Fanfan Hou

Folic Acid Therapy and Cardiovascular Disease in ESRD or Advanced Chronic Kidney Disease: A Meta-Analysis

BACKGROUND AND OBJECTIVES The efficacy of folic acid therapy to lower homocysteine (Hcy) levels in an effort to reduce cardiovascular disease (CVD) risk in patients with ESRD or advanced chronic kidney disease (ACKD; creatinine clearance, <30 ml/min) remains inconclusive. We conducted a meta-analysis of relevant randomized trials to further examine this issue. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This meta-analysis included 3886 patients with ESRD/ACKD from seven qualified randomized trials using folic acid therapy and with CVD reported as one of the end points. RESULTS When pooling the seven trials, folic acid therapy reduced the risk of CVD by 15% (RR, 0.85; 95% CI, 0.76 to 0.96; P = 0.009). A greater beneficial effect was observed among those trials with a treatment duration >24 months (RR, 0.84; 95% CI, 0.72 to 0.98; P = 0.02), a decrease in Hcy level >20% (RR, 0.83; 95% CI, 0.73 to 0.95; P = 0.007), and no or partial folic acid fortification (RR, 0.80; 95% CI, 0.65 to 0.99; P = 0.04). The beneficial effect also was seen when Hcy levels decreased >20%, even in the presence of folic acid fortification (RR, 0.85; 95% CI, 0.73 to 0.99; P = 0.04). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant. CONCLUSIONS Folic acid therapy can reduce CVD risk in patients with ESRD/ACKD by 15%. A greater beneficial effect was observed among those trials with no or partial folic acid fortification or a decrease in Hcy level >20% regardless of folic acid fortification.

Accumulation of tissue advanced glycation end products correlated with glucose exposure dose and associated with cardiovascular morbidity in patients on peritoneal dialysis

OBJECTIVES Accumulation of tissue advanced glycation end products (AGEs) is a marker of cumulative glycemic and/or oxidative stress. Cutaneous AGEs levels measured by skin autofluorescence correlate well with cardiovascular outcomes in diabetes and hemodialysis (HD) patients. The present study aimed to compare tissue AGEs levels with peritoneal dialysis (PD) and HD patients and to evaluate the relationship between skin autofluorescence and cardiovascular morbidity in patients on PD. METHODS A total of 2388 maintenance dialysis patients (613 PD and 1775 HD) were enrolled in this cross-sectional study. Skin autofluorescence was measured non-invasively with an autofluorescence reader. Cardiovascular morbidity was defined as clinically diagnosed ischemic heart disease, heart failure, stroke or peripheral vascular disease from initiation of dialysis. RESULTS More than 90% of patients on both PD and HD had met current dialysis adequacy targets. Compared to HD group, PD patients receiving conventional glucose-containing dialyzate had significantly higher skin autofluorescence values in each category of age and dialysis duration, irrespective of the presence or absence of diabetes. In PD patients, skin autofluorescence values were strongly correlated with the duration of PD and glucose exposure dose and independently associated with cardiovascular morbidity. Multivariate analysis revealed that glucose exposure dose and skin autofluorescence were the strongest risk factors for cardiovascular morbidity in PD patients after adjustment by age, gender, and other classic- or uremic-related risk factors. CONCLUSIONS Accumulation of tissue AGEs provides a potential link between PD exposure of metabolic stress and progression of cardiovascular disease in patients on PD.

Acute and acute-on-chronic kidney injury of patients with decompensated heart failure: impact on outcomes

