Juan-Jesus Carrero

Plasma Pentraxin 3 in Patients with Chronic Kidney Disease: Associations with Renal Function, Protein-Energy Wasting, Cardiovascular Disease, and Mortality

BACKGROUND AND OBJECTIVES Plasma protein pentraxin 3 concentrations are elevated in a wide range of diseased states. However, no study has evaluated protein pentraxin 3 in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Plasma protein pentraxin 3 concentrations were analyzed in relation to GFR, inflammation, cardiovascular disease, and protein-energy wasting in 71 patients with stages 3 to 4 chronic kidney disease, 276 patients with stage 5 chronic kidney disease, and 61 control subjects. Survival (5 yr) in patients with stage 5 chronic kidney disease was analyzed in relation to protein pentraxin 3 levels. RESULTS Both patient groups with chronic kidney disease had higher protein pentraxin 3 concentrations than control subjects, with the highest concentration in patients with stage 5 chronic kidney disease. In all patients with chronic kidney disease, protein pentraxin 3 correlated negatively with GFR and positively with inflammatory markers. Patients with protein-energy wasting, inflammation, and cardiovascular disease had higher concentrations of protein pentraxin 3 than their counterparts. Patients with high protein pentraxin 3 levels had higher all-cause and cardiovascular mortality. After adjustment for age, gender, C-reactive protein, and cardiovascular disease, all-cause mortality was still significantly higher in patients with high protein pentraxin 3. Finally, protein pentraxin 3 showed a predictive value of mortality similar to that of IL-6 and better than C-reactive protein. CONCLUSION Plasma protein pentraxin 3 increases as GFR declines and is associated with the presence of cardiovascular disease and protein-energy wasting. Furthermore, in patients with chronic kidney disease, elevated protein pentraxin 3 predicted all-cause mortality.

Cardiovascular and noncardiovascular mortality among men and women starting dialysis

BACKGROUND AND OBJECTIVES Although women have a survival advantage in the general population, women on dialysis have similar mortality to men. We hypothesized that this paired mortality risk during dialysis may be explained by a relative excess of cardiovascular-related mortality in women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We compared 5-year age-stratified cardiovascular and noncardiovascular mortality rates, relative risks, and hazard ratios in a European cohort of incident adult dialysis patients (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry) with the European general population (Eurostat). Cause of death was recorded by ERA-EDTA codes in dialysis patients and by International Statistical Classification of Diseases codes in the general population. RESULTS Overall, sex did not have a predictive effect on outcome in dialysis. Stratification into age categories and causes of death showed greater noncardiovascular mortality in young women (<45 years). In other age categories (45 to 55 and >55 years), women presented lower cardiovascular mortality. This cardiovascular benefit was, however, smaller than in the general population. Stratification by diabetic nephropathy showed that diabetic women in all age categories remained at increased mortality risk compared with men, an effect mainly attributed to the noncardiovascular component. CONCLUSIONS Mortality rates and causes of death in men and women on dialysis vary with age. Increased noncardiovascular mortality may explain the loss of the survival advantage of women on dialysis. Both young and diabetic women starting dialysis are at a higher mortality risk than equal men.

Increased expression of pro-inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients.

Abstract.  Witasp A, Carrero JJ, Heimbürger O, Lindholm B, Hammarqvist F, Stenvinkel P, Nordfors L (Karolinska Institutet, Stockholm, Sweden). Increased expression of pro‐inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients. J Intern Med 2011; 269: 410–419.

Dietary protein-fiber ratio associates with circulating levels of indoxyl sulfate and p-cresyl sulfate in chronic kidney disease patients

