Adjustment For Glomerular Filtration Rate Research Articles

Plasma metabolomics profiles in Black and White participants of the Adventist Health Study-2 cohort

BackgroundBlack Americans suffer disparities in risk for cardiometabolic and other chronic diseases. Findings from the Adventist Health Study-2 (AHS-2) cohort have shown associations of plant-based dietary patterns and healthy lifestyle factors with prevention of such diseases. Hence, it is likely that racial differences in metabolic profiles correlating with disparities in chronic diseases are explained largely by diet and lifestyle, besides social determinants of health.MethodsUntargeted plasma metabolomics screening was performed on plasma samples from 350 participants of the AHS-2, including 171 Black and 179 White participants, using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and a global platform of 892 metabolites. Differences in metabolites or biochemical subclasses by race were analyzed using linear regression, considering various models adjusted for known confounders, dietary and/or other lifestyle behaviors, social vulnerability, and psychosocial stress. The Storey permutation approach was used to adjust for false discovery at FDR < 0.05.ResultsLinear regression revealed differential abundance of over 40% of individual metabolites or biochemical subclasses when comparing Black with White participants after adjustment for false discovery (FDR < 0.05), with the vast majority showing lower abundance in Blacks. Associations were not appreciably altered with adjustment for dietary patterns and socioeconomic or psychosocial stress. Metabolite subclasses showing consistently lower abundance in Black participants included various lipids, such as lysophospholipids, phosphatidylethanolamines, monoacylglycerols, diacylglycerols, and long-chain monounsaturated fatty acids, among other subclasses or lipid categories. Among all biochemical subclasses, creatine metabolism exclusively showed higher abundance in Black participants, although among metabolites within this subclass, only creatine showed differential abundance after adjustment for glomerular filtration rate. Notable metabolites in higher abundance in Black participants included methyl and propyl paraben sulfates, piperine metabolites, and a considerable proportion of acetylated amino acids, including many previously found associated with glomerular filtration rate.ConclusionsDifferences in metabolic profiles were evident when comparing Black and White participants of the AHS-2 cohort. These differences are likely attributed in part to dietary behaviors not adequately explained by dietary pattern covariates, besides other environmental or genetic factors. Alterations in these metabolites and associated subclasses may have implications for the prevention of chronic diseases in Black Americans.

Serum Orotidine: A Novel Biomarker of Increased CVD Risk in Type 2 Diabetes Discovered Through Metabolomics Studies.

To identify novel biomarkers of cardiovascular disease (CVD) risk in type 2 diabetes (T2D) via a hypothesis-free global metabolomics study, while taking into account renal function, an important confounder often overlooked in previous metabolomics studies of CVD. We conducted a global serum metabolomics analysis using the Metabolon platform in a discovery set from the Joslin Kidney Study having a nested case-control design comprising 409 individuals with T2D. Logistic regression was applied to evaluate the association between incident CVD events and each of the 671 metabolites detected by the Metabolon platform, before and after adjustment for renal function and other CVD risk factors. Significant metabolites were followed up with absolute quantification assays in a validation set from the Joslin Heart Study including 599 individuals with T2D with and without clinical evidence of significant coronary heart disease (CHD). In the discovery set, serum orotidine and 2-piperidinone were significantly associated with increased odds of incident CVD after adjustment for glomerular filtration rate (GFR) (odds ratio [OR] per SD increment 1.94 [95% CI 1.39-2.72], P = 0.0001, and 1.62 [1.26-2.08], P = 0.0001, respectively). Orotidine was also associated with increased odds of CHD in the validation set (OR 1.39 [1.11-1.75]), while 2-piperidinone did not replicate. Furthermore, orotidine, being inversely associated with GFR, mediated 60% of the effects of declining renal function on CVD risk. Addition of orotidine to established clinical predictors improved (P < 0.05) C statistics and discrimination indices for CVD risk (ΔAUC 0.053, rIDI 0.48, NRI 0.42) compared with the clinical predictors alone. Through a robust metabolomics approach, with independent validation, we have discovered serum orotidine as a novel biomarker of increased odds of CVD in T2D, independent of renal function. Additionally, orotidine may be a biological mediator of the increased CVD risk associated with poor kidney function and may help improve CVD risk prediction in T2D.

