Nephrosclerosis Predict Progressive CKD and Mortality after Radical Nephrectomy for Tumor and Independent of Kidney Function.

Nephron hypertrophy and nephrosclerosis may be important determinants of CKD and mortality. However, studies of outcomes associated with these microstructural features have been limited to small tissue specimens from patients selected for either good kidney health or known kidney disease. To determine whether microstructural features are predictive of progressive CKD and mortality outcomes, we studied patients who underwent a radical nephrectomy for a tumor. Large wedge sections of renal parenchyma distal to the tumor were stained and scanned into high-resolution images; we annotated the cortex and all glomeruli to calculate glomerular volume, cortex volume per glomerulus, and percentage of globally sclerotic glomeruli. Morphometric measurements also included percentages of artery luminal stenosis and interstitial fibrosis/tubular atrophy (IF/TA) of the cortex. At follow-up visits every 6-12 months, we determined which patients experienced progressive CKD (defined as dialysis, kidney transplantation, or a 40% decline from postnephrectomy eGFR). Cox models for these outcomes were adjusted for age, sex, body mass index, hypertension, diabetes, smoking, eGFR, and proteinuria. Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73 m2), 117 progressive CKD events, 183 noncancer deaths, and 116 cancer deaths occurred during a median follow-up of 6.4 years. Larger glomerular volume, larger cortex per glomerulus, and higher percentage of globally sclerotic glomeruli or IF/TA predicted progressive CKD. Higher percentage IF/TA also predicted noncancer mortality. Microstructural features did not predict cancer mortality or recurrence. After a radical nephrectomy, larger nephrons and nephrosclerosis predicted progressive CKD, and IF/TA predicted noncancer mortality. Morphometric analysis of renal parenchyma can predict noncancer clinical events in patients long after their radical nephrectomy.

Coronary artery calcium progresses rapidly and discriminates incident cardiovascular events in chronic kidney disease regardless of diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background and aimsChronic kidney disease (CKD) is associated with high prevalence of cardiovascular disease (CVD) events. We sought to assess the prognostic utility of coronary artery calcium (CAC) scores in discriminating incident CVD events among subpopulations of CKD, particularly those without diabetes mellitus (DM). MethodsUsing the Multi-Ethnic Study of Atherosclerosis, we identified 4 groups based on present/absent CKD/diabetes (CKD-/DM-, n = 5308; CKD-/DM+, n = 586, CKD+/DM-, n = 620; CKD+/DM+, n = 266). Baseline and follow-up CAC (Agatston units) measurements, and association between CAC and incident CVD events in median follow-up of 13 years were evaluated using proportional hazards regression adjusting for demographics, clinical, biomarker variables. ResultsPrevalence of CKD and DM in the cohort was 13% and 12.5% respectively. Annual progression in adjusted median CAC score was 24.8%, 27.9%, 26.7%, 36.8% and unadjusted cumulative incident CVD rates were 12.6%, 22.3%, 23.1%, 39.8% for CKD-/DM-, CKD-/DM+, CKD+/DM-, CKD+/DM+, respectively. After full adjustment (CKD-/DM-referent), hazard ratios (HR, 95% CI) for incident CVD events were 1.25 (1.01–1.53) CKD-/DM+, 1.10 (0.90–1.33) CKD+/DM- and 2.18 (1.73–2.76) CKD+/DM+. Using CKD-/DM-/baseline CAC = 0 referent, adjusted HRs (95% CI) for incident CVD in CKD+/DM- were 1.30 (0.81–2.07), 2.05 (1.4–2.99), and 4.15 (2.94–5.86) for baseline CAC = 0, 1–100, and >300 Agatston units respectively while for CKD+/DM+, adjusted HRs were 3.15 (2.04–4.86), 3.56 (2.26–5.62), 7.90 (5.35–11.67), respectively. ConclusionsCAC provides incremental prognostic information to predict incident CVD events in CKD regardless of DM. Moreover, baseline CAC categories discriminate incident CVD among CKD without DM, which may have implications in individualizing approach to primary prevention in this high-risk population.