BACKGROUND AND AIMS Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are uremic toxins derived solely from colonic bacterial fermentation of protein. Dietary fiber may counteract this by limiting proteolytic bacterial fermentation. However, the influence of dietary intake on the generation of IS and PCS has not been adequately explored in chronic kidney disease (CKD). METHODS AND RESULTS This cross-sectional study included 40 CKD participants (60% male; age 69 ± 10 years; 45% diabetic) with a mean estimated glomerular filtration rate (eGFR) of 24 ± 8 mL/min/1.73 m(2), who enrolled in a randomized controlled trial of synbiotic therapy. Total and free serum IS and PCS were measured at baseline by ultra-performance liquid chromatography. Dietary intake was measured using in-depth diet histories collected by a dietitian. Associations between each toxin, dietary fiber (total, soluble and insoluble), dietary protein (total, and amino acids: tryptophan, tyrosine and phenylalanine), and the protein-fiber index (ratio of protein to fiber) were assessed using linear regression. Dietary fiber was associated with free and total serum PCS (r = -0.42 and r = -0.44, both p < 0.01), but not IS. No significant association was observed between dietary protein and either toxin. The protein-fiber index was associated with total serum IS (r = 0.40, p = 0.012) and PCS (r = 0.43, p = 0.005), independent of eGFR, sex and diabetes. CONCLUSION Dietary protein-fiber index is associated with serum IS and PCS levels. Such association, beyond fiber and protein alone, highlights the importance of the interplay between these nutrients. We speculate that dietary modification towards a lower protein-fiber index may contribute to lowering IS and PCS.

The relationship between thyroid function and estimated glomerular filtration rate in patients with chronic kidney disease

BACKGROUND Recent studies have shown an increasing risk of hypothyroidism with incrementally lower estimated glomerular filtration rate (eGFR) in cohorts comprised of patients with normal to mildly impaired kidney function. We sought to confirm these findings in a nationally representative cohort of Veterans Affairs patients with moderate-to-severe chronic kidney disease (CKD). METHODS This study examined the association between kidney function and hypothyroidism among 461 607 veterans with Stage 3 to 5 CKD who underwent repeated measurements of serum creatinine and thyrotropin (TSH) at identical time points between October 2004 and September 2006. Kidney function was defined by eGFR using the Chronic Kidney Disease Epidemiology Collaboration formula. In primary analyses, the association between eGFR and hypothyroidism (defined as serum TSH > 5 mIU/L and/or receipt of thyroid hormone supplementation) was estimated using multivariable random effects logistic regression. In secondary analyses, the association between eGFR and serum TSH level was estimated using multivariable random effects linear regression. RESULTS At baseline, 68.9, 25.5, 5.3 and 0.3% of patients had Stage 3A, 3B, 4 and 5 CKD, respectively. For every 10 mL/min/1.73 m(2) lower eGFR, there was an 18% higher risk of hypothyroidism: adjusted odds ratio 1.18 [95% confidence interval (CI) 1.17-1.20, P < 0.001]. In secondary analyses, we observed that a 10 mL/min/1.73 m(2) lower eGFR was associated with a 0.11 mIU/L higher serum TSH (95% CI 0.10-0.11 mIU/L higher serum TSH, P < 0.001). CONCLUSIONS In a nationally representative cohort of patients with moderate-to-severe CKD, there is an inverse association between eGFR and risk of hypothyroidism.

Global Cardiovascular and Renal Outcomes of Reduced GFR

The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval [95% UI], 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.

Visceral obesity assessed by computed tomography predicts cardiovascular events in chronic kidney disease patients

BACKGROUND AND AIM Cardiovascular disease is the leading cause of death among patients with chronic kidney disease (CKD). Although there is emerging evidence that excess visceral fat is associated with a cluster of cardiometabolic abnormalities in these patients, the impact of visceral obesity evaluated by a gold-standard method on future outcomes has not been studied. We aimed to investigate whether visceral obesity assessed by computed tomography was able to predict cardiovascular events in CKD patients. METHODS AND RESULTS We studied 113 nondialyzed CKD patients [60% men; 31% diabetics; age 55.3 ± 11.3 years; body mass index (BMI) 27.2 ± 5.3 kg/m(2); estimated glomerular filtration rate (GFR) 33.7 ± 13.6 ml/min/1.73 m(2)]. Visceral and subcutaneous abdominal fat were assessed by computed tomography at L4-L5. Visceral to subcutaneous fat ratio >0.55 (highest tertile cut-off) was defined as visceral obesity. Cardiovascular events including acute myocardial infarction, angina, arrhythmia, uncontrolled blood pressure, stroke and cardiac failure were recorded during 24 months. Cardiovascular events were 3-fold higher in patients with visceral obesity than in those without visceral obesity. The Kaplan-Meier analysis indicated that patients with visceral obesity had shorter cardiovascular event-free time than those without visceral obesity (P = 0.021). In the univariate Cox analysis, visceral obesity was associated with higher risk of cardiovascular events (hazard ratio = 3.4; 95% confidence interval = 1.1-10.5; P = 0.03). The prognostic power of visceral obesity for cardiovascular events remained significant after adjustments for sex, age, diabetes, previous cardiovascular disease, smoking, sedentary lifestyle, BMI, GFR, hypertension, dyslipidemia and inflammation. CONCLUSION Visceral obesity assessed by computed tomography was a predictor of cardiovascular events in CKD patients.