Cystatin C Predicts Adverse Outcomes In Heart Failure With Preserved Ejection Fraction

<h3>Background</h3> Serum creatinine (Cr) is used to estimate glomerular filtration rate (GFR). Cr levels vary with lean muscle mass and diet, confounding measurement of renal function. Cystatin C (CysC) is an alternative marker used to estimate GFR which is not subject to these sources of variability. In conditions where frailty and low muscle mass are common, such as heart failure with preserved ejection fraction (HFpEF), Cr may overestimate GFR, leading to under detection of renal disease. Chronic kidney disease (CKD) is a common co-morbidity in HFpEF and portends worse prognosis; however, there are currently minimal data on CysC in HFpEF. <h3>Methods</h3> Patients enrolled in the Johns Hopkins HFpEF Program from July 2014 to March 2020 were included for study. Patients underwent a comprehensive clinical evaluation and echocardiography. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations for Cr (CKD-EPIcr) and CysC (CKD-EPIcys). Distributions of GFR were compared with a Wilcoxon matched-pairs test. Trends in clinical and echocardiographic variables with CysC were assessed using multivariate linear regression. Cox proportional hazard models examined the association of CysC with the combined outcome of heart failure hospitalization and all-cause mortality. <h3>Results</h3> The study cohort included 190 patients. The average age was 64 years; 65% of patients were female and 59% were black. Median follow-up was 28 months. The median estimated GFR by CKD-EPIcr and CKD-EPIcys were 54.0 mL/min/1.73m² and 46.7 mL/min/1.73m², respectively (<b>Figure A and C;</b> z=3.81, p<0.001). As compared to CKD-EPIcr, CKD-EPIcys reclassified 74 patients (39% of cohort) to a higher stage of CKD (<b>Figure B and D</b>). CysC was significantly associated with greater left ventricular mass index (β =7.16 [0.23-14.01], p=0.043) and E/e' ratio (β=2.28 [0.33-4.22], p=0.022) after adjustment for GFR by CKD-EPIcr. CysC was predictive of the combined outcome in the univariate model and after adjustment for relevant medical comorbidities and estimated GFR by CKD-EPIcr (<b>Figure</b>). <h3>Conclusion</h3> In this prospective study, CysC estimated a lower median GFR in HFpEF patients as compared to Cr. CysC was predictive of worse diastolic function and adverse outcomes, even after accounting for GFR by CKD-EPIcr and relevant comorbidities. These results suggest CysC provides clinical and prognostic information beyond traditional Cr-based assessment of renal function in HFpEF. Further investigation of the use of CysC in clinical practice is warranted.

Bone metabolic disorder and its contributing factors in patients with chronic kidney disease; a three-year cohort study

Introduction: The prevalence of bone mineral disorder is best known in end-stage renal disease (ESRD) patients, but less data is available for the earlier stages. Objectives: We aimed to compare the prevalence of bone metabolic disorder at all stages of chronic kidney disease (CKD) and assess its contribution to CKD progression and patients’ outcome. Patients and Methods: In a retrospective cohort study, CKD patients who were under treatment for three years were selected from a nephrology clinic in Tehran, Iran. Patients’ demographic and laboratory data, as well as the outcome of their treatment were gathered and analyzed. Results: In 473 patients with an average age of 61.5, 60.1% were at stage III, 35.8% were at stage IV, and 4.1% were at stage V of CKD. There was a significant relationship between CKD stage and serum phosphate, calcium-phosphate product, and systolic blood pressure (SBP). Furthermore, the patients’ outcome was significantly related to advanced stages of CKD, higher first phosphate level, diabetes mellitus in medical history, and higher stages of SBP. By multiple Cox regression analysis, after adjustment for glomerular filtration rate (GFR), the first serum phosphate level, and the calcium-phosphate product did not contribute to the undesirable outcome. Conclusion: Although bone metabolic disorder is more frequently seen in advanced stages of chronic kidney disease, these changes can be seen even in earlier stages of the disease. The influence of phosphate abnormality in the patients’ outcome should be studied more in earlier stages for better control.

