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Kidney Dysfunction, Inflammation, and Coronary Events: A Prospective Study
Abstract
Kidney dysfunction and high C-reactive protein (CRP) levels are independently associated with coronary events. However, it is unclear whether the risk of coronary events associated with decreased kidney function is at least partially mediated by inflammation and whether the association between inflammatory biomarkers and coronary events is influenced by level of kidney function. With the use of a prospective, nested, case-control study design, the association among kidney function, inflammatory biomarker levels, and coronary events was studied. A total of 244 women who were participants in the Nurses' Health Study and had no history of cardiovascular disease received a diagnosis of an incident coronary event (defined as nonfatal myocardial infarction or death as a result of coronary disease) during the follow-up period from 1990 to 1998 and were matched to 486 control subjects. Serum creatinine and inflammatory biomarker levels were measured in blood samples collected in 1989. Creatinine clearance (CrCl) was estimated using creatinine, age, weight, and height. In multivariate analyses, the odds ratio (OR) for a coronary event in women with an estimated CrCl <60 ml/min was 2.33 (95% confidence interval [CI], 1.01 to 5.38) compared with those with a CrCl > or =90 ml/min. When soluble tumor necrosis factor receptor (sTNFR) I and II levels were added into this model individually, the observed OR for women with CrCl <60 ml/min was attenuated. In analyses stratified by estimated CrCl, higher high-sensitivity CRP (hs-CRP), IL-6, and sTNFR I and II levels each were significantly associated with an increased odds of coronary events in women with an estimated CrCl < or =74 ml/min but not in women with an estimated CrCl > or =75 ml/min. The OR per 5-mg/L unit increase in hs-CRP was 1.68 (95% CI, 1.13 to 2.52) for women with an estimated CrCl < or =74 ml/min, compared with 1.23 (95% CI, 0.86 to 1.76) and 0.99 (95% CI, 0.76 to 1.29) for women with an estimated CrCl 75 to 89 and > or =90 ml/min, respectively (P = 0.004 for interaction). In conclusion, kidney dysfunction is associated with an increased odds of coronary events, and inflammation, as assessed by higher sTNFR I and II levels, may mediate some of this risk. Higher inflammatory biomarkers levels, specifically, hs-CRP, IL-6, and sTNFR I and II, were significantly associated with coronary events only in women with reduced kidney function. These findings warrant further investigation in other populations.
... m 2 . Subsequently, Knight et al. [23] hypothesized that the relationship between renal dysfunction and coronary events was partly mediated by the inflammatory process. They reported that higher levels of high-sensitivity CRP (hs-CRP), IL-6, and soluble tumor necrosis factor receptors type 1 and 2 as well as lower levels of pyridoxal phosphate (PLP) were significantly associated with a higher risk of coronary events in women with a creatinine clearance of less than 75 mL/min as compared with those with a value of 75 mL/min or higher [23]. ...
... Subsequently, Knight et al. [23] hypothesized that the relationship between renal dysfunction and coronary events was partly mediated by the inflammatory process. They reported that higher levels of high-sensitivity CRP (hs-CRP), IL-6, and soluble tumor necrosis factor receptors type 1 and 2 as well as lower levels of pyridoxal phosphate (PLP) were significantly associated with a higher risk of coronary events in women with a creatinine clearance of less than 75 mL/min as compared with those with a value of 75 mL/min or higher [23]. ...
... In a study of Knight et al. [23], increased cardiovascular risk correlated with higher levels of proinflammatory cytokines only in women. The division of the study and control groups according to sex affected the obtained results, especially in analyses stratified by the glomerular filtration rate. ...
Fractalkine (CX3CL1) is a chemokine that plays a significant role in inflammation, one of the pathophysiological processes underlying end-stage renal disease (ESRD). Genetic factors are significantly involved in cytokine expression and have been studied as potential risk factors for chronic kidney disease (CKD). Objectives: We aimed to elucidate the association of CX3CR1 gene polymorphisms rs3732378 and rs3732379 with the levels of CX3CL1, CX3CL1 receptor (CX3CR1), as well as C-reactive protein (CRP). Patients and methods: We enrolled 198 participants, including 106 patients with ESRD and 92 controls. Peripheral blood samples were collected from each patient for genetic (rs3732378 and rs3732379 polymorphisms) and immunoenzymatic (fractalkine, CX3CR1, CRP) tests. Results: CX3CR1 and CRP levels were higher in patients with ESRD than in controls (p < 0.05). Fractalkine levels were significantly higher in ESRD patients who were homozygous for the G allele of the rs3732378 polymorphism and for the C allele of the rs3732379 polymorphism than in homozygous controls. Moreover, carriers of these alleles among patients with ESRD had significantly higher CX3CR1 levels than controls. Conclusions: The G allele of the rs3732378 polymorphism and the C allele of the rs3732379 polymorphism of the CX3CR1 gene are associated with higher CX3CL1 and CX3CR1 levels. Our study suggests that CX3CR1 gene polymorphisms could be potentially involved in the pathogenesis of ESRD, but the study needs to be replicated in a larger population with a longitudinal follow-up study. Identification of genetic factors associated with inflammation in ESRD may contribute to the development of targeted gene therapies in the future.
... Serum biomarkers of inflammation, such as C-reactive protein (CRP) and IL-6, are associated with increased CVD risk, not only in the general population, but also in patients with CKD [3,4]. In addition to systemic inflammation, local inflammatory activity of the arterial wall is also implicated in such phenomenon [5]. ...
... This calcification is associated with increased vascular stiffening and cardiac workload, poor coronary perfusion, and sudden cardiac death and is probably responsible for the high cardiovascular mortality observed in CKD patients. The prevalence of such complications is 2.5 times higher in patients on dialysis than in non-dialysis one [4]. ...
... The effect of factors related respectively to haemodialysis as nutritional [20][21][22][23][24] and inflammatory state [3][4][5]10,20,23,24], anemia [16,17,25], calcium and phosphorus metabolism disorders [16,21] and to diabetes as, duration of evolution [16,26,27], balance [16,17,25], tendency to obesity [1,16,27] on the development of foot complications, were also evaluated. Always, by comparing with literature data, we have described types of diabetic foot lesions [15,25,28], type of diabetic neuropathies [29] and calculate ABPI to explorate lower limbs arteriopathy of our patients [28,30]. ...
... Risk of cardiovascular diseases (CVD) is significantly elevated in patients with chronic kidney disease (CKD), and increased cardiovascular risk is only partially explained by traditional CV risk factors (1)(2)(3)(4)(5)(6). Chronic systemic inflammation is highly prevalent in CKD patients (measured as an elevated high-sensitivity C-reactive protein [hsCRP]) (7,8) and is an independent predictor of morbidity and mortality, including cardiovascular mortality (7)(8)(9)(10)(11). The recently completed Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial demonstrated that blocking the pro-inflammatory cytokine interleukin-1 β (IL-1 β) reduced major adverse cardiovascular events by 15% in adults with history of acute myocardial infarction and chronic inflammation (n=10,061) (12). ...
... Largescale genetic studies have demonstrated a gene-dosage dependent relationship between loss of IL-6 signaling and reductions in both hsCRP and cardiovascular events, indicating a strong causal role of IL-6 signaling in promotion of atherosclerosis and cardiovascular events (14)(15)(16)(17). Both IL-6 and hsCRP levels are elevated in patients with non-dialysis dependent CKD (7,8,18) and are independently associated with cardiovascular events and allcause/cardiovascular mortality in this population (11,19,20). Thus, use of an IL-6 blocker to suppress chronic inflammation represents a potential new paradigm for reducing cardiovascular risk in patients with CKD. ...
... Chronic low grade inflammation is highly prevalent in CKD patients and an independent predictor of morbidity and mortality, including cardiovascular mortality (7)(8)(9)(10)(11). ...
Background
Chronic systemic inflammation is highly prevalent in patients with CKD (measured as an elevated high-sensitivity C-reactive protein, hsCRP) and independently associated with cardiovascular events and all-cause mortality. An IL-6 blocker to suppress inflammation represents a potential novel paradigm to reduce cardiovascular risk in CKD.
Methods
A phase 1 trial of ziltivekimab, a fully human mAb against IL-6, was conducted in patients with moderate-to-severe nondialysis-dependent CKD (eGFR of 20–60 ml/min per 1.73 m ² ) and evidence of chronic inflammation (hsCRP level >2 mg/L over two consecutive measurements). Three cohorts of n =4 (3:1 active:placebo) were blindly randomized to a single dose of ziltivekimab (5 mg, 15 mg, and 50 mg subcutaneous injection), and followed for 12 weeks for safety and pharmacokinetic/pharmacodynamic assessments, with an additional 20 weeks for safety and antidrug antibody assessments.
Results
Participants were 67±11 years old; baseline eGFR: 40±13 ml/min per 1.73 m ² ; baseline hsCRP: 5.0±2.5 mg/L. Dose escalation was approved, and all adverse events were within the expected range for a CKD population with chronic inflammation. No serious adverse events were reported in any active cohort. hsCRP levels were substantially reduced with ziltivekimab. Of participants, 100% achieved suppression of hsCRP to <2 mg/L with the 15 mg and 50 mg dose, and several patients had undetectable levels of hsCRP with the 50 mg dose. The mean t 1/2 ranged from of 45 to 65 days.
Conclusions
In adults with moderate-to-severe CKD and evidence of chronic inflammation, a single-injection of the IL-6 inhibitor ziltivekimab was safe and highly effective at suppressing hsCRP over 12 weeks.
... underscoring that sTNFR1 and sTNFR2 with respective molecular weights of approximately 30 and 40 kDa, are probably mainly eliminated by renal clearance [16][17][18]. Also, in large cohort studies in the general population, sTNFR1 [19,20] and sTNFR2 [19,21] have been associated to an increased risk for major cardiovascular events [19,21] or mortality [20], even after adjustment for traditional risk factors [21]. However, in these cohorts, and in contrast to our study (Table 3), no corrections were made for kidney function [21] or the association was only found when creatinine clearance ranged up to 75 ml/min, which implies a much broader range of eGFR than in the present study [19]. ...
... underscoring that sTNFR1 and sTNFR2 with respective molecular weights of approximately 30 and 40 kDa, are probably mainly eliminated by renal clearance [16][17][18]. Also, in large cohort studies in the general population, sTNFR1 [19,20] and sTNFR2 [19,21] have been associated to an increased risk for major cardiovascular events [19,21] or mortality [20], even after adjustment for traditional risk factors [21]. However, in these cohorts, and in contrast to our study (Table 3), no corrections were made for kidney function [21] or the association was only found when creatinine clearance ranged up to 75 ml/min, which implies a much broader range of eGFR than in the present study [19]. ...
... underscoring that sTNFR1 and sTNFR2 with respective molecular weights of approximately 30 and 40 kDa, are probably mainly eliminated by renal clearance [16][17][18]. Also, in large cohort studies in the general population, sTNFR1 [19,20] and sTNFR2 [19,21] have been associated to an increased risk for major cardiovascular events [19,21] or mortality [20], even after adjustment for traditional risk factors [21]. However, in these cohorts, and in contrast to our study (Table 3), no corrections were made for kidney function [21] or the association was only found when creatinine clearance ranged up to 75 ml/min, which implies a much broader range of eGFR than in the present study [19]. ...
Soluble tumor necrosis factor receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated to progression of renal failure, end stage renal disease and mortality in early stages of chronic kidney disease (CKD), mostly in the context of diabetic nephropathy. The predictive value of these markers in advanced stages of CKD irrespective of the specific causes of kidney disease has not yet been defined. In this study, the relationship between sTNFR1 and sTNFR2 and the risk for adverse cardiovascular events (CVE) and all-cause mortality was investigated in a population with CKD stage 4-5, not yet on dialysis, to minimize the confounding by renal function.
In 131 patients, CKD stage 4-5, sTNFR1, sTNFR2 were analysed for their association to a composite endpoint of all-cause mortality or first non-fatal CVE by univariate and multivariate Cox proportional hazards models. In the multivariate models, age, gender, CRP, eGFR and significant comorbidities were included as covariates.
During a median follow-up of 33 months, 40 events (30.5%) occurred of which 29 deaths (22.1%) and 11 (8.4%) first non-fatal CVE. In univariate analysis, the hazard ratios (HR) of sTNFR1 and sTNFR2 for negative outcome were 1.49 (95% confidence interval (CI): 1.28-1.75) and 1.13 (95% CI: 1.06-1.20) respectively. After adjustment for clinical covariables (age, CRP, diabetes and a history of cardiovascular disease) both sTNFRs remained independently associated to outcomes (HR: sTNFR1: 1.51, 95% CI: 1.30-1.77; sTNFR2: 1.13, 95% CI: 1.06-1.20). A subanalysis of the non-diabetic patients in the study population confirmed these findings, especially for sTNFR1.
sTNFR1 and sTNFR2 are independently associated to all-cause mortality or an increased risk for cardiovascular events in advanced CKD irrespective of the cause of kidney disease.
... 4 In population-based cohorts with participants in early stages of CKD or studies involving small numbers of dialysis patients, measurement of a limited number of biomarkers has suggested an association between inflammation and CVD outcomes. [5][6][7] However, these results have not been confirmed in larger and more ethnically diverse CKD cohorts with a wide range of glomerular filtration rates (GFRs) and long-term follow-up for clinical outcomes. Recently, the ACC/AHA introduced the new Pooled Cohort Equations to estimate 10-year atherosclerotic vascular disease (ASVD) risk. ...
... In a prospective nested case-control study involving 244 Nurses' Health Study participants, increased hs-CRP, IL-6, and soluble TNF receptor I and II levels were found to be significantly associated with coronary events only in those with reduced kidney function. 7 High CRP level was also an independent risk factor for cardiovascular death in MDRD Study participants. 22 An inverse association between serum albumin level and ASVD is reported in the general population, as well as in patients with kidney disease. ...
Rationale & objective:
Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of chronic kidney disease (CKD). We sought to determine whether the addition of measures of inflammation and kidney function to traditional estimation tools improves prediction of these events in a diverse cohort of patients with CKD.
Study design:
Observational cohort study.
Setting & participants:
2,399 Chronic Renal Insufficiency Cohort (CRIC) Study participants without a history of cardiovascular disease at study entry.
Predictors:
Baseline plasma levels of biomarkers of inflammation (interleukin 1β [IL-1β], IL-1 receptor antagonist, IL-6, tumor necrosis factor α [TNF-α], transforming growth factor β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin), measures of kidney function (estimated glomerular filtration rate [eGFR] and albuminuria), and the Pooled Cohort Equation probability (PCEP) estimate.
Outcomes:
Composite of ASVD events (incident myocardial infarction, peripheral arterial disease, and stroke) and death.
Analytical approach:
Cox proportional hazard models adjusted for PCEP estimates, albuminuria, and eGFR.
Results:
During a median follow-up of 7.3 years, 86, 61, 48, and 323 participants experienced myocardial infarction, peripheral arterial disease, stroke, or death, respectively. The 1-decile greater levels of IL-6 (adjusted HR [aHR], 1.12; 95% CI, 1.08-1.16; P<0.001), TNF-α (aHR, 1.09; 95% CI, 1.05-1.13; P<0.001), fibrinogen (aHR, 1.07; 95% CI, 1.03-1.11; P<0.001), and serum albumin (aHR, 0.96; 95% CI, 0.93-0.99; P<0.002) were independently associated with the composite ASVD-death outcome. A composite inflammation score (CIS) incorporating these 4 biomarkers was associated with a graded increase in risk for the composite outcome. The incidence of ASVD-death increased across the quintiles of risk derived from PCEP, kidney function, and CIS. The addition of eGFR, albuminuria, and CIS to PCEP improved (P=0.003) the area under the receiver operating characteristic curve for the composite outcome from 0.68 (95% CI, 0.66-0.71) to 0.73 (95% CI, 0.71-0.76).
Limitations:
Data for cardiovascular death were not available.
Conclusions:
Biomarkers of inflammation and measures of kidney function are independently associated with incident ASVD events and death in patients with CKD. Traditional cardiovascular risk estimates could be improved by adding markers of inflammation and measures of kidney function.
... Although the mechanisms whereby inflammatory response alters renal function have not been completely elucidated, it is known that immune-inflammatory mediators modulate endothelial function, circulating immune cell migration and adhesion to renal interstitium and local fibroblast activation [13,75,76,77]. Among these mediators, it is noted that cytokines, their soluble receptors and CRP rise steadily in line with renal function deterioration [78,79]. IL-1β, IL-6, and TNF are some of the proinflammatory cytokines whose association with CKD pathophysiology is now well established [77][78][79][80][81]. On the other hand, not all cytokines have inflammatory effects. ...