BackgroundAcute worsening of renal function, an independent risk factor for adverse outcomes in acute decompensated heart failure (ADHF), occurs as a consequence of new onset kidney injury (AKI) or acute deterioration of pre-existed chronic kidney disease (CKD) (acute-on-chronic kidney injury, ACKI). However, the possible difference in prognostic implication between AKI and ACKI has not been well established.MethodsWe studied all consecutive patients hospitalized with ADHF from 2003 through 2010 in Nanfang Hospital. We classified patients as with or without pre-existed CKD based on the mean estimated glomerular filtration rate (eGFR) over a six-month period before hospitalization. AKI and ACKI were defined by RIFLE criteria according to the increase of the index serum creatinine.ResultsA total of 1,005 patients were enrolled. The incidence of ACKI was higher than that of AKI. The proportion of patients with diuretic resistance was higher among patients with pre-existed CKD than among those without CKD (16.9% vs. 9.9%, P = 0.002). Compared with AKI, ACKI was associated with higher risk for in-hospital mortality, long hospital stay, and failure in renal function recovery. Pre-existed CKD and development of acute worsening of renal function during hospitalization were the independent risk factors for in-hospital death after adjustment by the other risk factors. The RIFLE classification predicted all-cause and cardiac mortality in both AKI and ACKI.ConclusionsPatients with ACKI were at greatest risk of adverse short-term outcomes in ADHF. Monitoring eGFR and identifying CKD should not be ignored in patients with cardiovascular disease.

Accumulation of circulating advanced oxidation protein products is an independent risk factor for ischaemic heart disease in maintenance haemodialysis patients.

Aim:  Whether the burden of advanced oxidation protein products (AOPP) accumulation, a marker of oxidative stress, is affected by dialysis modality remains unclear. We compared the serum levels of AOPP in patients on haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) and tested the hypothesis that an accumulation of AOPP was an independent risk factor for cardiovascular disease.

In vivo ultrasound molecular imaging of inflammatory thrombosis in arteries with cyclic Arg-Gly-Asp-modified microbubbles targeted to glycoprotein IIb/IIIa.

ObjectiveUltrasound molecular imaging has the potential to detect activated platelets, thus identifying atherosclerotic plaque instability before onset of serious clinical events. However, it has not been well defined in inflammatory arterial thrombosis. We hypothesized that microbubbles (MBs) target glycoprotein IIb/IIIa (GP IIb/IIIa) could achieve a noninvasive in vivo detection of inflammatory thrombosis in large arteries through contrast-enhanced ultrasound (CEU) imaging. Materials and MethodsLipid shell–based gas-filled MBs were modified covalently with a cyclic Arg-Gly-Asp (RGD) peptide (MB-cRGD) targeted to activated GP IIb/IIIa or a negative control peptide (MB-CON) via thiol-maleimide coupling. Adherence of MB-cRGD and MB-CON to GP IIb/IIIa was determined in vitro by using a parallel plate flow chamber at variable shear stress (0.5–8 dynes/cm2). Inflammatory platelet thrombosis was induced by periadvential application of arachidonic acid (AA) to one of the bilateral carotids of C57BL/6 mice (n = 20) and confirmed through intravital fluorescence microscopy. Attachment of MBs was determined in vivo with CEU imaging of bilateral carotids in the AA application mice with (n = 10) or without (n = 10) pretreatment of GP IIb/IIIa antagonist. The expression of integrin GP IIb/IIIa was assessed through immunohistochemistry. ResultsMicrobubble-cRGD but not MB-CON had excellent affinity to GP IIb/IIIa under all shear stress conditions. Successful inflammatory platelet activation and thrombosis in AA application carotids were noted through intravital fluorescence microscopy. Contrast video intensity from adhered MB-cRGD in the thrombi was significantly higher than that from MB-CON (P < 0.05). Video intensity of MB-cRGD in the thrombi was suppressed significantly by preblocking with GP IIb/IIIa antagonist (P < 0.05) but not for MB-CON. Immunohistochemical finding demonstrates that expression of integrin GP IIb/IIIa in the thrombi was abundant; it was inhibited significantly through pretreatment with GP IIb/IIIa antagonist (P < 0.05). ConclusionsCyclic RGD–modified MBs targeted to GP IIb/IIIa with CEU are capable of detecting inflammation-activated platelets and thrombosis in large arteries, thus providing a potential tool for identification of vulnerable atherosclerotic plaques.

Mineral and bone disorder in Chinese dialysis patients: a multicenter study.