Galectin-3 is related to right ventricular dysfunction in heart failure patients with reduced ejection fraction and may affect exercise capacity

Galectin-3 is a biomarker of fibrosis, inflammation and oxidative stress, and its role in heart remodelling and exercise intolerance has not been conclusively proven in heart failure (HF) patients with reduced ejection fraction (rEF). We prospectively assessed 67 consecutive patients with symptomatic HF and left ventricular (LV) EF ≤ 35% during optimal medical therapy, with a mean serum galectin-3 concentration of 15.3 ± 6.4 and a median of 13.5 ng/mL. The group with galectin-3 concentrations greater than or equal to the median had significantly worse right ventricular (RV) systolic function parameters (s′, TAPSE), higher pulmonary artery systolic pressure, more advanced tricuspid regurgitation and lower RV-to-pulmonary circulation coupling index, while no significant differences were found in LV parameters. Moreover, this group achieved significantly lower parameters in cardiopulmonary exercise testing. Significant negative correlations were found between galectin-3 concentration and RV parameters and exercise capacity parameters and have persisted after adjustment for glomerular filtration rate, but not all of them have persisted after adjustment for NT-proBNP. Multivariate regression analysis revealed that TAPSE (β coefficient: − 0.605; p < 0.001) and heart rate at peak exercise (β coefficient: − 0.98; p = 0.009) were independently related to galectin-3 concentration. Elevated galectin-3 concentration in patients with HFrEF might indicate concomitant RV dysfunction and exercise intolerance.

Albumin downregulates Klotho in tubular cells.

Kidney tubular cells are the main sources of Klotho, a protein with phosphaturic action. Genetic Klotho deficiency causes premature cardiovascular aging in mice. Human chronic kidney disease (CKD) is characterized by acquired Klotho deficiency. Despite the lack of uremic toxin accumulation, Category G1 CKD [(normal glomerular filtration rate (GFR)] is already associated with decreased Klotho and with premature cardiovascular aging. We have explored whether albuminuria, a criterion to diagnose CKD when GFR is normal, may directly decrease Klotho expression in human CKD, preclinical models and cultured tubular cells. In a CKD cohort, albuminuria correlated with serum phosphate after adjustment for GFR, age and sex. In this regard, urinary Klotho was decreased in patients with pathological albuminuria but preserved GFR. Proteinuria induced in rats by puromycin aminonucleoside and in mice by albumin overload was associated with interstitial inflammation and reduced total kidney Klotho messenger ribonucleic acid (mRNA) expression. Western blot disclosed reduced kidney Klotho protein in proteinuric rats and mice and immunohistochemistry localized the reduced kidney Klotho expression to tubular cells in proteinuric animals. In cultured murine and human tubular cells, albumin directly decreased Klotho mRNA and protein expression. This was inhibited by trichostatin A, an inhibitor of histone deacetylases, but unlike cytokine-induced Klotho downregulation, not by inhibitors of nuclear factor kappa-light-chain-enhancer of activated B cells. In conclusion, albumin directly decreases Klotho expression in cultured tubular cells. This may explain, or at least contribute to, the decrease in Klotho and promote fibroblast growth factor 23 resistance in early CKD categories, as observed in preclinical and clinical proteinuric kidney disease.