... Among these mediators, it is noted that cytokines, their soluble receptors and CRP rise steadily in line with renal function deterioration [78,79]. IL-1β, IL-6, and TNF are some of the proinflammatory cytokines whose association with CKD pathophysiology is now well established [77][78][79][80][81]. On the other hand, not all cytokines have inflammatory effects. ...
Introduction:
Chronic kidney disease (CKD) has been considered an important public health issue in all countries. Experimental and clinical studies support the general idea that the pathophysiology of CKD is associated with the interaction of several endogenous mediators, including components of the renin-angiotensin system (RAS) and cytokines.
Objective:
This review aims to report available evidence on the interaction of RAS molecules and cytokines in CKD.
Results:
Therapeutic administration of angiotensin converting enzyme (ACE) inhibitors and/or angiotensin type 1 (AT1) receptor antagonists can slow down the deterioration of renal function. These medications reduce the formation (ACE inhibitor) or the receptor-mediated effects of Angiotensin II (AT1 antagonist) and by so doing inhibit cytokine-mediated kidney tissue inflammation. In sharp contrast, the activation of ACE2, the stimulation of Angiotensin-(1-7) synthesis and/or the effects mediated by its G-protein coupled receptor, named Mas receptor, ameliorates experimental renal injury by reducing renal tissue inflammation and fibrosis in many experimental models of renal diseases.
Conclusion:
Novel compounds that activate and/or stimulate ACE2-Angiontensin-(1-7)-Mas receptor axis may also play a role in the treatment of CKD, mainly by controlling inflammatory response and pathways of fibrosis at kidney tissue. Clinical trials with these new pharmacological compounds will, in due course, determine whether this promise will become a helpful treatment.
... TNFα is mediated via TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), which are membrane bound and soluble in plasma [12]. Elevated serum concentrations of circulating TNFRs have been found in chronic kidney disease [13][14][15][16][17], and recent studies reported a strong correlation with early and late renal progression in type 1 and 2 diabetes [18,19]. In addition, TNFα pathway markers were up-regulated in lupus nephritis along with elevated urinary TNFR1 excretion [20,21]. ...
... Our findings are consistent with several previous studies, indicating that circulating TNFRs were significantly correlated with the eGFR or proteinuria in patients with various kidney diseases [14][15][16][17]26,27]. The changes of uric acid level and serum albumin level following the elevated concentrations of TNFRs in this study were also attributed to the correlation between TNFRs and renal function. ...
The circulating tumor necrosis factor receptors (TNFRs) could predict the long-term renal outcome in diabetes, but the role of circulating TNFRs in other chronic kidney disease has not been reported. Here, we investigated the correlation between circulating TNFRs and renal histologic findings on kidney biopsy in IgA nephropathy (IgAN) and assessed the notion that the circulating TNFRs could predict the clinical outcome. 347 consecutive biopsy-proven IgAN patients between 2006 and 2012 were prospectively enrolled. Concentrations of circulating TNFRs were measured using serum samples stored at the time of biopsy. The primary clinical endpoint was the decline of estimated glomerular filtration rate (eGFR; ≥ 30% decline compared to baseline). Mean eGFR decreased and proteinuria worsened proportionally as circulating TNFR1 and TNFR2 increased (P < 0.001). Tubulointerstitial lesions such as interstitial fibrosis and tubular atrophy were significantly more severe as concentrations of circulating TNFRs increased, regardless of eGFR levels. The risks of reaching the primary endpoint were significantly higher in the highest quartile of TNFRs compared with other quartiles by the Cox proportional hazards model (TNFR1; hazard ratio 7.48, P < 0.001, TNFR2; hazard ratio 2.51, P = 0.021). In stratified analysis according to initial renal function classified by the eGFR levels of 60 mL/min/1.73 m2, TNFR1 and TNFR2 were significant predictors of renal progression in both subgroups. In conclusion, circulating TNFRs reflect the histology and clinical severity of IgAN. Moreover, elevated concentrations of circulating TNFRs at baseline are early biomarkers for subsequent renal progression in IgAN patients.
... 2 In addition to these risk factors, some metabolic problems due to absorption of glucose from peritoneal cavity as an osmotic agent and peritoneal damage via advanced glycosylation end products contribute to accelerated atherosclerosis in peritoneal dialysis (PD) patients. 3 Apelin, released from white adipose tissue, is an adipocytokine defined recently. It is expressed in endothelial cells and also other tissues including brain and kidney. ...
... These risk factors directly contribute to increase in cardiovascular mortality. 3 In this study, it was investigated that the relation between serum apelin level as a biomarker and inflammatory markers, echocardiographic findings and CIMT as an early finding of atherosclerosis in PD patients. In ESRD patients under renal replacement therapy, serum apelin level compared with healthy controls. ...
Background:
Cardiovascular disease (CVD) is the most important cause of morbidity and mortality in patients with end stage renal disease (ESRD). Apelin expressed in endothelial and other tissues including brain and kidney is an adipocytokine defined recently and is emerging an important mediator of cardiovascular homeostasis. The aim of this study was to test whether apelin levels might be associated with carotid artery atherosclerosis and left ventricular mass index (LVMI) in peritoneal dialysis patients.
Patients and methods:
Fifty peritoneal dialysis patients (25 female, mean age 41.4 ± 11.9 years, mean dialysis vintage 65.0 ± 35.4 months) and 18 healthy individuals (9 female, mean age 41.7 ± 6.8 years) were included in this cross-sectional study. Serum apelin 12 levels, echocardiographic findings and carotid intima media thickness (CIMT) were recorded as well as clinical and laboratory data.
Results:
There were no differences between the patient and the control groups with regard to demographic characteristics. In patient group, LVMI, CIMT, CRP and apelin levels were elevated compared to control group. However there was no association between apelin, LVMI and CIMT. There was a positive correlation between apelin and CRP, which was not statistically significant. When patients were divided into two groups according to the mean serum apelin levels, LVMI, CIMT and CRP were higher in the high apelin group but this difference did not reach statistical significance.
Conclusion:
We observed an increased inflammation and CVD risk in peritoneal dialysis patients. However, serum apelin levels seem not to be associated with cardiovascular risk in this group of patients.
... [26][27][28][29] Disorders in calcium and phosphorus metabolism, including hyperphosphatemia and hypocalcemia, along with elevated iPTH levels, can induce vascular wall smooth muscle cells to exhibit osteoblast-like activity, secrete bone morphogenetic proteins, and enhance the process of vascular calcification. 30 The studies conducted by Amdur et al. 32 and Knight et al. 33 have revealed that inflammatory biomarkers are independently associated with the occurrence of atherosclerotic vascular disease episodes and mortality in patients with CKD. Inflammation is widely recognized as a key contributor to the development of atherosclerosis. ...
... In addition to well-acknowledged traditional risk factors, nontraditional risk factors including systemic inflammation play an important role in CKD, especially in end-stage kidney disease (ESKD) patients [1]. Systemic inflammation is thought to be a contributor to worse outcomes in ESKD patients and high circulating concentrations of inflammation biomarkers, such as C-reactive protein (CRP) and interleukin-6 (IL-6), and low concentrations of serum albumin (s-albumin) are tightly associated with protein-energy wasting, atherosclerosis [2], and vascular calcification [3] and predict risk of CV events and mortality [4,5]. ...
Background:
In patients with chronic kidney disease (CKD), high interleukin-6 (IL-6) and low albumin circulating concentrations are associated with worse outcomes. We examined the IL-6 to albumin ratio (IAR) as a predictor of risk of death in incident dialysis patients.
Methods:
In 428 incident dialysis patients (median age 56 years, 62% men, 31% diabetes mellitus, 38% cardiovascular disease (CVD)), plasma IL-6 and albumin were measured at baseline to calculate IAR. We compared the discrimination of IAR with other risk factors for predicting 60 months mortality using receiver operating characteristic curve (ROC) and analysed the association of IAR with mortality using Cox regression analysis. We divided patients into IAR tertiles and analysed: 1) cumulative incidence of mortality and the association of IAR with mortality risk in Fine-Gray analysis taking kidney transplantation as competing risk; and 2) the restricted mean survival time (RMST) to 60 months mortality and differences of RMST (∆RMST) between IAR tertiles to describe quantitative differences of survival time.
Results:
For all-cause mortality, the area under the ROC curve (AUC) for IAR was 0.700, which was greater than for IL-6 and albumin separately, while for CV mortality, the AUC for IAR (0.658) showed negligible improvement over IL-6 and albumin separately. In Cox regression analysis, IAR was significantly associated with all-cause mortality but not with CV mortality. Both high vs low and middle vs low tertile of IAR associated with higher risk of all-cause mortality, subdistribution hazard ratio of 2.22 (95% CI, 1.40-3.52) and 1.85 (95% CI, 1.16-2.95) respectively after adjusting for age, sex, diabetes mellitus, CVD, smoking and estimated glomerular filtration rate (eGFR). ∆RMST at 60 months showed significantly shorter survival time in middle and high IAR tertiles compared with low IAR tertile for all-cause mortality.
Conclusions:
Higher IL-6 to albumin ratio was independently associated with significantly higher all-cause mortality risk in incident dialysis patients. These results suggest that IAR may provide useful prognostic information in patients with CKD.
... CKD is associated with systemic [6] and vascular inflammation [7]. It is known that inflammation is a key player in atherosclerotic and thrombotic disorders during CKD [8,9]. ...
Background:
Chronic kidney disease (CKD) is a major public health issue associated with increased cardiovascular, infectious and all-cause mortality. The neutrophil:lymphocyte ratio (NLR) is a predictive marker of the risk of death and cardiovascular events. Uremic toxins, notably indoxyl sulfate (IS), are involved in immune deficiency and cardiovascular complications associated with CKD. The aim of this study was to assess whether the NLR was related to uremic toxins and could predict clinical outcome in hemodialysis (HD) patients.
Methods:
We conducted a prospective cohort study of 183 patients on chronic HD. The main objective was to study the correlation between the NLR and uremic toxin serum levels. The secondary objective was to test if the NLR can predict the incidence of mortality, cardiovascular events and infectious events.
Results:
Patients were separated into two groups according to the NLR median value (3.49). The NLR at inclusion was correlated with the NLR at the 6-month (r = 0.55, P < 0.0001) and 12-month (r = 0.62, P < 0.0001) follow-up. Among uremic toxins, IS levels were higher in the group with high NLR (104 µmol/L versus 81 µmol/L; P = 0.004). In multivariate analysis, the NLR remained correlated with IS (P = 0.03). The incidence of death, cardiovascular events and severe infectious events was higher in the group with high NLR [respectively, 38% versus 18% (P = 0.004), 45% versus 26% (P = 0.01) and 33% versus 21% (P = 0.02)] than in the low NLR group. Multivariate analysis showed an independent association of the NLR with mortality (P = 0.02) and cardiovascular events (P = 0.03) but not with severe infectious events.
Conclusions:
In HD patients, the NLR predicted mortality and cardiovascular events but not severe infections and correlated positively with the level of the uremic toxin IS. The NLR could be an interesting marker for monitoring the risk of clinical events in CKD patients.
... The difference in the findings of Culleton et al could be explained by the differences in the ages of their study population, and prevalence of associated co-morbidities 13 . Although the mechanism by which CKD potentiates risk of death is unknown, possible explanations are coexistence with other cardiovascular risk factors like anaemia, diabetes, patients with renal disease receiving efficacious, but potentially toxic therapies, and associated vascular disease (atherosclerosis); these risk factors might contribute directly to mortality in these patients 14,[18][19][20] . ...
Background:
The burden of chronic kidney disease is increasing globally and prompt identification, coupled with improved management of CKD patients have increased the population of pre-dialysis patients. We, therefore, aimed to evaluate the predictors of survival among pre-dialysis CKD patients in South Africa.
Methods:
We conducted a cohort study of 256 consecutive consenting Black non-dialysis requiring CKD patients attending the renal outpatient clinic of a tertiary Hospital in South Africa from 1st June 2016 to 1st December 2016. Socio-demographic and clinical information of the participants were obtained. Descriptive statistics, Kaplan-Meier curves and Cox proportional hazard regression analyses were conducted to evaluate factors affecting the survival of the participants.
Results:
The mean age of the participants was 52.8±14.3 years and 48.0% were females, 52% were males. The death rate increased with worsening haemoglobin level from 0.96 among patients with mild anaemia to 4.29 per 100-person years among patients with severe anaemia. Anaemic patients with GFR < 30mls/min had significantly increased risk of death (HR 11.51, 95% CI 1.62-78.32, P < 0.001).
Conclusion:
Mortality in pre-dialysis CKD patients was associated with anaemia and hyperphosphatemia. Clinical interventions targeted at preventing these conditions may improve outcomes among this group of CKD patients.
... [17][18][19][20][21] In patients with CKD, elevated CRP levels are more prevalent than in non-CKD patients, and CRP can impact appetite, protein-energy wasting, and body size. 5,15,19,22,23,24 The obesity paradox has been observed in some cohorts of nondialysis-dependent CKD (NDD-CKD), but not in others, and with incomplete control for markers of inflammation including CRP. 5,14,25 It is unclear at which CKD stage the obesity-mortality association changes into an inverse relationship, thereby representing an obesity paradox, and whether the rise in inflammation across progressive CKD stages could explain these changes. ...
Objective
In advanced chronic kidney disease (CKD), patients with obesity often have better outcomes compared to patients without obesity, often called the ‘obesity paradox’. Yet, in CKD, the prevalence of inflammation increases as CKD progresses. While a potential confounder, inflammation may be left unaccounted in obesity–mortality studies. We examined the associations of body mass index (BMI) with all-cause and cause-specific mortality across CKD stages, with consideration for uncontrolled confounding due to unmeasured inflammation.
Methods
We investigated 2,703,512 patients with BMI data between 2004-2006. We used Cox models to examine the associations of BMI with all-cause, cardiovascular, and cancer mortality, (ref: BMI 25-<30 kg/m²), adjusted for clinical characteristics and stratified by CKD stages. To address uncontrolled confounding, we performed bias analysis using a weighted probabilistic model of inflammation given the observed data applied to weighted Cox models.
Results
The cohort included 5% females and 14% African Americans. In adjusted analyses, the associations of BMI with all-cause and cardiovascular mortality showed a reverse J-shape, where higher BMI (>40 kg/m²) was associated with higher risk. Conversely, lower mortality risk was observed with BMI 30-<35 kg/m² across all CKD stages, and for BMI >40 kg/m² in CKD stage 4/5. Cancer mortality analyses showed an inverse relationship. Bias analysis for uncontrolled confounding suggested that independent of inflammation, the obesity paradox was present.
Conclusion
We observed the presence of the obesity paradox in this study. This association was consistent in advanced CKD and in our bias analysis, suggesting that inflammation may not fully explain the observed BMI-mortality associations including in patients with CKD.
... Traditional CV risk factors such as diabetes, hypertension and dyslipidaemia are common in CKD. However, other non-traditional CV risk factors are also important, including endothelial dysfunction, vascular calcification, inflammation and mineral bone disease [2][3][4]. CKD-mineral bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that affects bone metabolism, bone turnover and vascular calcification [5]. Disturbances in mineral metabolism are associated with increased mortality and CV disease [6]. ...
Background:
Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality, and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers, and the association with inflammatory cytokines, and cardiovascular outcomes.
Methods:
This prospective study enrolled hemodialysis (HD) patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1 (Dkk-1), fibroblast growth factor 23 (FGF-23), leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest algorithm (RF). The association between bone-associated proteins with all-cause death, cardiovascular death, and CVEs was analyzed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data, and dialysis duration.
Results:
We enrolled 331 patients (63.7% men; mean [SD] age, 65 [14.6] years) in a prospective cohort study with five years follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death, and four biomarkers were associated with CVE. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins, and just OPG remained associated with CVE in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVE when added clinical information alone in integrated discrimination improvement and net reclassification improvement analyses.
Discussion:
OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD, and CTSL1) was affected by cytokine inflammation activity.
... On a cellular level, CRP can increase tau hyperphosphorylation and promote Aβ formation, suggesting a role in Alzheimer's pathophysiology (Bi et al., 2012;Guo et al., 2015) In the kidney, elevations in multiple inflammatory markers including CRP, IL-1, IL-1 receptor antagonist, IL-6, and TNF-α have been seen in chronic diseased state (Keller et al., 2008;Gupta et al., 2012). Higher levels of inflammatory cytokines and decreased albumin levels are associated with chronic kidney disease (CKD) progression and increased mortality in patients with CKD and end-stage renal disease (Alves et al., 2018;Kimmel et al., 1998;Panichi et al., 2004;Knight et al., 2004;Amdur et al., 2016;Senthilkumar et al., 2018). ...