Obstructive Sleep Apnea, Other Sleep Characteristics, and Risk of CKD in the Atherosclerosis Risk in Communities Sleep Heart Health Study.

Obstructive sleep apnea may be associated with development of CKD through hypoxia, inflammation, and oxidative stress. Individuals with this sleep disorder are also at increased risk for established CKD risk factors, including obesity, hypertension, and type 2 diabetes. We examined the association between obstructive sleep apnea, other sleep characteristics, and risk of incident CKD (stage 3 or higher) in 1525 participants (mean age, 62.5 years; 52.4% women) in the Atherosclerosis Risk in Communities (ARIC) study who completed in-home polysomnography assessments. We used the apnea-hypopnea index (events per hour) to define obstructive sleep apnea severity (normal, <5.0; mild, 5.0-14.9; moderate, 15.0-29.9; and severe, ≥30.0) and defined incident CKD (stage 3 or higher) as eGFR<60 ml/min per 1.73 m2 and ≥25% decline from baseline, CKD-related hospitalization or death, or ESKD. Cox proportional hazards regression was used to estimate obstructive sleep apnea severity with risk of incident CKD, adjusting for demographics, lifestyle behaviors, and cardiometabolic conditions. During 19 years (median) of follow-up, 461 CKD events occurred. After adjustment for demographics and lifestyle behaviors, severe obstructive sleep apnea associated with increased risk of CKD (hazard ratio [HR], 1.51; 95% confidence interval [95% CI], 1.08 to 2.10), which was attenuated after adjustment for body mass index (HR, 1.07; 95% CI, 0.75 to 1.52). No other sleep characteristics associated with incident CKD. We found a link between obstructive sleep apnea and an elevated risk of stage 3 CKD or higher, but this association was no longer significant after adjusting for obesity, a risk factor for both conditions. Given the high prevalence of obstructive sleep apnea and CKD among adults, further investigation is warranted.

Association of Serum Uromodulin with Death, Cardiovascular Events, and Kidney Failure in CKD.

Uromodulin is exclusively produced by tubular epithelial cells and released into urine and serum. Higher serum uromodulin has been associated with lower risk for kidney failure in Chinese patients with CKD and with lower risk for mortality in the elderly and in patients undergoing coronary angiography. We hypothesized that lower serum uromodulin is associated with mortality, cardiovascular events, and kidney failure in white patients with CKD. We measured serum uromodulin in 5143 participants enrolled in the German CKD (GCKD) study. The associations of baseline serum uromodulin with all-cause mortality, major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, nonfatal myocardial infarction or stroke, or incident peripheral vascular disease), and kidney failure (dialysis or transplantation) were evaluated using multivariable Cox proportional hazard regression analyses in a cohort study design, adjusting for demographics, eGFR, albuminuria, cardiovascular risk factors, and medication. The mean age of participants was 60±12 years, 60% were male. Mean serum uromodulin concentration was 98±60 ng/ml, eGFR was 49±18 ml/min per 1.73 m2, and 78% had eGFR <60 ml/min per 1.73 m2. Participants in lower serum uromodulin quartiles had lower eGFR and higher albuminuria, prevalence of diabetes, hypertension, coronary artery disease, and more frequent history of stroke at baseline. During a follow-up of 4 years, 335 participants died, 417 developed MACE, and 229 developed kidney failure. In multivariable analysis, the highest serum uromodulin quartile was associated with lower hazard for mortality (hazard ratio [HR], 0.57; 95% CI, 0.38 to 0.87), MACE (HR, 0.63; 95% CI, 0.45 to 0.90), and kidney failure (HR, 0.24; 95% CI, 0.10 to 0.55) compared with the lowest quartile. Higher serum uromodulin is independently associated with lower risk for mortality, cardiovascular events, and kidney failure in white patients with CKD. Deutsches Register für Klinische Studien (DRKS; German national database of clinical studies), DRKS00003971.