Urine matrix metalloproteinase-7 and risk of kidney disease progression and mortality in type 2 diabetes

AimsThe renin–angiotensin–aldosterone system (RAAS), bone morphogenetic protein (BMP) and WNT pathways are dysregulated in diabetic kidney disease (DKD). Urine excretion of angiotensinogen, gremlin-1 and matrix metalloproteinase-7 (MMP-7), components of the RAAS, BMP and WNT pathways, respectively, is increased in DKD. We asked if this increase is associated with subsequent progression to end-stage renal disease (ESRD) or death. MethodsUsing time-to-event analyses, we examined the association of baseline urine concentration of these proteins with progression to ESRD or death in a predominantly Mexican-American cohort with type 2 diabetes and proteinuric DKD (n=141). ResultsProgression to ESRD occurred for 38 participants over a median follow-up of 3.0years; 39 participants died over a median follow-up of 3.6years. Urine MMP-7 and gremlin-1 were associated with increased risk of ESRD after adjustment for demographic and clinical covariates. Angiotensinogen showed a U-shaped relationship with ESRD, with the middle tertile associated with lowest risk of ESRD. After additional adjustment for glomerular filtration rate and albuminuria, all associations with ESRD lost significance. Only urine MMP-7 was associated with mortality, and this association remained robust in the fully adjusted model with a Hazard ratio of 3.59 (95% confidence interval 1.31 to 9.85) for highest vs. lowest tertile. Serum MMP-7 was not associated with mortality and did not attenuate the association of urine MMP-7 with mortality (HR 4.03 for highest vs. lowest urine MMP-7 tertile). ConclusionsAmong people with type 2 diabetes and proteinuric DKD, urine MMP-7 concentration was strongly associated with subsequent mortality.

Subclinical carotid atherosclerosis and hyperuricemia in relation to renal impairment in a rural Japanese population: The Nagasaki Islands study

ObjectiveThe influence of hyperuricemia on atherosclerosis is controversial. Subclinical carotid atherosclerosis can be defined in two ways in terms of mean and maximum carotid intima-media thickness (CIMT): one with mean CIMT ≥ 1.1 mm and the other with maximum CIMT ≥ 1.1 mm. However, no studies have been reported of the association between hyperuricemia and subclinical carotid atherosclerosis while taking the two different ways of classification into account. MethodsWe conducted a cross-sectional study of 4133 subjects (1492 men and 2641 women) aged 30–89 years undergoing general health check-ups. For analysis of various associations, we calculated the multivariable odds ratios (ORs) for the two ways classifications of subclinical carotid atherosclerosis in relation to hyperuricemia. ResultsHyperuricemia-related renal impairment constitutes a significant marker for subclinical carotid atherosclerosis with mean CIMT ≥ 1.1 mm for both men and women, while hyperuricemia per se was found to be beneficially associated with risk of subclinical carotid atherosclerosis with maximum CIMT ≥ 1.1 mm for men. The classical cardiovascular risk factors without adjustment for glomerular filtration rate (GFR) of ORs for subclinical carotid atherosclerosis (mean CIMT ≥ 1.1 mm) and subclinical carotid atherosclerosis (maximum CIMT ≥ 1.1 mm) were 2.20(1.10–4.22) and 0.84(0.63–1.13) for men and 2.12(1.02–4.38) and 0.92(0.66–1.27) for women. After further adjustment for GFR, the corresponding values were 1.54(0.74–3.20) and 0.67(0.49–0.92) for men and 1.32(0.61–2.88) and 0.80(0.57–1.12) for women. ConclusionHyperuricemia-related renal impairment is a significant marker for subclinical carotid atherosclerosis for both men and women, while hyperuricemia per se may be inversely associated with subclinical carotid atherosclerosis for men as seen in a rural community-dwelling Japanese population.

Are Levels of NT-proBNP and SDMA Useful to Determine Diastolic Dysfunction in Chronic Kidney Disease and Renal Transplant Patients?

The aim of the study was to determine the clinical usefulness of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and symmetric dimethylarginine (SDMA) for detection of renal and left ventricular (LV) diastolic dysfunction in chronic kidney disease (CKD) patients and renal transplant (RT) recipients. We included 98 CKD and 44 RT patients. We assessed LV function using pulsed-wave Doppler ultrasound. Diastolic dysfunction was defined when the E:A ratio was <1. Independent predictors of NT-proBNP levels were age, creatinine, and albumin in CKD patients and age and urea in RT patients. Determinants of SDMA in CKD patients were glomerular filtration rate (GFR) and NT-proBNP and creatinine in RT patients. In RT patients with diastolic dysfunction, NT-proBNP and SDMA were significantly higher than in patients without diastolic dysfunction (F = 7.478, P < 0.011; F = 2.631, P < 0.017). After adjustment for GFR, the differences were not seen. In CKD patients adjusted NT-proBNP and SDMA values for GFR were not significantly higher in patients with diastolic dysfunction than in patients without diastolic dysfunction. NT-proBNP is useful for detection of LV diastolic dysfunction in RT recipients. When evaluating both NT-proBNP and SDMA it is necessary to consider GFR as a confounding factor.