Although microvascular dysfunction (MVD) has been well characterized in individual organs as different disease entities, clinical evidence is mounting in support of an underlying systemic process. To address this hypothesis, we systematically searched PubMed and Medline for studies in adults published between 2014-2019 that measured blood biomarkers of MVD in three vital organs i.e. brain, heart, and the kidney. Of the 9706 unique articles 321 met the criteria, reporting 49 biomarkers of which 16 were common to the three organs. Endothelial dysfunction, inflammation including reactive oxidation, immune activation, and coagulation were the commonly recognized pathways. Triglyceride, C-reactive protein, Cystatin C, homocysteine, uric acid, IL-6, NT-proBNP, thrombomodulin, von Willebrand Factor, and uric acid were increased in MVD of all three organs. In contrast, vitamin D was decreased. Adiponectin, asymmetric dimethylarginine, total cholesterol, high-density and low-density cholesterol were found to be variably increased or decreased in studies. We review the pathways underlying MVD in the three organs and summarize evidence supporting its systemic nature. This scoping review informs clinicians and researchers in the multi-system manifestation of MVD. Future work should focus on longitudinal investigations to evaluate the multi-system involvement of this disease.
... The 10-to 30-fold increase in mortality makes CKD patients the 'highest risk group' for subsequent cardiovascular events (Yadav et al., 2012).Traditional risk factors such as smoking, hypertension, and hypercholesterolemia can be identified, but do not explain the full magnitude of the increment in risk (Menon et al., 2005). It has been suggested that mortality and CVD are strongly associated with levels of certain proinflammatory cytokines and acute-phase proteins at the time of initiation of renal replacement therapy as well as on their profiles during dialysis treatment (Knight et al., 2004). One possible mechanism is through accelerated atherosclerosis. ...
Background: Chronic kidney disease (CKD), whether starting HD or not is associated with a sharp increase in the risk for cardiovascular disease, which can only be partially explained by known classical risk factors. However, chronic inflammation and endothelial dysfunction are key events in the development of atherosclerosis; both are observed in CKD and HD patients. A unique cytotoxic CD4+T cell population has been identified, which can be recognized by the loss of the costimulatory cell surface marker CD28, hence their name CD4+ CD28null T cells. These cells are highly proinflammatory.Aims: The aim of the present study is to determine the prevalence of CD4+CD28 null T Helper cells and its relation to atherosclerosis in CKD patients not starting HD and Patients on regular HD for more than 6 months. Materials and Methods: CD4+CD28null T cells were measured in the blood samples of 60 CKD patients (30 CKD patients not start HD (Group ΙΙ) and 30 CKD patients on regular HD more than six months (Group ΙΙΙ) and in comparison with 30 control subjects (Group Ι) (Control Group). Results:The mean value of CD4+CD28null T cells in the control group (1.5±0.49), the mean value in the CKD predialysis group (6.3±1.1) and The mean value in the CKD on HD group (7.5±3.7),thus The mean values of CD4+CD28null T cells in both CKD predialysis and CKD on HD groups were significantly higher than that of the control group (P1<0.001, P2<0.001),and The mean value of CD4+CD28null T cells in the CKD on HD was higher than that of CKD predialysis group, but there was no significant difference between CKD predialysis and CKD on HD groups (P3=0.25).Conclusions: CKD patients exhibit an increase in the circulating cytotoxic CD4 +CD28 null T lymphocyte population. CD4+CD28null T cells cell expansion correlated with preclinical atherosclerotic changes. There was an independent association between (CD4+CD28null T cells, age, hsCRP) and IMT in the CKD (predialysis, and on regular HD) groups.
... A unique research, done by Knight and colleagues [32], describes patients with CKD in stage I-II. The authors were searching for correlation between cardiovascular risk factors and renal insufficiency and whether presence of inflammatory markers influences them. ...
Cardiovascular diseases, including hypertension, congestive heart failure, myocardial infarction, stroke and atherosclerosis, are common in patients with chronic kidney disease. Aside from the standard biomarkers, measured to determine cardiovascular risk, new ones have emerged: markers of oxidative stress, apoptosis, inflammation, vascular endothelium dysfunction, atherosclerosis, organ calcification and fibrosis. Unfortunately, their utility for routine clinical application remains to be elucidated. A causal relationship between new markers and cardiovascular diseases in patients with chronic kidney disease remains to be established. First of all, there is a lack of large, randomized trials. Moreover, most studies focus on patients with end-stage renal disease as well as on dialysed patients. In such patients, cardiovascular diseases are already present and advanced while early detection of cardiovascular disease risk factor in patients with early-stages of chronic kidney disease would allow more precise prognosis and, as a result, changes in treatment algorithm. In this article, we conduct a comprehensive review of literature for publications relating to cardiovascular risk factors in patients with early-stages of chronic kidney disease. Overall, there are many encouraging advances in detection of cardiovascular risk factors that are making the future more promising for patients suffering from chronic kidney disease.
... Soluble TNF receptors are elevated in the setting of inflammation and chronic kidney disease. 53,54 Soluble TNF-R1 is independently associated with all-cause mortality and increased risk for cardiovascular events in advanced chronic kidney disease irrespective of the cause of kidney disease. 55 Soluble TNF-R1 predicts risk for ESRD in patients with type 2 diabetes even after adjustment for clinical covariates such as urinary albumin excretion. ...
Introduction:
HIV-positive (HIV+) kidney transplant recipients exhibit a 2- to 3-fold increased risk of allograft rejection. Dysregulated immune activation in HIV infection persists despite successful antiretroviral therapy and is associated with non-AIDS morbidity, including renal disease. We hypothesized that the pathological levels of inflammation and immune activation associated with chronic HIV infection could have clinical utility in the prediction of rejection in HIV+ kidney recipients.
Methods:
Prospective cohort study of 22 HIV-negative (HIV-; donor) to HIV+ (recipient) kidney transplant recipients who underwent biomarker assessment pretransplant and were subsequently followed for development of acute rejection. Plasma levels of markers of inflammation (soluble tumor necrosis factor receptor 1 [sTNF-R1] and C-reactive protein [CRP]) and microbial translocation (soluble CD14 and lipopolysaccharide) were measured by enzyme-linked immunosorbent assay or chromogenic endpoint assay. Levels of activated (CD38+HLADR+) CD4+ and CD8+ T cells, and T regulatory cells (CD4+CD25highFoxP3+) were measured by flow cytometry.
Results:
Among the biomarkers evaluated, only the pretransplant levels of sTNF-R1, CRP, and frequencies of CD38+HLADR+ CD8 T cells, were found to be at significantly higher levels among patients who experienced biopsy-proven acute rejection. Confirming our hypothesis, patients with high pretransplant levels of sTNF-R1 or activated CD8+ T cells had a significantly increased 200-day cumulative incidence of biopsy-proven acute rejection (0 vs. 38% for both; P = 0.01). Similarly, pretransplant CRP levels higher than 5 μg/ml were associated with increased risk of acute rejection within the first 6 months post-transplant (0 vs. 43%; P = 0.01).
Conclusion:
Biomarker-based identification of HIV+ recipients at increased risk for rejection might facilitate individualized induction immunosuppression regimens in this vulnerable patient population.
... It has been proposed that low levels of inflammation caused by SCT can contribute to CAD in scenarios where a second hit -most commonly severe exertion -provokes the release of pro-inflammatory substances [27,28]. The concurrent presence of CKD, itself an independent risk factor for inflammation, endothelial dysfunction and CVD [33,34], may also offer a second hit and therefore exacerbate the risk for CAD in SCT. Prior studies examining the association between CAD and SCT have not addressed the superimposition of CKD [7,30]. ...
Background:
Sickle cell trait (SCT) is common among African Americans and has been historically considered to be benign. Recently, SCT has been associated with an increased risk for chronic kidney disease (CKD) and cardiovascular disease in the general population. Our understanding of SCT has been extrapolated largely from data of patients with sickle cell disease (SCD). Notably, in SCD, the outcomes differ by sex. The effect of SCT on cardiovascular risk in the African American CKD population is unknown, and the interaction between SCT and sex on cardiovascular risk has not been investigated.
Methods:
We performed a 2-center retrospective cohort study of all African American patients with SCT using international classification of disease diagnosis codes and CKD (using the 2012 Kidney Disease Improving Global Outcomes criteria) with at least 1 year of follow-up between January 2005 and December 2017. A reference group of -African American CKD patients without SCT was used as a comparator during the same period. SCT patients and the reference patients were matched at baseline for age, sex, comorbidities, and proteinuria. Primary outcomes were incident coronary artery disease (CAD), incident stroke, and all-cause mortality. Analysis of effect modification between sex and SCT on primary outcomes was performed.
Results:
We identified 621 African American CKD patients, 217 SCT patients, and 404 reference patients. The mean age was 56 ± 13 years and 66% were female. The mean estimated glomerular filtration rate was 69 ± 30 mL/min. The mean follow-up time was 8 ± 4 years. There were no significant differences in the primary outcomes comparing SCT patients to matched controls. The interaction term between SCT and sex, however, was significant in the CAD model (p < 0.01). Stratification by sex showed no increased risk in females but a significantly increased risk for CAD in male SCT patients (hazard ratio [HR] 2.14; 95% CI 1.18-3.86), which persisted after multivariable analysis (HR 2.13; 95% CI 1.17-3.86).
Conclusion:
SCT is associated with an increased risk for CAD in African American males with CKD. The excess risk in males with SCT appears to follow the same pattern as risk in males with SCD. Larger studies are needed to confirm these findings.
... These comprise traditional and non-traditional risk factors; toxic, metabolic, and vascular factors; and considerations like hypervolemia, hypertension, and anemia. [15] It has been demonstrated in several studies that LV hypertrophy, LV dilatation, reduced EF, and diastolic dysfunction can develop as a result of these factors. However, data on the prevalence of RV dysfunction in patients undergoing chronic dialysis, especially PD, are still lacking. ...
Objective:
Cardiovascular disease is the leading cause of mortality in patients undergoing dialysis. Most of the available studies focus on left ventricular (LV) function in peritoneal dialysis (PD) patients; data about the effect of PD on right ventricular (RV) function are scarce. The aim of this study was to evaluate echocardiographic parameters of the RV in patients with end-stage renal disease (ESRD) undergoing PD.
Methods:
A total of 73 individuals were grouped as follows: PD patients (n=36) and healthy controls (n=37). Echocardiography of the RV was performed in all of the patients using tissue Doppler imaging (TDI).
Results:
The LV mass index (LVMI), left atrial (LA) diameter, posterior wall, and interventricular septum thicknesses were significantly greater in the PD group. The LV peak late diastolic atrial contraction (A) velocity was higher, and the peak early diastolic (E) velocity and the early diastolic velocity of the lateral mitral annulus (Em) were lower in the PD group compared with the control group. The right atrial (RA) diameter, RA area, RV fractional area change, RV myocardial performance index, and pulmonary vascular resistance values were similar in both groups, whereas the tricuspid annular plane systolic excursion (TAPSE) value was lower in the PD patients. The RV E; early diastolic (Ea), late diastolic (Aa), and systolic (Sa) velocities; deceleration time; and tricuspid regurgitation velocity were also similar in the 2 groups. Only the RV A velocity and the Ea/Aa ratio were significantly higher in the PD group, and the E/A ratio was lower in the PD group than in the control group.
Conclusion:
The results of conventional and TDI echocardiography indicated that RV systolic and diastolic functions were preserved in PD patients.
... 3,9 No association with mortality risk was found in patients undergoing hemodialysis. 45 These previous associations were generally independent of more established inflammatory markers, such as CRP, in most, 3,6,9,10,41,44,45 but not all, studies. 7,8 The present study is unique in that it reports the independent association between the TNFRs and the 10-year risk of adverse outcomes in patients with stable coronary heart disease. ...
Background:
We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.
Methods and results:
CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; P=0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; P<0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).
Conclusions:
Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.
Clinical trial registration:
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.
... Accumulating evidence indicates that inflammation plays a role in the initiation and progression of many forms of CKD, and accounts for at least part of the increased risk of CV events in CKD patients. Higher CRP levels are associated with a higher risk of CV events in CKD patients, 2 and with a decline in estimated glomerular filtration rate (eGFR). 3 Local inflammatory activity of the arterial wall can be assessed by measuring 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake with positron emission computed tomography, as illustrated in Figure 1. ...
Accumulating evidence indicates that inflammation plays a role in the initiation and progression of chronic kidney disease. In the Study of Heart and Renal Protection (SHARP) trial, higher baseline C-reactive protein and higher baseline low-density lipoprotein cholesterol levels were both associated with a higher risk of cardiovascular events, but higher baseline C-reactive protein levels were also associated with a higher risk of nonvascular events. Simvastatin/ezetimibe reduced cardiovascular events independent of baseline C-reactive protein levels. However, this observation does not exclude inflammation as a causal factor for cardiovascular disease development in chronic kidney disease patients.
... Because CKD increases pro-inflammatory mediators [29,30] and the association between PDGF and VEGF with miRs in IH pathogenesis has been reported [12,31,32], we evaluated the concentration in sera over time to determine the cascade of these mediators in Chr I/R mice. We found that serum miR-221 was the earliest detectable biomarker among these molecules (detectable in 5 mice (50%) at 12 weeks after right nephrectomy). ...
Intimal hyperplasia (IH) is a common cause of vasculopathy due to direct endothelial damage (such as post-coronary revascularization) or indirect injury (such as chronic kidney disease, or CKD). Although the attenuation of coronary revascularization-induced IH (direct-vascular-injury-induced IH) by cilostazol, a phosphodiesterase III inhibitor, has been demonstrated, our understanding of the effect on CKD-induced IH (indirect-vascular-injury-induced IH) is limited. Herein, we tested if cilostazol attenuated CKD-induced IH in a mouse model of ischemic-reperfusion injury with unilateral nephrectomy (Chr I/R), a normotensive non-proteinuria CKD model. Cilostazol (50 mg/kg/day) or placebo was orally administered once daily from 1-week post-nephrectomy. At 20 weeks, cilostazol significantly attenuated aortic IH as demonstrated by a 34% reduction in the total intima area with 50% and 47% decreases in the ratios of tunica intima area/tunica media area and tunica intima area/(tunica intima + tunica media area), respectively. The diameters of aorta and renal function were unchanged by cilostazol. Interestingly, cilostazol decreased miR-221, but enhanced miR-143 and miR-145 in either in vitro or aortic tissue, as well as attenuated several pro-inflammatory mediators, including asymmetrical dimethylarginine, high-sensitivity C-reactive protein, vascular endothelial growth factor in aorta and serum pro-inflammatory cytokines (IL-6 and TNF-α). We demonstrated a proof of concept of the effectiveness of cilostazol in attenuating IH in a Chr I/R mouse model, a CKD model with predominantly indirect-vascular-injury-induced IH. These considerations warrant further investigation to develop a new primary prevention strategy for CKD-related IH.
... More specifically, we recently demonstrated that treatment of VSMC with secondary CPP leads to pronounced and concentration-dependent calcification [2]. Consistent with this finding, calcification has been linked to oxidative stress [3] as well as elevation of some inflammatory cytokines and C-reactive protein in CKD patients [22,36]. An independent body of research has revealed that sulfide is involved in numerous physiological functions [39]. ...
Background and aims:
Vascular calcification is a common health problem related to oxidative stress, inflammation, and circulating calciprotein particles (CPP). Hydrogen sulfide is an endogenous signaling molecule with antioxidant properties and potential for drug development targeting redox signaling. Yet, its molecular mechanisms of action in vascular smooth muscle cell (VSMC) calcification have not been delineated. We therefore sought to identify key pathways involved in the calcification-inhibitory properties of sulfide employing our recently developed CPP-induced VSMC calcification model.
Methods:
Using next-generation sequencing, we investigated the transcriptomic changes of sodium hydrosulfide-treated versus non-treated calcifying VSMCs. The potential role of candidate genes and/or regulatory pathways in prevention of calcification was investigated by small interfering RNA (siRNA).
Results:
CPP led to a pronounced accumulation of cell-associated calcium, which was decreased by sulfide in a concentration-dependent manner. Both, CPP-induced hydrogen peroxide production and enhanced pro-inflammatory/oxidative stress-related gene expression signatures were attenuated by sulfide-treatment. Gene ontology enrichment and in silico pathway analysis of our transcriptome data suggested NAD(P)H dehydrogenase [quinone] 1 (NQO1) as potential mediator. Corroborating these findings, silencing of Kelch-like ECH-associated protein 1 (KEAP1), an inhibitor of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear activity, enhanced NQO1 expression, whereas NRF2 silencing reduced the expression of NQO1 and abrogated the calcification-suppressing activity of sulfide. Moreover, immunofluorescence microscopy and Western blot analysis confirmed nuclear translocation of NRF2 by sulfide in VSMC.