BackgroundMineral and bone disorder (MBD) in patients with chronic kidney disease is associated with increased morbidity and mortality. Studies regarding the status of MBD treatment in developing countries, especially in Chinese dialysis patients are extremely limited.MethodsA cross-sectional study of 1711 haemodialysis (HD) patients and 363 peritoneal dialysis (PD) patients were enrolled. Parameters related to MBD, including serum phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH) were analyzed. The achievement of MBD targets was compared with the results from the Dialysis Outcomes and Practice Study (DOPPS) 3 and DOPPS 4. Factors associated with hyperphosphatemia were examined.ResultsTotal 2074 dialysis patients from 28 hospitals were involved in this study. Only 38.5%, 39.6% and 26.6% of them met the Kidney Disease Outcomes Quality Initiative (K/DOQI) defined targets for serum P, Ca and iPTH levels. Serum P and Ca levels were statistically higher (P < 0.05) in the HD patients compared with those of PD patients, which was (6.3 ± 2.1) mg/dL vs (5.7 ± 2.0) mg/dL and (9.3 ± 1.1) mg/dL vs (9.2 ± 1.1) mg/dL, respectively. Serum iPTH level were statistically higher in the PD patients compared with those of HD patients (P = 0.03). The percentage of patients reached the K/DOQI targets for P (37.6% vs 49.8% vs 54.5%, P < 0.01), Ca (38.6% vs 50.4% vs 56.0%, P < 0.01) and iPTH (26.5% vs 31.4% vs 32.1%, P < 0.01) were lower among HD patients, compared with the data from DOPPS 3 and DOPPS 4. The percentage of patients with serum phosphorus level above 5.5 mg/dL was 57.4% in HD patients and 47.4% in PD patients. Age, dialysis patterns and region of residency were independently associated with hyperphosphatemia.ConclusionsStatus of MBD is sub-optimal among Chinese patients receiving dialysis. The issue of hyperphosphatemia is prominent and needs further attention.

China collaborative study on dialysis: a multi-centers cohort study on cardiovascular diseases in patients on maintenance dialysis

BackgroundCardiovascular disease (CVD) is the main cause of death in patients on chronic dialysis. The question whether dialysis modality impacts cardiovascular risk remains to be addressed. China Collaborative Study on Dialysis, a multi-centers cohort study, was performed to evaluate cardiovascular morbidity during maintenance hemodialysis (HD) and peritoneal dialysis (PD).MethodThe cohort consisted of chronic dialysis patients from the database of 9 of the largest dialysis facilities around China. The inclusion period was between January 1, 2005, and December 1, 2010. Cardiovascular morbidity was defined as the presence of clinically diagnosed ischemic heart disease, heart failure, peripheral vascular disease, and/or stroke. The patients who had cardiovascular morbidity before initiation of dialysis were excluded. Data collection was based on review of medical record.ResultA total of 2,388 adult patients (1,775 on HD and 613 on PD) were enrolled. Cardiovascular morbidity affected 57% patients and was comparable between HD and PD patients. However, clinically diagnosed ischemic heart disease and stroke was more prevalent in PD than HD patients. When the patients were stratified by age or dialysis vintage, the cardiovascular morbidity was significantly higher in PD than HD among those aged 50 years or older, or those receiving dialysis over 36 months. Multivariate analysis revealed that the risk factors for cardiovascular morbidity had different pattern in PD and HD patients. Hyperglycemia was the strongest risk factor for cardiovascular morbidity in PD, but not in HD patients. Hypertriglyceridemia and hypoalbuminemia were independently associated with CVD only in PD patients.ConclusionsCardiovascular morbidity during chronic dialysis was more prevalent in PD than HD patients among those with old age and long-term dialysis. Metabolic disturbance-related risk factors were independently associated with CVD only in PD patients. Better understanding the impact of dialysis modality on CVD would be an important step for prevention and treatment.