Assessment of Endothelial Dysfunction: The Role of Symmetrical Dimethylarginine and Proinflammatory Markers in Chronic Kidney Disease and Renal Transplant Recipients

Objectives. The study was designed to evaluate associations between symmetric dimethylarginine (SDMA), inflammation, and superoxide anion (O2∙−) with endothelial function and to determine their potential for screening of endothelial dysfunction in patients with chronic kidney disease (CKD) and renal transplant (RT) recipients. Materials and Methods. We included 64 CKD and 52 RT patients. Patients were stratified according to brachial artery flow-mediated dilation (FMD). Results. Logistic regression analysis showed that high SDMA and high sensitive C-reactive protein (hs-CRP) were associated with impaired FMD in CKD and RT patients, after adjustment for glomerular filtration rate. The ability of inflammation, SDMA, and O2∙− to detect impaired FMD was investigated by receiving operative characteristic analysis. Hs-CRP (area under the curves (AUC) = 0.754, P < 0.001), IL-6 (AUC = 0.699, P = 0.002), and SDMA (AUC = 0.689, P = 0.007) had the highest ability to detect impaired FMD. SDMA in combination with inflammatory parameters and/or O2∙− had better screening performance than SDMA alone. Conclusions. Our results indicate a strong predictable association between hs-CRP, SDMA, and endothelial dysfunction in CKD patients and RT recipients. The individual marker that showed the strongest discriminative ability for endothelial dysfunction is hs-CRP, but its usefulness as a discriminatory marker for efficient diagnosis of endothelial dysfunction should be examined in prospective studies.

Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community

Fibroblast growth factor-23 (FGF23), a regulator of mineral metabolism, has been linked to cardiovascular disease in chronic kidney disease. As community-based data of the longitudinal association between FGF23 and cardiovascular events are lacking, we investigated a possible relationship in 727 men of the Uppsala Longitudinal Study of Adult Men population-based cohort (mean age 77 years). During a median follow-up of 9.7 years, 110 participants died of cardiovascular causes. In Cox regression models adjusted for age and established cardiovascular risk factors, higher serum FGF23 was associated with a significantly increased risk for cardiovascular mortality (hazard ratio (HR) per increased s.d. of 1.36). This relationship remained significant, albeit attenuated, after adjustment for glomerular filtration rate (GFR) (HR 1.21). FGF23 was also associated with all-cause mortality, although the association was weaker than that with cardiovascular mortality, and it was nonsignificant in fully adjusted multivariate models. Spline analysis suggested a log-linear relationship between FGF23 and outcome. Participants with a combination of high FGF23 (>60 pg/ml), low GFR (<60 ml/min), and micro-/macro-albuminuria (albumin/creatinine ratio above 3 mg/ml) had an almost eightfold increased risk compared with participants without these abnormalities. Thus, a higher FGF23 level is associated with an increased cardiovascular mortality risk in the community. Clinical trials are needed to determine whether FGF23 is a modifiable risk factor.