Conclusions:
Sulfide attenuates CPP-induced VSMC calcification in vitro via the KEAP1-NRF2 redox sensing/stress response system by enhancing NQO1 expression.
... Previous reports have suggested various possibilities in CKD, including increased calcium or phosphorous concentrations 27 or inflammation. 28 CMBs are indicative of hemosiderin deposits, which can remain in macrophages for years following a microhemorrhage. Growing evidence suggests a correlation between CMBs and increased stroke risk, especially intracerebral hemorrhage. ...
Background:
Cerebrovascular disease is a major cause of mortality and morbidity. Chronic kidney disease (CKD) is prevalent in stroke patients. This study evaluated the correlation between kidney dysfunction and asymptomatic findings on carotid ultrasonography (US) and brain magnetic resonance imaging (MRI) in a Japanese population with health checkups.Methods and Results:In total, 1,716 subjects aged 40-80 years, who received health checkups from January 1 to December 31, 2015, were included. Common carotid artery intima-media thickness (CCA-IMT) and carotid plaques by US, and the presence of old non-lacunar infarctions, lacunar infarctions, white matter lesions (WMLs), cerebral microbleeds (CMBs), and atrophy by brain MRI were evaluated. After adjusting for cardiovascular risk factors, multiple regression analyses revealed that an eGFR ranging from 15 to 44 mL/min/1.73 m(2)was independently associated with CCA plaques and hypoechoic or heterogeneous plaques. Proteinuria was associated with CCA or internal carotid artery plaques, the number of carotid plaques, and the presence of old non-lacunar infarctions and CMBs.
Conclusions:
Decreased eGFR and proteinuria were independent risk factors for asymptomatic abnormalities on carotid US and brain MRI, which are surrogate markers for cerebrovascular diseases. Evaluation of these abnormalities may be useful for prevention of symptomatic cerebrovascular events in CKD patients.
... [6][7][8] Increased systemic inflammation in patients with CKD is associated with increased risk of cardiovascular mortality. 9,10 Whether inhibiting IL-1 can reduce cardiovascular risk in patients with CKD is currently unknown. ...
Vascular endothelial dysfunction and increased arterial stiffness contribute to increased cardiovascular risk in patients with CKD who exhibit chronic systemic inflammation. Because chronic inflammation contributes to vascular dysfunction, blocking inflammation may reduce cardiovascular risk in patients with CKD. In a two-site, double-blind trial, we randomized 42 adult patients with stage 3-4 CKD who were already receiving optimal background therapy to receive either IL-1 trap rilonacept or placebo for 12 weeks. Coprimary end points included change in brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV) after 4, 8, and 12 weeks. Exploratory end points included change in high-sensitivity C-reactive protein (hsCRP), FMDBA after acute ascorbic acid infusion, and vascular endothelial cell protein expression of NADPH oxidase. Participants were 63 +/- 11 (mean +/- SD) years of age and 24% were women; mean eGFR was 38 +/- 13 ml/min per 1.73 m(2). Compared with placebo, rilonacept improved FMDBA (baseline: 3.36%+/- 2.06% [mean +/- SD], 12 weeks: 2.45%+/- 2.29% with placebo and baseline: 3.75%+/- 3.12%, 12 weeks: 4.86%+/- 3.20% with rilonacept; P<0.01), without changing aPWV (P=0.56). Rilonacept also reduced hsCRP levels (median [interquartile range]) (baseline: 4.60 [1.90-8.22] mg/L, 12 weeks: 2.16 [0.92-7.38] mg/L; P<0.01) and endothelial cell NADPH oxidase expression (P<0.05). Acute infusion of ascorbic acid to inhibit superoxide production associated with a nonsignificant trend toward increased FMDBA in the placebo group (P=0.07) but not the rilonacept group (P=0.56). Rilonacept was well tolerated (five adverse events versus two with placebo). In conclusion, treatment with an IL-1 trap improved FMDBA without changing aPWV and reduced systemic inflammation in patients with CKD.
... Serum biomarkers of inflammation, such as C-reactive protein (CRP) and IL-6, are associated with increased CVD risk, not only in the general population, but also in patients with CKD. 6,7 Furthermore increased CRP levels were known to correlate with eGFR decline. 8 The prevailing mechanisms behind this relationship are still unclear. ...
CKD associates with a 1.5- to 3.5-fold increased risk for cardiovascular disease. Both diseases are characterized by increased inflammation, and in patients with CKD, elevated C-reactive protein level predicts cardiovascular risk. In addition to systemic inflammation, local arterial inflammation, driven by monocyte-derived macrophages, predicts future cardiovascular events in the general population. We hypothesized that subjects with CKD have increased arterial and cellular inflammation, reflected by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography computed tomography (PET/CT) of the arterial wall and a migratory phenotype of monocytes. We assessed (18)F-FDG uptake in the arterial wall in 14 patients with CKD (mean±SD age: 59±5 years, mean±SD eGFR: 37±12 ml/min per 1.73 m(2)) but without cardiovascular diseases, diabetes, or inflammatory conditions and in 14 control subjects (mean age: 60±11 years, mean eGFR: 86±16 ml/min per 1.73 m(2)). Compared with controls, patients with CKD showed increased arterial inflammation, quantified as target-to-background ratio (TBR) in the aorta (TBRmax: CKD, 3.14±0.70 versus control, 2.12±0.27; P=0.001) and the carotid arteries (TBRmax: CKD, 2.45±0.65 versus control, 1.66±0.27; P<0.001). Characterization of circulating monocytes using flow cytometry revealed increased chemokine receptor expression and enhanced transendothelial migration capacity in patients with CKD compared with controls. In conclusion, this increased arterial wall inflammation, observed in patients with CKD but without overt atherosclerotic disease and with few traditional risk factors, may contribute to the increased cardiovascular risk associated with CKD. The concomitant elevation of monocyte activity may provide novel therapeutic targets for attenuating this inflammation and thereby preventing CKD-associated cardiovascular disease.
... The first NHS analyses on biomarker data in relation to CVD risk linked inflammatory markers, such as C-reactive protein, interleukin-6, and tumor necrosis factor receptors I and II to CHD incidence and found that these markers were predictive of coronary events. 39,40 In addition, low levels of HDL and high levels of homocysteine and lipoprotein(a) were associated with elevated CHD risk. Also, higher levels of plasma long chain n-3 fatty acids were associated with a lower risk of nonfatal myocardial infarction. ...
Objectives:
To review the contributions of the Nurses' Health Studies (NHSs) to the understanding of cardiovascular disease etiology in women.
Methods:
We performed a narrative review of the publications of the NHS and NHS II between 1976 and 2016.
Results:
Diets low in trans fat, saturated fat, refined carbohydrates, and sugar-sweetened beverages and rich in fruits and vegetables, whole grains, and sources of unsaturated fats are associated with reduced risk of cardiovascular disease. Healthy lifestyle choices include smoking avoidance, regular physical activity, maintaining a normal body mass index, and moderate alcohol consumption. Adherence to a combination of these healthy diet and lifestyle behaviors may prevent most vascular events. Studies also covered oral contraceptive use, postmenopausal hormone therapy, shift work, sleep duration, psychosocial factors, and various biomarkers and genetic factors. Findings, such as the association of trans fat with cardiovascular disease, have helped shaped medical guidelines and government policies.
Conclusions:
The NHS has provided compelling evidence that the majority of vascular events may be prevented by avoiding smoking, participating in regular physical activity, maintaining normal body mass index, and eating a healthy diet. (Am J Public Health. Published online ahead of print July 26, 2016: e1-e8. doi:10.2105/AJPH.2016.303316).
... Interestingly, both inflammation and vascular calcification commonly co-exist in patients with CKD [41], and several mediators of inflammation such as oxidation, C-reactive protein, and cytokines have been suspected to directly stimulate vascular calcification and coronary events [20,46]. Moreover, inflammation is associated with lower circulating fetuin-A levels [24], Since fetuin-A retards the transformation of primary to secondary CPP, inflammation may well promote the maturation of CPP [17]. ...
Background and aims:
Vascular calcification is prevalent in clinical states characterized by low-grade chronic inflammation, such as chronic kidney disease (CKD). Calciprotein particles (CPP) are calcium phosphate-containing nano-aggregates, which have been found in the blood of CKD patients and appear pro-inflammatory in vitro. The interplay of CPPs and inflammatory cytokines with regard to the calcification of vascular smooth muscle cells (VSMC), in vitro, has not been investigated yet.
Methods:
Primary or secondary CPP were generated using phosphate-enriched culture medium (DMEM/10% FBS) incubated at 37 °C. Human VSMC were cultured with these media and mineralization was measured. Expression of TNF-α was detected by qPCR, ELISA and Western blot in calcified VSMC. To further characterize the significance of TNF-α and its receptors for the calcification of VSMC, RNA interference experiments using siTNF-α, siTNFR1 and siTNFR2 were performed.
Results:
The addition of phosphate to cell culture medium containing DMEM/10% FBS led to the rapid formation of primary CPP, which underwent spontaneous transformation to secondary CPP. Exposure of VSMC towards secondary CPP led to pronounced and concentration-dependent calcification, whereas exposure towards primary CPP did not. Importantly, secondary CPP induced oxidative stress, and led to the up-regulation and release of TNF-α. Addition of TNF-α to the cell culture medium enhanced, whereas the suppression of endogenous TNF-α or TNF receptor type 1 (TNFR1) expression by siRNA, ameliorated calcification.
Conclusions:
Secondary, but not primary CPP, induce VSMC calcification. Secondary CPP induce the expression and release of TNF-α, which enhances calcification via its receptor TNFR1.
... Plusieurs études ont montré que les patients atteints d'IRC présentent un état inflammatoire chronique [50-52]. Des niveaux élevés des marqueurs inflammatoires tels que la CRP sont associés à une perte excessive de la fonction rénale [52][53][54][55]. ...
... TNF-α binds to cell surface receptors on target cells and induces expression of adhesion molecules, chemokines for leukocytes, and apoptosis in susceptible cells (Laster et al., 1988). Soluble TNF receptors are elevated in the setting of inflammation and chronic kidney disease (Knight et al., 2004). Thus, TNF-α also appears to have multiple roles that could mediate progressive renal injury, and both soluble TNF receptor II (sTNFrii) and CRP may be used as markers of inflammation (Tonelli et al., 2005). ...
This study aimed to assess the nephroprotective effects of two pomegranate extracts, pomegranate juice (PJ) and pomegranate peel methanol extract (PPME) in rats with chronic renal failure (CRF) induced by adenine (AD). Thirty six male rats were allocated into six groups: Control (CO), PJ, PPME, AD, AD+PJ and AD+PPME groups. The obtained results showed a significant increase in serum levels of creatinine (Cr), blood urea nitrogen (BUN), uric acid (UA) in AD-fed rats. In addition, relative kidney weight, urine volume and urine NAG activity were significantly increased, while creatinine clearance was decreased. A significant disturbance was observed in antioxidant system of AD-fed rat group represented by elevations in thiobarbituric acid reactive substance (TBARS) and protein carponyl (PC) as well as depletion in the activities of SOD and CAT. Also, a significant increases in concentration of both serum tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) accompanied by decrease in nitric oxide level were observed. Administration of pomegranate extracts, either PJ or PPME significantly mitigated all the signs of AD-induced CRF. The results suggested that the renoprotective efficacy of pomegranate can be attributed to antioxidant, anti-inflammatory and different signaling pathway mechanisms.
... homocysteinemia. These risk factors may directly contribute to increased cardiovascular mortality (16). In addition, cardiac functions are affected from hemodynamic, toxic, metabolic, and vascular factors in CKD. ...
OBJECTIVE: To analyze the effect of peritoneal dialysis (PD) treatment on left ventricular systolic and diastolic function in patients with end-stage renal disease (ESRD).
MATERIAL and METHODS: The study population consisted of 51 patients with ESRD. Before a PD catheter was inserted, the patients were evaluated by echocardiography and Doppler tissue imaging (DTI). Then, a PD catheter was inserted. After 6 months, the second echocardiographic evaluations were performed. Left ventricular systolic and diastolic function parameters were compared.
RESULTS: The mean age was 47 ± 13 years and 38 (74.5%) of the patients were male. No significant difference was found in echocardiographic parameters including ejection fraction, fractional shortening, left ventricular mass, left ventricular mass index, left ventricular posterior wall thickness, inter ventricular septal thickness, left atrial diameter, early diastolic filling/late diastolic filling ratio before and after the period of PD. Left ventricular end-systolic diameter and left ventricular end-diastolic diameter values were significantly lower found in the period after PD.
CONCLUSION: Our findings appear to reflect somewhat the favourable changes in LV diastolic and systolic functions in PD patients.
... (E26 transformation-specific sequence), a key regulator of vascular inflammation, is upregulated in the presence of Ang II via ROS production by NADPH oxidase and it participates in inflammation by recruiting T-cells and monocytes/macrophages into the vessel walls (57). In CKD patients, the cytokines; IL-6, IL-1β, and TNF-α are elevated causing the cardiovascular outcomes (58)(59)(60). The TAM (Tyro 3, Axl, Mer) ligand-receptor pathway is involved in the regulation of inflammatory processes. ...
Chronic kidney disease (CKD), diabetes mellitus (DM) and cardiovascular diseases (CVD) are complex disorders of partly unknown genesis and mostly known progression factors. CVD and DM are the risk factors of CKD and are strongly intertwined since DM can lead to both CKD and/or CVD and CVD can lead to kidney disease. In recent years our knowledge of CKD, DM and CVD has been expanded and several important experimental, clinical and epidemiological associations have been reported. The tight cellular and molecular interactions between the renal, diabetic and cardiovascular systems in acute or chronic disease settings is becoming increasingly evident. However, the (patho-) physiological basis of the interactions of CKD, DM and CVD with involvement of multiple endogenous and environmental factors is highly complex and our knowledge still at its infancy. Not only single pathways and mediators of progression of these diseases have to be considered in these processes, but also the mutual interactions of these factors are essential. The recent advances in proteomics and integrative analysis technologies have allowed rapid progress in analyzing complex disorders and clearly show the opportunity for new efficient and specific therapies. More than a dozen pathways have been identified so far, including hyperactivity of the renin-angiotensinaldosterone system, osmotic sodium retention, endothelial dysfunction, dyslipidemia, RAS/RAF/ERK pathway, modification of the purinergic system, phosphatidylinositol 3-kinase (PI 3-kinase)-dependent signaling pathways, andinflammation, all leading to histomorphological alterations of the kidney and vessels of diabetic and non-diabetic patients. Since a better understanding of the common cellular and molecular mechanisms of these diseases may be a key to successful identification of new therapeutic targets, we review in this paper the current literature about cellular and molecular mechanisms of CKD.
... Renal dysfunction and albuminuria could be as new cardiovascular risk factors. Both estimated glomerular filtration rate (eGFR) and microalbuminuria share a common association with atherosclerosis, which may be explained in part by inflammation, metabolic abnormality of calcium and phosphorus, endothelial damage or dysfunction (9)(10)(11). ...
Many epidemiological studies have shown that low bone mineral density (BMD) and atherosclerosis appear to be related. However, their precise correlation is not completely understood after full adjustment the shared confounders of atherosclerosis and bone metabolism. The aim of this cross-sectional study was to investigate the relationship between BMD and subclinical atherosclerosis in a healthy Chinese population and the difference in gender.
The study population consisted of 2,487 subjects (1,467 men, 1,020 women) who participated in health check-up programs and were selected to be free of major diseases which might affect atherosclerosis and bone metabolism. Bone status was assessed by BMD in lumbar spine. The brachial-ankle PWV (baPWV) was assessed as a functional marker of atherosclerosis. The ankle-brachial index (ABI), carotid artery intima-media thickness (CIMT), estimated glomerular filtration rate (eGRF) and microalbuminuria were evaluated as indexes of structural markers of atherosclerosis.
After adjustment for risk factors, significant association was shown between baPWV and BMD in both genders (male: r=-0.084, P=0.035; female: r=-0.088, P=0.014). The correlation was stronger in females than in males, and in females, the correlation was stronger after menopause. Similarly, mean baPWV differed significantly according to the decreased BMD (normal BMD, Osteopenia, Osteoporosis). In contrast, no significant differences were observed for ABI, CIMT, eGFR or microalbuminuria with BMD.