Detection of High-Risk Atherosclerotic Plaques with Ultrasound Molecular Imaging of Glycoprotein IIb/IIIa Receptor on Activated Platelets

Objective: Ultrasound molecular imaging (UMI) of glycoprotein (GP) IIb/IIIa receptor on activated platelets offers a unique means of identifying high-risk atherosclerosis. We hypothesized that contrast-enhanced ultrasound with microbubbles (MBs) targeted to GP IIb/IIIa could be used to detect and quantify activated platelets on the surface of advanced plaques. Methods and Results: A mouse model of advanced atherosclerosis was generated by maintaining apolipoprotein E-deficient (ApoE-/-) mice on a hypercholesterolemic diet (HCD). The three other experimental groups consisted of ApoE-/- and wild-type (C57BL/6) mice fed a normal chow diet and C57BL/6 mice on an HCD diet. Plaque formation was confirmed by histological and immunohistochemical methods using light, fluorescence, and electron microscopy. Mice were injected with a lipid MB-conjugated cyclic Arg-Gly-Asp peptide or nonspecific control peptide, and the abdominal aorta was examined by UMI. The accumulation of GP IIb/IIIa and activated platelets on the surface of atherosclerotic plaques was highest in the ApoE-/-+HCD group, followed by ApoE-/-+chow, C57BL/6+HCD, and C57BL/6+chow groups (P<0.05). Notably, GP IIb/IIIa expression was associated with the vulnerability index and necrotic center/fiber cap ratio (P<0.05), and contrast video intensity from adhered cyclic Arg-Gly-Asp-modified MBs (MB-cRGDs) was correlated with GP IIb/IIIa expression on the plaque surface (P<0.05). Conclusion: GP IIb/IIIa of activated platelets on the atherosclerotic endothelium is a biomarker for high-risk plaques that can be quantified by UMI using MB-cRGDs, providing a noninvasive means for detecting high-risk plaques and preventing acute cardiovascular events.

Alteration of the gut microbiota in Chinese population with chronic kidney disease

We evaluated differences in the compositions of faecal microbiota between 52 end stage renal disease (ESRD) patients and 60 healthy controls in southern China using quantitative real-time polymerase chain reaction (qPCR) and high-throughput sequencing (16S ribosomal RNA V4-6 region) methods. The absolute quantification of total bacteria was significantly reduced in ESRD patients (p < 0.01). In three enterotypes, Prevotella was enriched in the healthy group whereas Bacteroides were prevalent in the ESRD group (LDA score > 4.5). 11 bacterial taxa were significantly overrepresented in samples from ESRD and 22 bacterial taxa were overrepresented in samples from healthy controls. The butyrate producing bacteria, Roseburia, Faecalibacterium, Clostridium, Coprococcus and Prevotella were reduced in the ESRD group (LDA values > 2.0). Canonical correspondence analysis (CCA) indicated that Cystatin C (CysC), creatinine and eGFR appeared to be the most important environmental parameters to influence the overall microbial communities. In qPCR analysis, The butyrate producing species Roseburia spp., Faecalibacterium prausnitzii, Prevotella and Universal bacteria, were negatively related to CRP and CysC. Total bacteria in faeces were reduced in patients with ESRD compared to that in healthy individuals. The enterotypes change from Prevotella to Bacteroides in ESRD patients. The gut microbiota was associated with the inflammatory state and renal function of chronic kidney disease.

Hyperhomocysteinemia predicts renal function decline: A prospective study in hypertensive adults

Hyper-homocysteinemia (HHcy) is associated with microalbuminuria and glomerular injury in general and diabetic populations. However, HHcy’s role in hypertensive patients was not studied. We investigated whether HHcy is an independent risk factor for renal function decline and development of chronic kidney disease (CKD) in hypertensive men and women. This was a community-based prospective cohort study of 2,387 hypertensive adults without CKD at baseline, with a mean follow-up of 4.4 years. Baseline and follow-up levels of plasma Hcy, folate, vitamin B12, blood pressure and other pertinent covariables were obtained. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/per 1.73 m2 and an eGFR decline rate >1 ml/min/per 1.73 m2/year. There was a graded association between Hcy tertiles and eGFR decline. Subjects in the 3rd tertile of Hcy levels had an accelerated rate of eGFR decline and an increased risk of incident CKD, as compared with those in the 1st tertile, after adjusting for age, gender, baseline diabetes, SBP, BMI, smoking, dyslipidemia, eGFR, folate and vitamin B12 levels. In conclusion, in this prospective cohort of Chinese hypertensive adults, elevated baseline plasma Hcy can serve as an independent biomarker to predict renal function decline and incident CKD.