Performance of serum cystatin C versus serum creatinine as a marker of glomerular filtration rate as measured by inulin renal clearance

Serum cystatin C was recently proposed as an alternative marker of glomerular filtration rate (GFR), with a suggested better performance than creatinine. However, detailed studies are limited. We evaluated the performance of cystatin C as a GFR marker. GFR was measured by inulin clearance in 763 Japanese subjects. Factors other than GFR influencing serum cystatin C or serum creatinine were analyzed by multivariate analyses. After adjustment for GFR, the value of serum creatinine was 25.2% lower in females than males, and decreased by 5.2% for every 20 years of age. Serum cystatin C was 8.2% lower in females, and did not change significantly with aging. Creatinine but not cystatin C was significantly affected by body weight, height and body mass index after adjustment for GFR, gender and age. The correlation coefficient between GFR and 1/cystatin C was significantly higher than that of 1/creatinine in total subjects (0.866 and 0.810, respectively, p < 0.001). Unlike serum creatinine, serum cystatin C did not increase in association with the reduction of GFR in subjects with very low GFR. The regression line of 1/cystatin C against GFR showed a significantly negative intercept of about -8 ml/min/1.73 m(2). The performance of serum cystatin C was not good in the subjects with very low GFR. Non-renal elimination of cystatin C may contribute to the result. The correlation between reciprocal cystatin C and GFR suggested its superiority in predicting GFR compared to creatinine in subjects with normal and mildly reduced GFR.

Serum Bicarbonate and Long-term Outcomes in CKD

A low serum bicarbonate level is prevalent in chronic kidney disease (CKD); however, its relationship to long-term outcomes is unclear. Cohort study. The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and blood pressure control on progression of kidney disease. This analysis includes 942 screened but non-randomized individuals and 839 randomized participants with baseline serum bicarbonate measurements with stage 2-4 CKD. Serum bicarbonate level categorized into quartiles. Kidney failure, all-cause mortality, and a composite outcome of mortality and kidney failure. Local laboratories at each participating site measured bicarbonate in fasting serum samples. Kidney failure outcomes were obtained from the US Renal Data System, and mortality data, from the National Death Index. Mean glomerular filtration rate (GFR) was 39 ± 21 (SD) mL/min/1.73 m(2) and serum bicarbonate level was 23.3 ± 3.8 mEq/L. Kidney failure rates were 72%, 64%, 50%, and 41%; mortality rates were 31%, 25%, 21%, and 25%, and rates of the composite outcome were 78%, 71%, 58%, and 54% in bicarbonate quartiles 1, 2, 3, and 4, respectively. In analyses adjusted for demographic and cardiovascular disease factors, serum albumin level, proteinuria, and cause of kidney disease, compared with quartile 4, quartile 1 was associated with a 2.22 HR (95% CI, 1.83-2.68) of kidney failure; 1.39 HR (95% CI, 1.07-1.18) of all-cause mortality; and 1.36 HR (95% CI, 1.15-1.62) of the composite outcome. These associations were rendered nonsignificant with adjustment for GFR (kidney failure HR, 1.05 [95% CI, 0.87-1.28]; all-cause mortality HR, 0.99 [95% CI, 0.75-1.13]; composite HR, 1.04 [95% CI, 0.87-1.24]). Single baseline measurement of serum bicarbonate. Low serum bicarbonate level was associated with increased risk of long-term outcomes in nondiabetic patients with CKD. However, this risk is not independent of baseline GFR. Clinical trials are necessary to evaluate whether bicarbonate supplementation slows the progression of CKD.

Factors other than glomerular filtration rate affect serum cystatin C levels

Cystatin C is an endogenous glomerular filtration marker hence its serum level is affected by the glomerular filtration rate (GFR). To study what other factors might affect it blood level we performed a cross-sectional analysis of 3418 patients which included a pooled dataset of clinical trial participants and a clinical population with chronic kidney disease. The serum cystatin C and creatinine levels were related to clinical and biochemical parameters and errors-in-variables models were used to account for errors in GFR measurements. The GFR was measured as the urinary clearance of 125I-iothalamate and 51Cr-EDTA. Cystatin C was determined at a single laboratory while creatinine was standardized to reference methods and these were 2.1+/-1.1 mg/dL and 1.8+/-0.8 mg/L, respectively. After adjustment for GFR, cystatin C was 4.3% lower for every 20 years of age, 9.2% lower for female gender but only 1.9% lower in blacks. Diabetes was associated with 8.5% higher levels of cystatin C and 3.9% lower levels of creatinine. Higher C-reactive protein and white blood cell count and lower serum albumin were associated with higher levels of cystatin C and lower levels of creatinine. Adjustment for age, gender and race had a greater effect on the association of factors with creatinine than cystatin C. Hence, we found that cystatin C is affected by factors other than GFR which should be considered when the GFR is estimated using serum levels of cystatin C.