Independent of confounding factors, low BMD is associated with the functional marker of subclinical atherosclerosis (increased baPWV), but not with structural markers (ABI, CIMT, eGFR or microalbuminuria) among healthy females and males.
... In accordance with our findings where sTNFR1 was associated with cardiovascular mortality after adjustments for CRP and IL-6, sTNFR1 but not IL-6 and CRP was associated with left ventricular mass in a study of over 600 patients with stroke [22]. Elevated levels of sTNFR1 and STNFR2 have also been associated with incident coronary heart disease in women with a low kidney function [23,24], and elevated levels of sTNFR2 were associated with incident coronary heart disease independently of hyperglycemia a 10-year follow-up of almost one thousand nurses with diabetes [25]. ...
Circulating soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) are associated with chronic kidney disease (CKD) progression in patients with CKD or diabetes, and with higher mortality. However, data in patients with end-stage renal disease are scarce. Therefore, we analyzed serum levels of sTNFR1 and sTNFR2 and investigated their association with inflammatory markers and mortality in dialysis patients.
This was a longitudinal cohort study of 207 prevalent patients (median age 66 years, 56% men) undergoing hemodialysis in Stockholm, Sweden. Demographics, clinical characteristics, including comorbidities and laboratory data, were obtained at baseline, together with prospective follow-up for mortality.
The median sTNFR1 and sTNFR2 levels were 17,680 ng/l [95% confidence interval (CI) 17,023-18,337] and 24,450 ng/l (95% CI 23,721-25,179), respectively. During a follow-up of 31 months (interquartile range, 21-38), 77 patients died. There was no association between the levels of sTNFRs and mortality in Cox regression models, and no consistent trend towards higher or lower mortality was seen in Laplace regression models. sTNFR1 and sTNFR2 levels were highly associated with other inflammatory markers including interleukin-6, pentraxin 3 and TNF-α.
Prevalent hemodialysis patients have several-fold higher levels of sTNFRs compared to previous studies in CKD stage 4 patients. As no consistent association between TNFR and mortality was observed, clinical implications of measuring these receptors to predict outcome end-stage renal disease patients provide limited results.
... Patients with kidney dysfunction have higher levels of homocysteine and C-reactive protein, and lower levels of apolipoprotein A1, which have been associated with an increased risk for cardiovascular disease [21]. Increased inflammation can also play a role, as elevated levels of inflammatory biomarkers, including interleukin-6, tumor necrosis factor, and C-reactive protein, have been found in patients with renal insufficiency [22]. It is unclear whether this reflects impaired renal clearance of inflammatory biomarkers, or a causal role in acceleration of atherosclerosis and therefore worse outcomes [3]. ...
Renal insufficiency is associated with an increased incidence of poor outcomes, including cardiovascular events and death, in the general population. Renal dysfunction appears to have a particularly negative impact in patients undergoing vascular surgery and endovascular therapy. Although the exact mechanism is unknown, increased levels of inflammatory and biochemical modulators associated with adverse cardiovascular outcomes, as well as endothelial dysfunction, appear to play a role in the association between renal insufficiency and adverse outcomes. Outcomes after the surgical and endovascular treatment of abdominal aortic aneurysms, carotid disease, and peripheral arterial disease are all negatively affected by renal insufficiency. Patients with renal dysfunction may warrant intervention for the treatment of critical limb ischemia and symptomatic carotid stenosis, given the comparatively worse outcomes associated with medical management. Open repair of aortic aneurysms and carotid intervention for asymptomatic disease in patients with severe renal dysfunction should be performed with significant caution, as the risks of repair may outweigh the benefits in this population. Further study is needed to better delineate the risks of medical management for these conditions in patients with coexisting severe renal dysfunction. Lastly, current guidelines for the management of vascular diseases, including objective performance goals for critical limb ischemia, are likely not applicable in patients with severe renal insufficiency.
Published by Elsevier Inc.
... Systemic inflammation is also associated with impaired renal function (7); it can predict worsening of renal function in both patients with manifest chronic kidney disease (7) and patients with subclinical renal disease (19). In this very vulnerable population, CRP is a relevant prognostic indicator of adverse cardiovascular events (20). ...
Objectives:
This study sought to investigate whether the beneficial impact of high-dose rosuvastatin against contrast-induced acute kidney injury (CI-AKI) in acute coronary syndrome (ACS) patients varied in relation to baseline high-sensitivity C-reactive protein (hs-CRP) levels.
Background:
High-dose rosuvastatin administered on admission has been shown to prevent CI-AKI and improve short- and mid-term clinical outcome in ACS patients.
Methods:
All 504 statin-naïve ACS patients enrolled in the PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in ACS Patients) study were stratified into baseline hs-CRP tertiles: <2.7 mg/l, ≥2.7 to <7.5 mg/l, and ≥7.5 mg/l. The primary endpoint was CI-AKI occurrence (creatinine ≥0.5 mg/dl or ≥25% above baseline within 72 h). Logistic regression models were used to evaluate the relationship between hs-CRP levels and effects of rosuvastatin.
Results:
Patients with higher baseline hs-CRP values presented a significantly higher incidence of CI-AKI (5.4%, 8.7%, and 18.3% in the first, second, and third tertiles, respectively; p = 0.0001). The beneficial effect of rosuvastatin was markedly significant in the third hs-CRP tertile (odds ratio: 0.20; 95% confidence interval: 0.07 to 0.54; p = 0.002). Statin-treated patients in the third tertile presented a significantly lower rate of adverse events at 30 days (7.2% vs. 17.4%, p = 0.043) with a trend toward better outcome at 6 months (6.02% vs. 13.04%, p = 0.12).
Conclusions:
High-dose rosuvastatin administered on admission appears to exert more effective kidney protection in ACS subjects with higher baseline hs-CRP levels resulting in better short- and mid-term clinical outcome. (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Nephropathy and Myocardial Damage in Patients With Acute Coronary Syndrome Undergoing Coronary Intervention [PRATO-ACS]; NCT01185938).
Background
Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide with a rising burden in sub-Saharan Africa. Evidence from previous studies suggest high oxidative stress levels in CKD patients. Anti-oxidative enzymes such as superoxide dismutase (SOD) are impaired in kidney disease. Oxidative stress situations result in red blood cell dysfunction, platelet destruction and tissue injury. In this study we investigated hematological indices and superoxide dismutase activity during CKD.
Methods
The study utilized a cross-sectional design consecutively recruiting patients attending the Renal Unit of Korle-Bu Teaching Hospital (KBTH), Accra, with known CKD (n = 41). Healthy subjects (n = 41) from the Outpatients Department (KBTH) were recruited as controls. Blood samples were collected to determine hematological indices. The oxidative stress level in cases and control groups were determined by measuring superoxide dismutase enzyme activity. A diagnostic predictability analysis was also performed for the various parameters measured in this work.
Results
SOD activity level was significantly lower in CKD patients than in the control group (p < 0.0001). Red blood cell (r = 0.299; p = 0.039) hemoglobin (r = 0.383; p = 0.001) and hematocrit (r = 0.306; p = 0.005) correlated positively with SOD activity in cases compared with control group. Patients with CKD had significantly higher numbers of white blood cells (p < 0.0001), neutrophils (p < 0.0001) and lymphocytes (p = 0.0001) comparing with controls. White blood cell (WBC) (r= -0.331; p = 0.002), platelet levels (r= -0.234; p = 0.034) and neutrophil level (r= -0.238; p = 0.031) correlated negatively with SOD activity. In predicting CKD, SOD activity had sensitivity of 66% and specificity of 100% while WBC had higher sensitivity of 76% and comparable specificity of 90%.
Conclusion
SOD activity correlated negatively with total white blood cell, neutrophils and platelets. Red blood cells, hemoglobin concentration, and hematocrit indices had positive correlation with SOD activity. Both SOD and WBC had high specificity, 100% and 90%, respectively for the occurrence of CKD. In predicting CKD, WBC had a relatively higher sensitivity to SOD and could play a role in risk stratifying patients in resource-limited settings.
CAD (coronary artery disease) has a link with the long-lasting kidney issues. The people suffering from some kidney issue may develop coronary artery disorder and its risk factors are very similar to the risk factors in other cases. Objective: To assess the parameters of CKD (coronary kidney disease) and CAD (coronary artery disease). There was need for the establishment of some efficient predictive methods or biomarkers for the indication of the coronary disorder. Methods: To proceed with this study 301 patients were selected. All of these patients were admitted in the cardiology ward of the hospital. Among them 151 patients had ACS along with CDK while on the other hand, 150 patients had ACS but they do not have any coronary artery disease. Both categories of the patients had made, according to the presence or absence of coronary artery disease. The progression of Coronary disease was estimated by KDIGO (improving global outcome). Results: For the prediction of results, all the attributes related to kidney issues as well as coronary artery were analyzed. Different parameters like disease history of the patients, regulatory parameter of both ACS and CKD, cardio graphical results and angiography states, were carefully estimated for both categories. The characteristics related to increased level of myocardial infarction indicated by STEMI. All these inferred that the level of initiation of coronary disease is much higher in the group without chronic kidney disease. It was estimated about 42 %. However, in the case of CKD group having coronary issues, the raise of non-segmented myocardial infarction is lower (28 %). Conclusion: There is increased level of CAD in case of kidney disease and in CAD. The different indicators and markers for the coronary and kidney disease as well as different cardiological methods were assessed in this study.
The main causes of death in patients with chronic kidney disease (CKD) are of cardiovas-22 cular nature. The interaction between traditional cardiovascular risk factors (CVRF) and non-tradi-23 tional risk factors (RF) triggers various complex pathophysiological mechanisms that will lead to 24 accelerated atherosclerosis in the context of decreased renal function. In terms of mortality, CKD 25 should be considered equivalent to ischemic coronary artery disease (CAD) and properly moni-26 tored. Vascular calcification, endothelial dysfunction, oxidative stress, anemia, and inflammatory 27 syndrome represents the main uremic RF triggered by accumulation of the uremic toxins in CKD 28 subjects. Proteinuria that appears due to kidney function decline may initiate an inflammatory sta-29 tus and alteration of the coagulation-fibrinolysis systems, favorizing acute coronary syndromes 30 (ACS) occurrence. All these factors represent potential targets for future therapy that may improve 31 CKD patient's survival and prevention of CV events. Once installed, the CAD in CKD population 32 is associated with negative outcome and increased mortality rate, that is the reason why discovering 33 the complex pathophysiological connections between the two conditions and a proper control of 34 the uremic RF are crucial and may represent the solutions for influencing the prognostic. Exclusion 35 of CKD subjects from the important trials dealing with ACS and improper use of the therapeutical 36 options because of the declined kidney functioned are issues that need to be surpassed. New ongo-37 ing trials with CKD subjects and platelets reactivity studies offers new perspectives for a better 38 clinical approach and the expected results will clarify many aspects. 39
Background
Metabolic syndrome (MS) and diabetes mellitus (DM) are risk factors for cardiovascular diseases in general population. However, there was a paucity of studies investigating their impact in primary glomerular diseases (PGD).
Hypothesis
MS and concomitant DM are associated with higher risk of cardiovascular comorbidity in PGD.
Methods
In a retrospective observational design, we analyzed 3622 hospitalized adult PGD patients and compared the prevalence of cardiovascular comorbidity in non‐MS, MS with and without DM. Risk factors for cardiovascular comorbidity were identified using univariate and multivariate logistic regression.
Results
Among 3622 PGD patients, 308 (8.5%) cases accompanied with MS, including 180 (5.0%) patients with DM and 128 (3.5%) without DM. One hundred and sixty four (4.5%) cases coexisted with cardiovascular comorbidity. Patients with MS and concomitant DM exhibited a higher prevalence of cardiovascular comorbidity than those without MS stratified by estimated glomerular filtration rate and pathological types. Logistic regression showed that MS and concomitant DM (OR: 2.496, 95% CI: 1.600‐3.894, P < .001), older age (OR: 1.060, 95% CI: 1.047‐1.074, P < .001), male (OR: 1.536, 95% CI: 1.072‐2.200, P = .019), higher level of serum ti (OR: 1.002, 95% CI: 1.001‐1.003, P < .001), hyperuricemia (OR: 1.901, 95% CI: 1.327‐2.725, P < .001), idiopathic membranous nephropathy (OR: 2.874, 95% CI: 1.244‐6.640, P < .001) and focal segmental glomerulosclerosis (OR: 2.906, 95% CI: 1.147‐7.358, P < .001) were independently associated with a higher risk for cardiovascular comorbidity.
Conclusions
In PGD patients, MS and concomitant DM are associated with an increased risk for cardiovascular comorbidity. More evidence for the causal link between MS/DM and cardiovascular outcomes is needed to be clarified.
The systematic inflammatory response might confound renal impairment, and both have been reported to affect clinical outcomes after acute coronary syndrome. We examined the impacts of the high-sensitivity C-reactive protein (hsCRP) level and estimated glomerular filtration rate level on the prognosis for acute coronary syndrome patients who underwent aggressive lipid-lowering therapy in contemporary practice. This was a subanalysis of the HIJ-PROPER study, and 1,734 patients were enrolled. Patients were divided into 4 groups using an hsCRP value of 10mg/L and an estimated glomerular filtration rate value of 60 ml/min/1.73 m2 as the cut-off points. Groups were defined as follows: group A, low hsCRP and normal or mild renal impairment; group B, low hsCRP and renal impairment; group C, high hsCRP and normal or mild renal impairment; and group D, high hsCRP and renal impairment. The primary end point was defined as the composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina or coronary revascularizations. The median follow-up period was 3.9years, and the follow-up rate was 99%. Compared with group A, the 2 higher hsCRP groups (groups C and D) showed a significantly higher incidence of primary end points (hazard ratio 1.36, 95% confidence interval 1.12 to 1.65, p = 0.002; and hazard ratio 1.40, 95% CI 1.10 to 1.80, p = 0.008). Such a difference was not found compared with group B. In conclusion, patients with higher hsCRP levels had worse prognoses regardless of renal impairment and aggressive lipid-lowering therapy.
Background:
Extracellular fluid (ECF) excess is an independent predictor of cardiovascular morbidity in patients undergoing dialysis. This study aimed to investigate the relationship between ECF status, which is affected by renal function, and coronary artery calcification (CAC), which is a marker of cardiovascular disease, in patients with chronic kidney disease (CKD).
Methods and results:
A total of 1741 patients at all stages of pre-dialysis CKD from the prospective observational cohort of CMERC-HI (Cardiovascular and Metabolic Disease Etiology Research Center-High Risk) were analyzed for the association between ECF status and CAC. ECF status was defined as extracellular water-to-total body water ratio (ECW/TBW) measured using bioelectrical impedance analysis. ECF excess was defined as ECW/TBW ≥0.390 or ≥0.400 depending on its severity. To define CAC, Agatston coronary artery calcium scores were measured. A total coronary artery calcium score of ≥400 was defined as CAC. The CKD stages were defined according to estimated glomerular filtration rate calculated using the CKD Epidemiology Collaboration equation. ECW/TBW and the proportion of ECF excess increased with progressing CKD stages. Multivariable logistic regression analyses showed that ECW/TBW was independently associated with CAC (per 0.01 increase of ECW/TBW, odds ratio 1.168, 95% confidence interval, 1.079-1.264, P<0.001). The adjusted R2 for predicting higher coronary artery calcium scores and CAC significantly improved after ECW/TBW was added to conventional factors. This association was further confirmed by net reclassification and integrated discriminant improvements, sensitivity analysis, and subgroup analysis.
Conclusions:
ECF status is independently associated with a high risk of CAC in patients with CKD.
Study registration:
URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02003781.
Chronic, low-grade inflammation is a common comorbid condition in chronic kidney disease (CKD), and particularly in chronic dialysis patients. In this review, we consider the question of whether inflammation affects outcomes in dialysis patients. Levels of proinflammatory cytokines, as well as C-reactive protein, are elevated in chronic dialysis patients. Multiple factors likely contribute to chronic inflammatory activation in kidney disease patients including the uremic milieu, lifestyle and epigenetic influences, infectious and thrombotic events, the dialysis process, and dysbiosis. Increased inflammatory markers in both CKD and chronic dialysis patients are associated with adverse clinical outcomes including all-cause mortality, cardiovascular events, kidney disease progression, protein energy wasting and diminished motor function, cognitive impairment, as well as other adverse consequences including CKD-mineral and bone disorder, anemia, and insulin resistance. Strategies that have been shown to reduce chronic systemic inflammation in CKD and chronic dialysis patients include both pharmacological and nonpharmacological interventions. However, despite evidence that systemic inflammatory markers can be lowered in kidney disease patients treated with various strategies, evidence that this improves clinical outcomes is largely unavailable and represents an important future research direction. Overall, there is strong observational evidence that inflammation is high in chronic dialysis patients and that this is independently associated with numerous adverse clinical outcomes. Targeting inflammation represents a potentially novel and attractive strategy if it can indeed improve adverse outcomes common in this population.