Healthy Dietary Patterns and Risk of Mortality and ESRD in CKD: A Meta-Analysis of Cohort Studies

BACKGROUND AND OBJECTIVES Patients with CKD are advised to follow dietary recommendations that restrict individual nutrients. Emerging evidence indicates overall eating patterns may better predict clinical outcomes, however, current data on dietary patterns in kidney disease are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This systematic review aimed to evaluate the association between dietary patterns and mortality or ESRD among adults with CKD. Medline, Embase, and reference lists were systematically searched up to November 24, 2015 by two independent review authors. Eligible studies were longitudinal cohort studies reporting the association of dietary patterns with mortality, cardiovascular events, or ESRD. RESULTS A total of seven studies involving 15,285 participants were included. Healthy dietary patterns were generally higher in fruit and vegetables, fish, legumes, cereals, whole grains, and fiber, and lower in red meat, salt, and refined sugars. In six studies, healthy dietary patterns were consistently associated with lower mortality (3983 events; adjusted relative risk, 0.73; 95% confidence interval, 0.63 to 0.83; risk difference of 46 fewer (29-63 fewer) events per 1000 people over 5 years). There was no statistically significant association between healthy dietary patterns and risk of ESRD (1027 events; adjusted relative risk, 1.04; 95% confidence interval, 0.68 to 1.40). CONCLUSIONS Healthy dietary patterns are associated with lower mortality in people with kidney disease. Interventions to support adherence to increased fruit and vegetable, fish, legume, whole grain, and fiber intake, and reduced red meat, sodium, and refined sugar intake could be effective tools to lower mortality in people with kidney disease.

Temporal discrepancies in the association between the apoB/apoA-I ratio and mortality in incident dialysis patients

Background.  In the general population, a high apoB/apoA‐I ratio is a strong risk factor for cardiovascular disease and mortality. However, whether this is the case in chronic kidney disease (CKD) patients is currently unknown.

Endostatin Level is Associated with Kidney Injury in the Elderly: Findings from Two Community-Based Cohorts

Background: We aimed to investigate the associations between circulating endostatin and the different aspects of renal dysfunction, namely, estimated (cystatin C) glomerular filtration rate (GFR) and urine albumin-creatinine ratio (ACR). Methods: Two independent longitudinal community-based cohorts of elderly. ULSAM, n = 786 men; age 78 years; median GFR 74 ml/min/1.73 m2; median ACR 0.80 mg/mmol); and PIVUS, n = 815; age 75 years; 51% women; median GFR; 67 ml/min/1.73 m2; median ACR 1.39 mg/mmol. Cross-sectional associations between the endostatin levels and GFR as well as ACR, and longitudinal association between endostatin at baseline and incident CKD (defined as GFR <60 ml/min/1.73 m2) were assessed. Results: In cross-sectional regression analyses adjusting for age, gender, inflammation, and cardiovascular risk factors, serum endostatin was negatively associated with GFR (ULSAM: B-coefficient per SD increase -0.51, 95% CI (-0.57, -0.45), p < 0.001; PIVUS -0.47, 95% CI (-0.54, -0.41), p < 0.001) and positively associated with ACR (ULSAM: B-coefficient per SD increase 0.24, 95% CI (0.15, 0.32), p < 0.001; PIVUS 0.13, 95% CI (0.06-0.20), p < 0.001) in both cohorts. Moreover, in longitudinal multivariable analyses, higher endostatin levels were associated with increased risk for incident CKD defined as GFR <60 ml/min/1.73 m2 at re-investigations in both ULSAM (odds ratio per SD increase of endostatin 1.39 (95% CI 1.01-1.90) and PIVUS 1.68 (95% CI 1.36-2.07)). Conclusions: Higher circulating endostatin is associated with lower GFR and higher albuminuria and independently predicts incident CKD in elderly subjects. Further studies are warranted to investigate the underlying mechanisms linking endostatin to kidney pathology, and to evaluate the clinical relevance of our findings. i 2014 S. Karger AG, Basel