Cardiovascular remodelling and extracellular fluid excess in early stages of chronic kidney disease

Patients with a mild to moderate decrease of glomerular filtration rate (GFR) are at risk of cardiovascular (CV) events and CV remodelling has been demonstrated in patients with advanced chronic kidney disease (CKD). However, early stages of CKD and the mechanisms involved in these modifications have not been studied. A total of 104 patients with early CKD (mean GFR 60+/-21 ml/min/1.73 m(2)) had cardiac and vascular ultrasound study and measurement of extracellular fluid by multifrequence spectroscopic bioimpedance. GFR decline was associated with left ventricular (LV) remodelling or hypertrophy in 58 and 68% of DOQI-2 and DOQI-3 patients, respectively and impaired LV diastolic function. GFR decrease was also associated with common carotid remodelling and increased aorta stiffness. Cardiac and vascular remodelling were significantly associated with an excess of extracellular fluid (ECFe) evidenced as early as DOQI-2 stage. In multivariate analysis with adjustment for GFR, ECFe, age and systolic blood pressure (sBP), GFR was no longer independently associated with cardiac and vascular remodelling, whereas ECFe was an independent determinant of LV hypertrophy, left atrium enlargement, common carotid diameter and intima media thickness. This study shows that CV remodelling and ECF excess occurred at a very early stage of CKD. The independent association between ECF excess and cardiac and vascular remodelling and hypertrophy may be instrumental in the increased cardiovascular risk in CKD patients. Early therapeutic control of ECF may reduce CV events in CKD patients.

Relationship Between Homocysteine and Mortality in Chronic Kidney Disease

The relationship between total homocysteine (tHcy) and outcomes has not been investigated in patients with chronic kidney disease stages 3 to 4. The Modification of Diet in Renal Disease Study was a randomized, controlled trial of 840 patients. Serum tHcy was measured in frozen samples collected at baseline (n=804). Survival status and cause of death were obtained from the National Death Index. To evaluate its association with all-cause and cardiovascular disease (CVD) mortality, tHcy was evaluated both as tertiles (<14.7, 14.7 to 19.5, > or =19.6 micromol/L) and as a continuous variable (per 10/micromol/L). Participants had a mean age of 52+/-12 years and glomerular filtration rate (GFR) of 33+/-12 mL/min per 1.73 m2; 60% were male, and 85% were white. During a median follow-up of 10 years, 195 (24%) died from any cause, and 118 (15%) from CVD. The level of GFR was lower and proteinuria higher in the highest tHcy tertile. There was no association between the highest tertile of tHcy and all-cause (hazard ratio [HR]; 95% confidence interval [CI[, 1.32, 0.94 to 1.85) or CVD (HR; 95% CI, 1.50, 0.96 to 2.34) mortality in univariate analyses; this association was further attenuated by adjustment for GFR (HR; 95% CI all-cause, 1.04, 0.72 to 1.51; CVD, 1.20, 0.73 to 1.95). There was no association between tHcy as a continuous variable and all-cause (0.98, 0.83 to 1.16) or CVD (1.04, 0.85 to 1.27) mortality. Hyperhomocystinemia does not appear to be a risk factor for all-cause or CVD mortality in the Modification of Diet in Renal Disease Study. Prior studies demonstrating an association between tHcy and CVD risk may have inadequately adjusted for the confounding effects of kidney function.