Objectives:
To examine the prospective association between kidney function and three outcomes: survival to age 85 with functional independence, survival to age 85 with disability, and death before age 85.
Design:
Prospective study.
Setting:
Women's Health Initiative, conducted at 40 U.S. clinical centers.
Participants:
Postmenopausal women enrolled between 1993 and 1998 with baseline biomarker assessments who had the potential to reach age 85 before September 2013 (N = 7,178).
Measurements:
Kidney function was measured according to estimated glomerular filtration rate (eGFR) calculated from serum creatinine collected at baseline. Outcomes were survival to age 85 with functional independence, survival with disability, or death before age 85. Disability was defined as mobility or activity of daily living limitations measured by questionnaire.
Results:
eGFR was greater than 90 mL/min per 1.73 m2 in 22.7% of women, 60 to 89 mL/min per 1.73 m2 in 66.5%, 45 to 59 mL/min per 1.73 m2 in 8.7%, and less than 45 mL/min per 1.73 m2 in 2.0%. Median follow-up was 15 years. Of 4,953 survivors, 3,155 reported no physical disability at age 85. Two thousand two hundred twenty-five participants died before age 85. Women with an eGFR of 90 mL/min per 1.73 m2 or greater had 2.71 times greater odds of survival to age 85 with functional independence than of dying before 85 (95% confidence interval (CI) = 1.62-4.51) than those with an eGFR less than 45 mL/min per 1.73 m2 , women with an eGFR of 60 to 89 mL/min per 1.73 m2 had 3.04 times (95% CI = 1.85-5.00) greater odds, and women with an eGFR of 45 to 59 mL/min per 1.73 m2 had 2.22 times (95% CI = 1.31-3.76) greater odds. Similar, but slightly weaker odds were seen for survival to age 85 with disability. Better kidney function was not significantly associated with greater likelihood of survival to age 85 with independent function than of surviving with disability.
Conclusion:
Better kidney function was associated with greater likelihood of survival to age 85 with and without disability.
Background:
Chronic kidney disease is increasing in prevalence. The association between low baseline estimated glomerular filtration rate (eGFR) and future myocardial infarction has not been comprehensively assessed.
Methods:
A systematic review and meta-analysis of observational studies evaluating the risk for future myocardial infarction associated with eGFR <60 and 60-90ml/min/1.73m(2) was completed. Data sources included PubMed, EMBASE, and the Cochrane Library. Included studies were required to have prospectively collected data, followed subjects for at least 6months, and reported baseline eGFR levels and the multivariable-adjusted relative risk for future myocardial infarction. A random effects model was used and subgroup analyses were conducted.
Results:
26 publications representing 41 observational cohorts were selected. In total, 1,986,850 participants with more than 35,752 documented myocardial infarctions (follow-up range: 9months to ~20years) were evaluated. eGFR <60ml/min/1.73m(2) was associated with a relative risk of 1.52 (95% confidence interval 1.39-1.67; p<0.00001) while eGFR 60-90ml/min/1.73m(2) was associated with a relative risk of 1.21 (1.09-1.34; p=0.0002) for myocardial infarction. Significant heterogeneity existed among both eGFR groups. Subgroup analysis found a further increase in risk for myocardial infarction as eGFR declined from 30 to 60 to <30ml/min/1.73m(2) (1.40, 95% confidence interval, 1.21-1.61 vs.1.94, 95% confidence interval, 1.51-2.50; p=0.03).
Conclusions:
Decreased baseline eGFR is independently associated with increased future myocardial infarction, and the risk increases with advanced renal insufficiency. Clinicians should be wary of acute coronary syndromes in patients with CKD.
Chronic inflammation is increased in patients with chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality. Specific immune mechanisms and pathways that drive and maintain chronic inflammation in CKD are not well described. The TAM ligands (Gas6 and protein S) and receptors (Axl and Mer) have been recently recognized as playing a prominent role in immune regulation. The receptors exist in both soluble and cell-bound forms; the soluble receptors (sAxl and sMer) are believed to compete with the bound receptors and thus inhibit their function. In this study, we determined the expression of cell-bound and soluble TAM proteins in patients with CKD. CKD patients had significantly lower expression of Mer in monocytes, yet increased expression of soluble TAM receptors sAxl and sMer in plasma compared to controls. The metalloproteinase ADAM 17, responsible for cleavage of Mer to its soluble form, was increased in patient monocytes. Elevated levels of soluble TAM receptors were more evident in patients with progressive renal failure. These observations suggest that functional deficiency of TAM receptor-mediated regulation of inflammation may contribute to chronic inflammation in patients with CKD.
Copyright © 2015 Elsevier Inc. All rights reserved.
OVERVIEW: As kidney disease advances and the glomerular filtration rate declines, fluid, electrolyte, and hormonal imbalances increase. Almost all of the body’s systems are adversely affected. This article describes three major complications of chronic kidney disease: renal osteodystrophy (including the role of secondary hyperparathyroidism), nutritional disturbances (such as protein-energy malnutrition), and inflammation. It also addresses the possibility that there is a malnutrition–inflammation complex syndrome, as well as the impact of kidney disease and its complications on the quality of patients’ lives and the usefulness of the Kidney Disease Quality of Life assessment tool.
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
We investigated whether inflammatory cytokines or oxidized low density lipoproteins (Ox-LDL) present in human atheroma modulate
extracellular matrix degradation by inducing membrane type 1-matrix metalloproteinase (MT1-MMP) expression. Cultured human
endothelial cells (EC) constitutively expressed MT1-MMP mRNA and protein with enzymatic activity. Tumor necrosis factor-α
(TNF-α), interleukin-1α, or interleukin-1β caused a time-dependent increase in the steady-state MT1-MMP mRNA levels within
4 h of exposure, peaking about 4-fold by 6 h, and remaining elevated for 12 h. Increased MT1-MMP mRNA correlated with a 2.5-fold
increase in MT1-MMP protein in EC membranes. Ox-LDL also increased MT1-MMP mRNA levels that varied with the duration of exposure
and degree of LDL oxidation. The increase in MT1-MMP mRNA occurred within 6 h of exposure to Ox-LDL and peaked over 3-fold
by 6 h. Ox-LDL, but not native LDL, increased MT1-MMP protein by 2-fold in EC membranes. A combination of TNF-α and Ox-LDL
was additive in increasing MT1-MMP expression. Nuclear run-on assays showed that TNF-α or Ox-LDL augmented steady-state mRNA
levels by increased transcription of the MT1-MMP gene. These findings indicate that activation of EC by inflammatory cytokines
and/or Ox-LDL increase MT1-MMP expression. Since MT1-MMP promotes matrix degradation by activating pro-MMP-2, these results
suggest a novel mechanism whereby cytokines or Ox-LDL may influence extracellular matrix remodeling.
High lipoprotein(a) (Lp(a)) serum concentrations and the underlying apolipoprotein(a) (apo(a)) phenotypes are risk factors for cardiovascular disease in the general population as well as in patients with renal disease. Lp(a) concentrations are markedly elevated in patients with end-stage renal disease. However, nothing is known about the changes of Lp(a) depending on apo(a) size polymorphism in the earliest stages of renal impairment. In this study, GFR was measured by iohexol technique in 227 non-nephrotic patients with different degrees of renal impairment and was then correlated with Lp(a) serum concentrations stratified according to low (LMW) and high (HMW) molecular weight apo(a) phenotypes. Lp(a) increased significantly with decreasing GFR. Such an increase was dependent on apo(a) phenotype. Only renal patients with HMW apo(a) phenotypes expressed higher median Lp(a) concentrations, i.e., 6.2 mg/dl at GFR >90 ml/min per 1.73 m2, 14.2 at GFR 45 to 90 ml/min per 1.73 m2, and 18.0 mg/dl at GFR <45 ml/min per 1.73 m2. These values were markedly different when compared with apo(a) phenotype-matched control subjects who had a median level of 4.4 mg/dl (ANOVA, linear relationship, P < 0.001). In contrast, no significant differences were observed at different stages of renal function in patients with LMW apo(a) phenotypes when compared with phenotype-matched control subjects. The elevation of Lp(a) was independent of the type of primary renal disease and was not related to the concentration of C-reactive protein. Multiple linear regression analysis found that the apo(a) phenotype and GFR were significantly associated with Lp(a) levels. Non-nephrotic-range proteinuria modified the association between GFR and Lp(a) levels. In summary, an increase of Lp(a) concentrations, compared with apo(a) phenotype-matched control subjects, is seen in non-nephrotic patients with primary renal disease even in the earliest stage when GFR is not yet subnormal. This change is found only in subjects with HMW apo(a) phenotypes, however.
The potential role of physical activity in the primary prevention of non-insulin-dependent diabetes mellitus (NIDDM) is largely unknown. We examined the association between regular vigorous exercise and the subsequent incidence of NIDDM in a prospective cohort of 87,253 US women aged 34-59 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1980. During 8 years of follow-up, we confirmed 1303 cases of NIDDM. Women who engaged in vigorous exercise at least once per week had an age-adjusted relative risk (RR) of NIDDM of 0.67 (p less than 0.0001) compared with women who did not exercise weekly. After adjustment for body-mass index, the reduction in risk was attenuated but remained statistically significant (RR = 0.84, p = 0.005). When analysis was restricted to the first 2 years after ascertainment of physical activity level and to symptomatic NIDDM as the outcome, age-adjusted RR of those who exercised was 0.5, and age and body-mass index adjusted RR was 0.69. Among women who exercised at least once per week, there was no clear dose-response gradient according to frequency of exercise. Family history of diabetes did not modify the effect of exercise, and risk reduction with exercise was evident among both obese and nonobese women. Multivariate adjustments for age, body-mass index, family history of diabetes, and other variables did not alter the reduced risk found with exercise. Our results indicate that physical activity may be a promising approach to the primary prevention of NIDDM.
We investigated the effect of several immune-relevant cytokines on expression of the chemoattractant intercrine/chemokine RANTES in a mouse mesangial cell line (MMC). Fifty ng/ml recombinant tumor necrosis factor alpha (TNF alpha) induced a marked increase in RANTES transcripts after two hours. RANTES mRNA remained elevated for 24 to 48 hours after stimulation, and could be abolished by co-incubation with 30 micrograms/ml of a neutralizing rabbit anti-TNF alpha antibody. Protein expression of RANTES, as assessed by indirect immunofluorescence and Western blotting, increased in MMCs 24 hours after TNF alpha stimulation. Interleukin-1 beta, tumor necrosis factor beta (TNF beta), and lipopolysaccharide (LPS) also increased expression of RANTES mRNA. In addition, RANTES mRNA expression was stimulated in glomeruli harvested from rats following renal in vivo perfusion with TNF alpha. Our results indicate that mesangial cells produce the small cytokine RANTES. This factor, in concert with other chemoattractants, may play a role in the glomerular recruitment of inflammatory cells like macrophages/monocytes.
Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.
Chronic renal failure (CRF) is associated with an increased risk of ischaemic heart disease (IHD), but the mechanisms responsible are controversial. We investigated the relationship of two sets of candidate mechanisms-indices of LDL oxidation and markers of inflammatory activity-with vascular endothelial dysfunction (VED).
We carried out cross-sectional analysis of 23 dialysed and 16 non-dialysed CRF patients, 28 healthy controls, and 20 patients with stable angina and normal renal function. The following were determined: (i) LDL oxidation by Cu(2+) and ultraviolet light, serum autoantibodies to oxidized LDL (oxLDL); (ii) forearm flow-mediated vasodilatation, plasma concentrations of adhesion molecules, and von Willebrand factor (vWF); and (iii) circulating levels of TNF-alpha and IL-6, C-reactive protein (CRP), and fibrinogen.
Endothelium-dependent vasodilatation (EDV) was lower in angina, pre-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compared with controls, vWf (P<0.005) and adhesion molecules (vCAM-1, P<0.005; iCAM-1, P=0.01; E-selectin, P=0.05) were raised in dialysis, and vCAM-1 (P=0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL cholesterol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxidation was similar in all groups. Autoantibodies to oxLDL were raised in angina (P<0.005) and pre-dialysis (P=0.006), but were absent in most dialysed patients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevated in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-alpha correlated negatively with EDV, HDL cholesterol, and positively with triglyceride, blood pressure, vWf, iCAM-1, vCAM-1 and E-selectin (r=-0.43 to +0.70, all P<0.05).
Endothelial dysfunction is unrelated to LDL oxidation, suggesting that LDL oxidation might not be a major cause of VED in CRF. In contrast VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chronic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.
Elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events. Statin therapy reduces the level of C-reactive protein independently of its effect on lipid levels. We hypothesized that statins might prevent coronary events in persons with elevated C-reactive protein levels who did not have overt hyperlipidemia.
The level of C-reactive protein was measured at base line and after one year in 5742 participants in a five-year randomized trial of lovastatin for the primary prevention of acute coronary events.
The rates of coronary events increased significantly with increases in the base-line levels of C-reactive protein. Lovastatin therapy reduced the C-reactive protein level by 14.8 percent (P<0.001), an effect not explained by lovastatin-induced changes in the lipid profile. As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol was higher than the median ratio, regardless of the level of C-reactive protein (number needed to treat for five years to prevent 1 event, 47; P=0.005). However, lovastatin was also effective among those with a ratio of total to HDL cholesterol that was lower than the median and a C-reactive protein level higher than the median (number needed to treat, 43; P=0.02). In contrast, lovastatin was ineffective among participants with a ratio of total to HDL cholesterol and a C-reactive protein level that were both lower than the median (number needed to treat, 983; P=0.80).
Statin therapy may be effective in the primary prevention of coronary events among subjects with relatively low lipid levels but with elevated levels of C-reactive protein.
To assess the validity of self-reported illnesses, medical records were reviewed for participants reporting major illnesses on the biennial follow-up questionnaires used in a prospective cohort study which began in 1976. In over 90% of cases of cancer of the breast, skin, large bowel, and thyroid, histopathology reports confirmed the subjects' self-report. Lower levels of confirmation were obtained for cancers of the lung, ovary, and uterus. Application of strict diagnostic criteria also gave lower levels of confirmation for myocardial infarction (68%) and stroke (66%). Among random samples of women reporting fractures and hypertension all records obtained confirmed self-reports. For self-reported elevated cholesterol levels 85.7% of self-reports were confirmed. Self-report is a valuable epidemiologic tool but may require additional documentation when the disease is diagnostically complex.
Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.
The advanced lesions of atherosclerosis represent the culmination of a specialized form of chronic inflammation followed by a fibroproliferative process that takes place within the intima of the affected artery. Proliferation of smooth muscle cells and generation of connective tissue occur. Proliferation results from interactions between arterial smooth muscle, monocyte-derived macrophages, T lymphocytes, and endothelium. The initial lesion of atherosclerosis, the fatty streak, begins as an accumulation of monocytederived macrophages and T lymphocytes, which adhere and migrate into the intima of the affected artery. Smooth muscle cells, which are present in the intima or which migrate into the intima from the media, then replicate. Monocyte-derived macrophages and T cells also replicate during lesion formation and progression due to the production of cytokines and growth-regulatory molecules. These molecules determine whether there is proliferation and lesion progression or inhibition of proliferation and lesion regression. Several growthregulatory molecules may play critical roles in this process, including platelet-derived growth factor (PGDF), transforming growth factor beta, fibroblast growth factor, heparinbinding epidermal growth factor-like growth factor, and others. PDGF may be one of the principal components in this process because protein containing the PDGF B-chain has been demonstrated within activated lesion macrophages during every phase of atherogenesis. The presence of this growth factor and its receptors on lesion smooth muscle cells creates opportunities for smooth muscle chemotaxis and replication. Smooth muscle proliferation depends upon a series of complex signals based upon cellular interactions in the local microenvironment of the artery. The intracellular signalling pathways for mitogenesis versus chemotaxis are being investigated for smooth muscle. The roles of the cytokines and growth-regulatory peptides involved in these cellular interactions represent critical points of departure for intervention and the development of new diagnostic methods. In addition, magnetic resonance imaging has been developed to demonstrate the fine structure of lesions of atherosclerosis in peripheral arteries not subject to cardiac motion. This noninvasive methodology holds great promise for the future of these approaches.
Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. In uremic patients resistance to the action of insulin has been documented, but it is not known at what stage of renal disease it appears. We therefore examined 29 patients with IgA glomerulonephritis (IgAGN) and 21 patients with adult polycystic kidney disease (ADPKD) in different stages of renal failure, and in addition, healthy age-matched subjects. Insulin sensitivity and other variables of glucose metabolism were assessed using a frequent sampling intravenous glucose tolerance test (minimal-model technique). Glomerular filtration rate (GFR) was assessed in renal patients using the inulin-clearance technique. Mean insulin sensitivity index (SI), that is, insulin sensitivity, was significantly lower (P < 0.001) in all patients combined than in matched healthy subjects (N = 16; 14 males, mean age 42 3 years; mean SI 8.6 0.8 min-1 U/ml). The mean SI was not significantly different in patients with renal disease of immune (IgAGN) or non-immune (ADPKD) origin, and it was not correlated with GFR (r = 0.01, P < 0.52), intact PTH (r = -0.23, P < 0.11) or calcitriol concentration (r = -0.03, P < 0.82). Consequently, the mean SI was similar in renal patients with GFR within the normal range (N = 19; 17 males, mean age 41 2 years; mean GFR 119 5 ml/min/1.73 m2; mean SI 5.1 0.7 min-1 U/ml), in patients with mild to moderate renal failure (N = 16; 15 males, 46 3 years; 67 4 ml/min/1.73 m2; 5.1 0.7 min-1 U/ml) and in patients with advanced renal failure (N = 15; 13 males, 46 3 years; 25 2 ml/min/1.73 m2; 4.7 0.6 min-1 U/ml). Mean fasted plasma insulin concentration, the area under the curve for plasma insulin concentration (AUC) and total insulin delivery (TID) during the glucose tolerance test were significantly higher in patients than in healthy subjects, reflecting hyperinsulinemia in renal patients. Further, fasted plasma insulin concentration (r = -0.32, P < 0.009), AUC (r = -0.62, P < 0.0001) and TID (r = -0.34, P < 0.004) in patients were significantly correlated with insulin sensitivity (SI). The present data document that insulin resistance and concomitant hyperinsulinemia are present early in the course of renal disease, that is, even in patients with GFR within the normal range, irrespective of the type of renal disease. This observation may have potential implications with respect to the high cardiovascular morbidity and mortality in patients with renal disease.Keywords: ADPKD, insulin resistance, glucose metabolism, IgA glomerulonephritis, renal disease, uremia
An improved method for the determination of pyridoxal-5-phosphate using tyrosine decarboxylase is described.
Understanding of the pathophysiology of atherogenesis has evolved substantially during the last few decades. Atherosclerosis was once identified as a lipid-storage disease, but is now recognized as a subacute inflammatory condition of the vessel wall, characterized by infiltration of macrophages and T cells, which interact with one another and with cells of the arterial wall. The pathological mechanisms of obesity recapitulate many features of the inflammatory processes at work in atherosclerosis. Our current appreciation of the similarities between obesity and atherosclerosis has already fostered innovations for the diagnosis, prognosis, and prevention of these two conditions.
Existing methods for predicting creatinine clearance provide accurate estimates for normal-weight patients but not for patients who are obese. Studies into this problem began with an animal model of obesity, the obese overfed rat. Mean creatinine clearance was found to vary in direct proportion to fat-free body mass, determined in both obese and normal animals. The relevance of this observation to renal function in humans was evaluated by analyzing published studies reporting creatinine clearance and creatinine excretion rates in obese and normal persons. Measured creatinine clearance correlated well with estimated fat-free body mass (r = 0.772, p less than 0.02), and urinary excretion of creatinine normalized to fat-free mass correlated impressively with age (r = 0.960). Formulas derived from these observations allow for the prediction of creatinine clearance at steady state: (formula; see text) In initial tests of these formulas, their predictions appeared to be as accurate as existing methods for the normal-weight population and far superior to these methods when applied to the obese population. Therefore, when creatinine clearance is not measured in obese patients, the estimation of this parameter with the proposed formulas should improve the ability to select the appropriate dose for drugs that are cleared principally by renal filtration.
A simple, sensitive and precise method for the determination of both free and total homocysteine in human plasma is presented. The total homocysteine in plasma consists of free homocysteine (i.e. reduced plus oxidized homocysteine in the non-protein fraction of plasma) and protein-bound homocysteine. The thiol compounds in plasma, which are reduced or liberated from plasma proteins with tri-n-butylphosphine, are derivatized with a thiol-specific fluorogenic reagent, ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulphonate. The derivatives are separated by reversed-phase high-performance liquid chromatography. The concentrations (mean +/- S.D.) of free and total homocysteine in plasma from 35 normal subjects were 1.94 +/- 0.46 and 6.18 +/- 1.19 nmol/ml, respectively.
To investigate the relationship between atherosclerotic vascular disease and age-associated changes in the normal human kidney, autopsy findings and renal histology from 57 individuals with mild systemic atherosclerosis (group I), were compared to 57 sex- and age-matched individuals with moderate-to-severe atherosclerosis (group II). Age, sex, body build, the presence or absence of hypertension, semiquantitative aorta and coronary-artery atherosclerosis scores, organ weights, and the percent of globally sclerotic glomeruli were determined in each. Glomerular area, arcuate/interlobular arteries, and percent interstitial fibrosis were measured using standard morphometric techniques. Group I individuals had a 8.3 +/- 7.0% incidence of sclerotic glomeruli, compared to 15.4 +/- 16.3% in group II (mean +/- SD, P less than 0.01). Relative intrarenal arterial wall area was increased in group II (60 +/- 12%) compared to group I (55 +/- 11%, P less than 0.05). The mean glomerular area of nonsclerotic glomeruli was greater in group II (23,700 +/- 6,000 sq mu) than in group I (19,600 +/- 3,700 sq mu, P less than 0.01), suggesting that there were compensatory increases in glomerular size in group II. Interstitial fibrosis was similar in both groups. The relative impact of age, sex, body build, hypertension, systemic atherosclerosis, intrarenal vascular disease and interstitial fibrosis on glomerulosclerosis and glomerular size was investigated using multiple linear regression. Both age and intrarenal vascular disease exhibited highly significant, independent associations with glomerulosclerosis. Glomerular area was positively correlated with heart weight and coronary artery atherosclerosis. In contrast, there was no independent correlation between glomerular area and glomerulosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
A weight-height index of adiposity should indicate the relative fatness of subjects of differing height unless obesity is itself correlated with height. The average body fat among adult women attending a hospital outpatient clinic for obesity was 40.5 percent of body weight. The height of an unselected series of 286 of these outpatients was found to be similar to that of the general population of women of similar age, which indicates that obesity in adult women is not significantly related to height. Body composition was measured by body density, body water and body potassium in a series of 104 female and 24 male subjects aged 14-60 years. In both sexes density, water and potassium gave progressively higher estimates of body fat (kg), and there was a significant difference between the values by different methods. The average of the estimates by these three methods was taken to be the 'true' value for each individual (F kg). Regression of F/H2 on W/H2 (Quetelet's index) gave a correlation coefficient of 0.955 for women and 0.943 for men. The deviation of the body fat estimated from Quetelet's formula from the 'true' value was not much greater than that when density, water or potassium were used as a basis for estimating body fat. It is concluded that Quetelet's formula is both a convenient and reliable indicator of obesity.
We assessed the validity of a self-administered semiquantitative food frequency questionnaire by comparing carotene and vitamin E intake scores derived from form with plasma carotenoid and alpha-tocopherol levels among a group of 59 men and women. The simple correlation between carotene intake and plasma carotenoid was 0.29 (p = 0.02) and the partial correlation was 0.35 (p = 0.005) after adjustment for age, sex, total caloric intake, and plasma cholesterol and triglycerides. The simple correlation between vitamin E intake and plasma alpha-tocopherol was 0.12 (p = 0.19). However, adjustment for total caloric intake and plasma lipids each substantially increased this association so that the partial correlation adjusting simultaneously for caloric intake, plasma lipids, age, and sex was 0.34 (p = 0.006). As expected on the basis of previous randomized trials, the correlation between preformed vitamin A intake and plasma retinol was weak and not statistically significant. These data support the utility of self-administered food frequency questionnaires for use in epidemiological studies. In addition, they illustrate the importance of adjusting blood alpha-tocopherol levels for lipid concentrations when the former are used as surrogates for vitamin E intake.
Several statistics have recently been proposed for the purpose of assessing the goodness of fit of an estimated logistic regression model. These statistics are reviewed and compared to other, less formal, procedures in the context of applications in epidemiologic research. One statistic is recommended for use and its computation is illustrated using data from a recent study of mortality of intensive care unit patients.
The reproducibility and validity of self-administered questionnaires on physical activity and inactivity were examined in a random (representative) sample of the Nurses' Health Study II cohort and a random sample of African-American women in that cohort.
Repeat questionnaires were administered 2 years apart. Past-week activity recalls and 7-day activity diaries were the referent methods; these instruments were sent to participants four times over a 1-year period.
The 2-year test-retest correlation for activity was 0.59 for the representative sample (n = 147) and 0.39 for the African-American sample (n = 84). Correlations between activity reported on recalls and that reported on questionnaire were 0.79 and 0.83 for the representative and African-American samples, respectively. Correlations between activity reported in diaries and that reported on questionnaire were 0.62 and 0.59, respectively. Test-retest coefficients for inactivity were 0.52 and 0.55, respectively. Correlations between inactivity reported in diaries and that reported on questionnaire were 0.41 and 0.44, respectively.
The simple, short questionnaires on activity and inactivity used in the Nurses' Health Study II are reasonably valid measures for epidemiological research.
In this study, clearance of sTNFR was investigated. The data show that bilateral nephrectomy results in an increase of the levels of both sTNFR after which a new steady state situation develops, suggesting that other organs, apart from the kidneys, are involved in clearing of sTNFR. Bilateral nephrectomy also leads to an increase in circulating TNF. This TNF was detected by ELISA and appeared to be not biologically active. To investigate whether the endotoxin induced increase in sTNFR is dependent of renal function, endotoxin was injected in nephrectomized mice. The data show that nephrectomy followed by endotoxin injection resulted in a further increase of the levels of both sTNFR. However, the endotoxin induced increase in nephrectomized mice was similar to the situation in normal mice after LPS indicating that the endotoxin induced increase is kidney independent in these mice. To investigate the relative participation of various organs in sTNFR clearance, 125I labelled sTNFR-P75 was injected. The data reveal that the majority of the sTNFR is removed from the circulation by the kidneys although indications for involvement of the liver and the lungs were also obtained. Calculation of the parametric clearance revealed that nephrectomy resulted in a 50% reduction of sTNFR-P75 clearance. Furthermore, the data presented strongly suggest that sTNFR release seems to be a continuous process, which is in balance with clearance of the sTNFR by the kidney, although other organs such as the liver and the lungs are involved.
Tumor necrosis factor-alpha (TNF-alpha) has been found to be elevated in patients during hemodialysis and is thought to mediate some of the immune and metabolic dysfunctions in these patients. It has been speculated that infusions of soluble TNF receptor (sTNF-R) may prevent some of the cytotoxic effects of TNF. However, little is still known about preexisting serum TNF-R levels in patients with chronic renal failure, with or without hemodialysis. Therefore we analyzed serum samples of sTNF-R in 26 patients with chronic renal failure (group I), 61 hemodialysis patients (group II), 9 renal transplant recipients with acute renal failure requiring posttransplant dialysis (group III), 13 renal transplant patients with rejection and moderate kidney dysfunction (group IV), and 21 renal transplant recipients with borderline kidney dysfunction and diverse infectious complications (group V). Control groups consisted of 34 blood donors and diseased controls (11 renal transplant recipients with normal kidney function without complications). All patient groups showed significantly higher sTNF-R levels compared to the control groups. In groups I, IV, and V comparable levels were observed. In group I there was a clear correlation between sTNF-R levels and serum creatinine. The highest sTNF-R serum levels were seen in groups II and III, but there was no correlation with creatinine. In the posttransplant cases (group III and diseased controls) there was a decrease in sTNF-R with improvement of kidney function. These data strongly suggest that sTNF-R serum levels are dependent on kidney function.
In patients with diabetic nephropathy blood pressure increases progressively before the conventional threshold of normal blood pressure (140/90 mm Hg) is transgressed. In patients with glomerulonephritis, no information on this point is available. To clarify this issue we sequentially examined 20 untreated patients with biopsy-proven primary chronic glomerulonephritis (GN) who had casual blood pressure below 140/90 mm Hg and normal GFR by inulin clearance. Patients were compared with normotensive healthy controls who were matched for BMI, gender and age. We measured ambulatory 24-hour blood pressure (SpaceLab system), echocardiography (ASE criteria, Acuson 128 XP 10), CIn and CPAH, urinary Na excretion, PRA and insulin concentration. In patients with GN, the median 24 hour (P < 0.0005), daytime (P < 0.001) and nocturnal sleeping time (P < 0.0001) MAP values were significantly higher than in matched controls (daytime, mean 97 mm Hg, 85 to 106 GN vs. 89 controls range 82 to 102; nocturnal sleeping time, mean 80.3 mm Hg, 71 to 89.5 GN vs. 73 controls, range 63 to 84). Echocardiographic examination showed significantly greater posterior wall thickness (P < 0.01) and ventricular septal thickness (P < 0.003). In addition the early diastolic to late diastolic (E/A) ratio of mitral valve peak inflow velocity was significantly (P < 0.0008) lower in patients. The data point to left ventricular wall thickening accompanied by LV diastolic malfunction. The study documents elevated ambulatory blood pressure in patients with primary chronic glomerulonephritis despite normal body weight and normal GFR. This is associated with evidence of target organ damage in the heart. The findings suggest that in patients with glomerulonephritis blood pressure increases initially within the normotensive range. This observation in conjunction with evidence of early target organ changes provides an argument for early antihypertensive intervention, but controlled trials to test efficacy and safety of this proposal are necessary.
Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available.
To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD.
Prospective cohort study.
In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6.
Nonfatal MI and fatal CHD confirmed by World Health Organization criteria.
During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58).
These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.
Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR).
To develop an equation to predict GFR from serum creatinine concentration and other factors.
Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease.
1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patients constituted the validation sample.
The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample.
To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively.
The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
A number of kidney diseases, and their progression to end-stage renal disease, are driven, in part, by the effects of angiotensin II. Increasing levels of angiotensin II may in turn up-regulate the expression of growth factors and cytokines, such as transforming growth factor-beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), osteopontin, vascular cell adhesion molecule-1 (VCAM-1), nuclear factor-kappaB (NF-kappaB), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor. Most of these compounds promote cell growth and fibrosis. Angiotensin II also stimulates oxidative stress. This stress in turn may potentiate the vasoconstrictor effect of the peptide due, in part, to increased catabolism of nitric oxide (NO). Oxidative stress, fueled in part by angiotensin II, up-regulates the expression of adhesion molecules, chemoattractant compounds and cytokines. The angiotensinogen gene, which provides the precursor for angiotensin production, is stimulated by NF-kappaB activation. NF-kappaB is activated by angiotensin in the liver and in the kidney. This provides an autocrine reinforcing loop that up-regulates angiotensin production. Angiotensin II activates NF-kappaB through both AT1 and AT2 receptors. In addition, angiotensin-converting enzyme (ACE) inhibition markedly decreases NF-kappaB activation in the setting of renal disease.
Macrophage (Mphi) infiltration may contribute to chronic renal injury. We therefore sought to examine the expression of genes associated with Mphi recruitment in the rat remnant kidney model.
Male Munich Wistar rats underwent 5/6 nephrectomy or sham operation (SHM, N = 18) and received no treatment (VEH, N = 18), enalapril 100 mg/L (ENA, N = 18), or candesartan 70 mg/L (CSN, N = 24) in drinking water. Competitive, quantitative reverse transcription-polymerase chain reaction was used to determine renal cortex mRNA levels for cell adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), the Mphi chemoattractant monocyte chemoattractant protein-1 (MCP-1), Mphi products interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), and the profibrotic cytokine transforming growth factor-beta1 (TGF-beta1), at intervals post-nephrectomy.