Relationship of Phosphorus and Calcium-Phosphorus Product With Mortality in CKD

Abnormalities of mineral metabolism are prevalent in patients with kidney failure and are associated with increased risk for cardiovascular events. There are limited data investigating relationships of phosphorus and calcium-phosphorus product with outcomes in patients with chronic kidney disease (CKD) stages 3 to 4. Serum phosphorus and calcium were measured at baseline in 840 participants from the randomized cohort of the Modification of Diet in Renal Disease Study. Survival status until December 31, 2000, was obtained from the National Death Index. Cox models were performed to assess the relationship of serum phosphorus level and calcium-phosphorus product with all-cause and cardiovascular disease (CVD) mortality. Mean serum phosphorus level was 3.8 +/- 0.7 mg/dL (1.23 +/- 0.23 mmol/L), calcium-phosphorus product was 34.7 +/- 6.3 mg2/dL2, and glomerular filtration rate (GFR) was 33 +/- 12 mL/min/1.73 m2 (0.55 +/- 0.20 mL/s/1.73 m2). All-cause and CVD mortality rates were 25% and 15%. Serum phosphorus level was not related to all-cause mortality in multivariable models (P = 0.46). In unadjusted analysis, serum phosphorus level was associated with (hazard ratio [HR] per 1 mg/dL increase, 1.34; 95% confidence interval [CI], 1.05 to 1.71; P = 0.02) increased risk for CVD mortality, but this association was partly attenuated and not statistically significant after adjustment for GFR and other confounders (HR, 1.27; 95% CI, 0.94 to 1.73; P = 0.12). Calcium-phosphorus product was not associated with all-cause mortality in unadjusted (P = 0.23) or multivariate analysis (P = 0.35). Calcium-phosphorus product was related to CVD mortality in unadjusted (HR per 10 mg2/dL2 increase, 1.30; 95% CI, 1.01 to 1.69; P = 0.04) analysis, but this association was not statistically significant after adjustment for GFR and other confounders (HR, 1.22; 95% CI, 0.89 to 1.66; P = 0.23). In the Modification of Diet in Renal Disease Study cohort, serum phosphorus level and calcium-phosphorus product were not statistically associated with all-cause or CVD mortality after adjustment for GFR; however larger studies with additional statistical power are needed to evaluate these relationships, especially in the context of current practice patterns in patients with CKD.

N-Terminal Pro-B-Type Natriuretic Peptide for Predicting Coronary Disease and Left Ventricular Hypertrophy in Asymptomatic CKD Not Requiring Dialysis

N-Terminal pro-B-type natriuretic peptide (NT-proBNP) level predicts underlying heart disease in the general population. However, because NT-proBNP clearance may depend on renal function, the significance of an elevated level in patients with chronic kidney disease (CKD) without cardiac symptoms is uncertain. We sought to determine whether there is an association between NT-proBNP level and coronary artery disease (CAD) and left ventricular hypertrophy (LVH) in this population. We enrolled 207 ambulatory patients with CKD not on dialysis therapy. Medical records were reviewed for cardiac history and risk factors. NT-proBNP and troponin T (cTnT) levels were measured. Echocardiograms were analyzed from 99 patients. NT-proBNP levels were elevated in 116 patients (56%), and 67 patients (33%) had experienced prior CAD events (myocardial infarction or revascularization). The prevalence of advanced age, diabetes, prior CAD events, myocardial injury (cTnT > 0.03 ng/mL [>0.03 microg/L]), and LVH increased, whereas glomerular filtration rate decreased, across quartiles of NT-proBNP levels. After adjustment for glomerular filtration rate, cTnT level, age, and diabetes, NT-proBNP remained an independent indicator of prior CAD events compared with quartile 1 (cTnT range, 4 to 116 pg/mL) for quartile 2 (range, 122 to 490 pg/mL): odds ratio, 1.6; 95% confidence interval, 0.5 to 5.0; for quartile 3 (range, 490 to 1,819 pg/mL): odds ratio, 5.3; 95% confidence interval, 1.7 to 16.2; and for quartile 4 (>1,975 pg/mL): odds ratio, 4.1; 95% confidence interval, 1.3 to 13.5. For patients with echocardiograms, NT-proBNP level predicted prior CAD events independent of LVH. NT-proBNP level elevation in asymptomatic patients with CKD reflects underlying ischemic heart disease and hypertrophy independent of renal function in a population with anticipated high cardiac morbidity.