Glomerular and interstitial Mphi infiltration in VEH rats was associated with an early (4 week) and sustained rise in MCP-1 and TGF-beta1 mRNA levels. Progressive increases in ICAM-1, VCAM-1, IL-1beta, and TNF-alpha expression followed at 8 and 12 weeks. Immunostaining in VEH rats localized TGF-beta1 to glomeruli, tubules, and interstitium; MCP-1 to tubules and interstitial cells; ICAM-1 to glomeruli; and IL-1beta and TNF-alpha to tubules and interstitial cells. At 12 weeks, both treatments normalized systolic blood pressure (ENA, 105 +/- 6; CSN, 97 +/- 3 mm Hg) and the urinary protein excretion rate (ENA, 8.4 +/- 0.9; CSN, 5.7 +/- 0.8 mg/day), prevented renal injury (focal and segmental glomerulosclerosis: ENA, 3.3 +/- 0.9; CSN, 1.3 +/- 0.4%), and suppressed Mphi infiltration and cytokine expression (with the exception of TNF-alpha) to near SHM levels.
These findings support the hypothesis that the coordinated up-regulation of several molecules regulating Mphi recruitment and activation is a fundamental response to renal mass ablation and is dependent on an intact renin-angiotensin system. We speculate that these responses may play a role in the pathogenesis of the ensuing glomerulosclerosis and tubulointerstitial fibrosis.
The cardiovascular risk associated with early renal insufficiency is unknown. Clinicians are often reluctant to use angiotensin-converting enzyme inhibitors in patients with renal insufficiency.
To determine whether mild renal insufficiency increases cardiovascular risk and whether ramipril decreases that risk.
Post hoc analysis.
The Heart Outcomes and Prevention Evaluation (HOPE) study, a randomized, double-blind, multinational trial involving 267 study centers.
980 patients with mild renal insufficiency (serum creatinine concentration >/= 124 micromol/L [>/=1.4 mg/dL]) and 8307 patients with normal renal function (serum creatinine concentration < 124 micromol/L [<1.4 mg/dL]) Patients with a baseline serum creatinine concentration greater than 200 micromol/L (2.3 mg/dL) were excluded.
The primary outcome measure was incidence of cardiovascular death, myocardial infarction, or stroke.
Cumulative incidence of the primary outcome was higher in patients with renal insufficiency than in those without (22.2% vs. 15.1%; P < 0.001) and increased with serum creatinine concentration. Patients with renal insufficiency had a substantially increased risk for cardiovascular death (11.4% vs. 6.6%) and total mortality (17.8% vs. 10.6%) (P < 0.001 for both comparisons). The effect of renal insufficiency on the primary outcome (adjusted hazard ratio, 1.40 [95% CI, 1.16 to 1.69]) was independent of known cardiovascular risks and treatment. Ramipril reduced the incidence of the primary outcome in patients with and those without renal insufficiency (hazard ratio, 0.80 vs. 0.79; P > 0.2 for the difference).
In patients who had preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril reduced cardiovascular risk without increasing adverse effects.
Lower vitamin B(6) concentrations are reported to confer an increased and independent risk for cardiovascular disease (CVD). The mechanism underlying this relationship, however, remains to be defined. Other diseases, such as rheumatoid arthritis, are associated with reduced vitamin B(6) levels. Despite a clear distinction in pathophysiology, inflammatory reaction may be the major link between these diseases. We hypothesized a relationship between pyridoxal 5'-phosphate (PLP), the active form of vitamin B(6), and the marker of inflammation C-reactive protein (CRP). We also evaluated whether total plasma homocysteine (tHcy), a well-defined risk factor for CVD and a major determinant of plasma PLP levels, had a possible role as a mediator of this hypothesized relationship.
Data from 891 participants from the population-based Framingham Heart Study cohort were analyzed. Subjects were divided into 2 groups according to normal or elevated CRP values: group 1, CRP <6 mg/L; group 2, CRP >/=6 mg/L. Plasma PLP levels were substantially lower in group 2 than in group 1 (mean values in group 2, 36.5 nmol/L versus 55.8 nmol/L in group 1, P<0.001). In a multiple logistic regression model adjusted for tHcy, the association of PLP with CRP remained highly significant (P=0.003).
Low plasma PLP is associated with higher CRP levels independently of tHcy. This observation may reflect a vitamin B(6) utilization in the presence of an underlying inflammatory process and represent a possible mechanism to explain the decreased vitamin B(6) levels in CVD.
Several cardiovascular risk factors are present in patients with chronic renal failure (CRF), among which are systemic inflammation and hyperhomocysteinemia. Increased oxidative stress, endothelial activation/dysfunction, and coagulation activation are considered integral components of the inflammatory response, but have also been proposed as mediators of plasma homocysteine (tHcy)-induced cell damage. Using correlation analysis, we assessed the relative contributions of inflammation and hyperhomocysteinemia in the abnormal oxidative stress, endothelial activation/dysfunction, and hemostasis activation in patients with CRF.
The relationships of inflammatory proteins and tHcy with plasma markers of these processes were studied in 64 patients with CRF (serum creatinine 526 +/- 319 micromol/L) on conservative treatment, comparing the results with healthy controls (N = 15 to 40, depending on the measured variable) of similar sex and age.
Patients had significant increases in inflammatory cytokines (TNF-alpha and IL-8) and acute-phase proteins (C-reactive protein, fibrinogen and alpha1-antitrypsin). tHcy was increased in 87.5% of patients (mean = 27.1 micromol/L, range 6.5 to 118). Patients had significant increases in (1) indices of oxidative stress: TBARS (thiobarbituric acid-reactive species), a marker of lipid peroxidation and AOPP (advanced oxidation protein products), a marker of protein oxidation; (2) endothelial cell markers such as von Willebrand factor (vWF:Ag), soluble ICAM-1 and soluble thrombomodulin (sTM); (3) markers of intravascular thrombin generation: thrombin-antithrombin complexes (TAT) and prothrombin fragment F(1+2) (PF(1+2)); and (4) indices of activation of fibrinolysis: plasmin-antiplasmin complexes (PAP), fibrin degradation products (FnDP) and fibrinogen degradation products (FgDP). tHcy was significantly correlated with plasma creatinine (r = 0.29, P < 0.018) and with serum folate (r = -0.38, P < 0.002). However, no significant correlations were observed between tHcy and TBARS, AOPP, vWF:Ag, sICAM-1, sTM, TAT, F(1+2), sTF, PAP, FnDP, and FgDP. Conversely, acute-phase proteins showed significant, positive correlations with most markers of oxidative stress, endothelial dysfunction and hemostatic activation.
Systemic inflammation, which is closely associated with augmented oxidative stress, endothelial cell dysfunction and hemostatic activation, emerges as a major cardiovascular risk factor in CRF. tHcy is unrelated to these events. Thus, alternative mechanisms through which hyperhomocysteinemia could predispose to vascular lesion and thrombotic events in CRF needs to be investigated.
Increased prevalence of small-sized low-density lipoprotein (LDL) subclass B (diameter < 25.5 nm) possibly is involved in the multifactorial process of cardiovascular disease in patients with end-stage renal disease. Given these epidemiological observations, mechanisms underlying the combined effect of a proinflammatory insult and LDL of different subclasses (subclass A, diameter > 25.5 nm, and subclass B) in a cellular model were investigated. For this, human umbilical vein endothelial cells were preexposed to LDL, then stimulated with tumor necrosis factor-alpha (TNF-alpha). Modulatory effects of LDL phenotypes on the activation of adhesion molecules, monocyte adherence, and transcriptional activity of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) were investigated. Our data show that subclass B LDLs were metabolized through nonspecific scavenger receptors and specific LDL-receptor pathways in endothelial cells. Furthermore, LDL subclass B in comparison to subclass A more effectively enhanced monocyte recruitment and adhesive properties of endothelial cells in response to TNF-alpha. These effects appeared not to be mediated by oxidative stress-responsive NF-kappaB because modulation of this transcription factor by LDL was moderate and similar for both LDL phenotypes. Conversely, effects of LDL subclass B were considered to be caused by augmented AP-1 binding activity. In conclusion, the present model provides new clues in atherogenic mechanisms of small-sized LDLs, which sensitize vascular cells to inflammatory signals more effectively than normal-sized LDLs.
Several studies have provided convincing evidence that in apparently healthy subjects elevated serum levels of plasma C-reactive protein (CRP) are associated with an increased risk of experiencing myocardial infarction and sudden cardiac death. It has been claimed that, in dialytic patients, the hepatic synthesis of this 'acute phase response' plasma protein is primarily induced by the macrophage-derived interleukin 6 (IL-6). Little information is available, however, regarding CRP and IL-6 plasma levels in pre-dialytic renal failure.
Plasma CRP by a modification of the laser nephelometry technique, IL-6 and serum albumin were determined in 103 chronic pre-dialytic patients (mean age 50 +/- 6.3 years; creatinine clearance (Cr.cl.) 36.3 +/- 23.1 ml/min).
CRP was >5 mg/l (normal upper range) in 42% of the global population. CRP and IL-6 were significantly related (r = 0.35, p < 0.0004). CRP and IL-6 were related to renal function (CRP vs. Cr.cl., r = -0.56, p < 0.0001; IL-6 vs. Cr.cl., r = -0.55, p < 0.0001, Spearman correlation coefficient). When patients were divided in tertiles according to renal function, CRP median value resulted 7.9 mg/l (interquartile interval: 5-12) in the first tertile (Cr.cl. <18.5 ml/min), 4.0 mg/l (3-6) in the second tertile (Cr.cl. 18.5-45 ml/min) and 3.2 mg/l (2.7-4.0) in the last tertile (Cr.cl. >45 ml/min) (p < 0.0001). A negative correlation between CRP and S-albumin was also found (r = -0.52, p < 0.0001, Spearman correlation coefficient).
IL-6 and CRP were increased and were inversely related to creatinine clearance in our population of 103 chronic predialytic patients. The possibility of a decreased renal clearance of CRP and/or cytokines as a cause of an activated acute-phase response is discussed. A negative correlation between CRP and S-albumin was found confirming the link between chronic inflammation and malnutrition in chronic renal patients.
Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.
Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease.
The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged > or =65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar.
Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.
There is a high prevalence of both reduced kidney function as well as cardiovascular disease (CVD) in the elderly. We evaluated whether the level of kidney function is an independent risk factor for CVD outcomes in the Cardiovascular Health Study (CHS), a cohort of subjects whose age at baseline was 65 years old or older.
Cox proportional-hazards regression was used to evaluate the association of predicted glomerular filtration rate (GFR) with CVD after adjustment for the major CVD risk factors. We searched for nonlinear relationships between GFR and CVD, as well as interactions between level of kidney function and major CVD risk factors on CVD.
A total of 4893 subjects with predicted GFR of 15 to 130 mL/min/1.73 m2 were included in the analysis. Fifty-six percent were female and the mean age was 73.4 years. Of the subjects, 549 (11.2%) died and 1229 (25.1%) experienced CVD events in 5.05 years of follow-up. Each 10 mL/min/1.73 m2 lower GFR was associated with an adjusted hazard ratio for CVD, de novo CVD, recurrent CVD and all-cause mortality of 1.05 (1.02, 1.09), 1.07 (1.01, 1.12), 1.04 (0.99, 1.09), and 1.06 (1.00, 1.12), respectively. There was no significant interaction between level of GFR and other traditional CVD risk factors on CVD outcomes. A linear model best described the relationship between GFR and CVD.
The level of GFR is an independent risk factor for CVD, de novo CVD, and all-cause mortality in the elderly.
Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: Impact on cardiovascular disease. Despite significant progress in renal replacement therapy, the mortality from cardiovascular disease (CVD) in patients with chronic renal failure (CRF) is many times higher than in the general population. The traditional risk factors are frequently present in CRF patients. However, based upon conventional risk factor analysis, these factors do not fully explain the extraordinary increase in morbidity and mortality in CVD among patients with CRF. Accumulating evidence suggests that CRF is associated with impaired endothelial cell function.
In recent years, the role of endothelial dysfunction (ED) and excessive oxidative stress (OS) in the development of CVD has been highlighted. ED is an early feature of vascular disease in different diseases such diabetes, hypertension, hypercholesterolemia, and coronary heart disease.
The precise mechanism which induces ED is not clear. Several factors however, including OS-related accumulation of uremic toxins, hypertension and shear stress, dyslipidemia with cytotoxic lipoprotein species such as small, dense low-density lipoprotein (LDL) particles, competitive inhibition of endothelial nitric oxide (NO) by increased production by asymmetrical dimethylarginine (ADMA) are pathogenic.
In addition, it is known that excessive OS causes ED. An overproduction of reactive oxygen species (ROS) may injure the endothelial cell membrane, inactivate NO, and cause oxidation of an essential cofactor of nitric oxide synthase (NOS). Recent studies have demonstrated that an impaired endothelium-dependent vasodilation and OS are closely related to each other in patients with CRF.
We sought to determine whether the association of higher C-reactive protein levels (CRP) and more extensive coronary artery disease (CAD) explains the high cardiovascular risk of renal insufficiency (RI).
Renal insufficiency and renal failure (RF) have been associated with increased cardiovascular risk in several studies, and it has been suggested that this association may be due to higher CRP levels and greater extent of CAD. To what extent CRP or severity of CAD explains this risk is uncertain.
A total of 1,484 patients without myocardial infarction (MI) undergoing angiography were entered and followed for 3.0 +/- 1.6 years; RI and RF were defined as estimated glomerular filtration rates (GFR) of 30 to 60 and <30 ml/min; CRP was measured by immunoassay and > or = 1.0 mg/dl defined as elevated. A CAD score was determined by extent and severity of angiographic disease. Multivariate Cox regressions were performed using seven standard risk factors, homocysteine, GFR, CRP, and CAD score.
Mean age was 64 years, and 67% were men; CAD was absent in 24%, mild in 11%, and severe (> or =70% stenosis) in 60%; CRP and CAD scores increased with declining renal function (median CRP: 1.2, 1.4, 2.2 mg/dl, p < 0.001 and CAD score: 8.1, 8.7, 9.3, p = 0.008 for no-RI, RI, and RF). During follow-up, 208 patients (15%) died or had nonfatal MI. Unadjusted hazard ratio (HR) for death/MI was 2.3 for RI and 5.1 for RF (p < 0.0001). Adjustment for CRP (HR, 2.2, 4.5), CAD score (HR, 2.1, 5.1), and all other risk factors (HR, 1.7, 4.5) had minimal or modest impact on RI and RF risk; HR increased to 5.4 (p < 0.001) for presence of both elevated CRP and RI/RF.
Renal insufficiency, CRP, and angiographic CAD, although correlated, are largely independent predictors of cardiovascular risk, suggesting the importance of both inflammation and as yet undefined RI-related risk factors.
Risk for coronary heart disease is high among patients with chronic kidney disease.
To compare the prevalence of low apolipoprotein A1 levels and elevated apolipoprotein B, plasma fibrinogen, lipoprotein(a), homocysteine, and C-reactive protein levels by estimated glomerular filtration rate (GFR).
Cross-sectional study.
Third National Health and Nutrition Examination survey.
12 547, 3180, and 744 persons with estimated GFRs of at least 90, 60 to 89, or less than 60 mL/min per 1.73 m2, respectively, who were at least 18 years of age.
Chronic kidney disease was defined as an estimated GFR of less than 60 mL/min per 1.73 m2 based on the abbreviated Modification of Diet in Renal Disease formula.
After standardization for age, race or ethnicity, and sex, lower estimated GFR (> or =90, 60 to 89, or <60 mL/min per 1.73 m2) was associated with lower average levels of apolipoprotein A1 (1.44, 1.43, and 1.35 g/L) and higher levels of apolipoprotein B (1.03, 1.06, and 1.08 g/L), plasma fibrinogen (8.43, 8.44, and 9.53 micromol/L), homocysteine (8.5, 10.0, and 13.2 micromol/L), and C-reactive protein (3.0, 2.9, and 3.9 mg/L) (P < 0.05 for all values). The multivariate-adjusted odds ratios of an apolipoprotein A1 level of less than 1.2 g/L, a serum lipoprotein(a) level of at least 1.61 micromol/L (> or =45.3 mg/dL), a plasma fibrinogen level of at least 10.35 micromol/L, a serum homocysteine level of at least 15 micromol/L, and a C-reactive protein level of at least 10.0 mg/L for participants with chronic kidney disease compared with those with a GFR of at least 90 mL/min per 1.73 m2 or greater were 1.92 (95% CI, 1.02 to 3.63), 1.82 (CI, 1.06 to 3.13), 1.74 (CI, 1.35 to 2.24), 8.23 (CI, 5.00 to 13.6), and 1.93 (CI, 1.33 to 2.81), respectively.
Levels of apolipoprotein A1 are decreased and levels of homocysteine, lipoprotein(a), fibrinogen, and C-reactive protein are increased among patients with chronic kidney disease.
- Gbh Rose
Rose GBH. Cardiovascular Survey Methods, Geneva, World
Health Organization, 1982 (WHO monograph series)