Effects of intensive blood pressure control on mortality and cardiorenal function in chronic kidney disease patients

BackgroundBlood pressure (BP) variability is highly correlated with cardiovascular and kidney outcomes in patients with chronic kidney disease (CKD). However, appropriate BP targets in patients with CKD remain uncertain.MethodsWe searched PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) of CKD patients who underwent intensive BP management. Kappa score was used to assess inter-rater agreement. A good agreement between the authors was observed to inter-rater reliability of RCTs selection (kappa = 0.77; P = 0.005).ResultsTen relevant studies involving 20 059 patients were included in the meta-analysis. Overall, intensive BP management may reduce the incidence of cardiovascular disease mortality (RR: 0.69, 95% CI: 0.53 to 0.90, P: 0.01), all-cause mortality (RR: 0.77, 95% CI: 0.67 to 0.88, P < 0.01) and composite cardiovascular events (RR: 0.84 95% CI: 0.75 to 0.95, P < 0.01) in patients with CKD. However, reducing BP has no significant effect on the incidence of doubling of serum creatinine level or 50% reduction in GFR (RR: 1.26, 95% CI: 0.66 to 2.40, P = 0.48), composite renal events (RR 1.07, 95% CI: 0.81 to 1.41, P = 0.64) or SAEs (RR: 0.97, 95% CI: 0.90 to 1.05, P = 0.48).ConclusionIn patients with CKD, enhanced BP management is associated with reduced all-cause mortality, cardiovascular mortality, and incidence of composite cardiovascular events.     

Placental Growth Factor as a Predictor of Cardiovascular Events in Patients with CKD from the NARA-CKD Study

Placental growth factor (PlGF) contributes to atherogenesis through vascular inflammation and plaque destabilization. High levels of PlGF may be associated with mortality and cardiovascular disease, but the relationship between PlGF level and adverse outcomes in patients with CKD is unclear. We conducted a prospective cohort study of 1351 consecutive participants with CKD enrolled in the Novel Assessment of Risk management for Atherosclerotic diseases in CKD (NARA-CKD) study between April 1, 2004, and December 31, 2011. During a median follow-up of 3 years, 199 participants died and 383 had cardiovascular events, defined as atherosclerotic disease or heart failure requiring hospitalization. In adjusted analyses, mortality and cardiovascular risk increased in each successive quartile of serum PlGF level; hazard ratios (HRs) (95% confidence intervals [95% CIs]) for mortality and cardiovascular risk, respectively, were 1.59 (0.83 to 3.16) and 1.55 (0.92 to 2.66) for the second quartile, 2.97 (1.67 to 5.59) and 3.39 (2.20 to 5.41) for the third quartile, and 3.87 (2.24 to 7.08) and 8.42 (5.54 to 13.3) for the fourth quartile. The composite end point of mortality and cardiovascular events occurred during the study period in 76.4% of patients in both the highest PlGF quartile (≥19.6 pg/ml) and the lowest eGFR tertile (<30 ml/min per 1.73 m²). The association between PlGF and mortality or cardiovascular events was not attenuated when participants were stratified by age, sex, traditional risk factors, and eGFR. These data suggest elevated PlGF is an independent risk factor for all-cause mortality and cardiovascular events in patients with CKD.     

Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease

The length polymorphism of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with cardiovascular events and mortality in high-risk populations. Experimental data suggest that heme oxygenase-1 protects against kidney disease. However, the association between this polymorphism and long-term risk of CKD in high-risk patients is unknown. We analyzed the allelic frequencies of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter in 386 patients with coronary artery disease recruited from January 1999 to July 2001 and followed until August 31, 2012. The S allele represents short repeats (<27), and the L allele represents long repeats (≥27). The primary renal end points consisted of sustained serum creatinine doubling and/or ESRD requiring long-term RRT. The secondary end points were major adverse cardiovascular events and mortality. At the end of study, the adjusted hazard ratios (95% confidence intervals) for each L allele in the additive model were 1.99 (1.27 to 3.14; P=0.003) for the renal end points, 1.70 (1.27 to 2.27; P<0.001) for major adverse cardiovascular events, and 1.36 (1.04 to 1.79; P=0.03) for mortality. With cardiac events as time-dependent covariates, the adjusted hazard ratio for each L allele in the additive model was 1.91 (1.20 to 3.06; P=0.01) for the renal end points. In conclusion, a greater number of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with higher risk for CKD, cardiovascular events, and mortality among patients with coronary artery disease.     

EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

Hyperuricemia is an independent risk factor for CKD and contributes to kidney fibrosis. In this study, we investigated the effect of EGF receptor (EGFR) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN induced by feeding a mixture of adenine and potassium oxonate, increased EGFR phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of gefitinib, a highly selective EGFR inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. Gefitinib treatment also inhibited hyperuricemia-induced activation of the TGF-β1 and NF-κB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, gefitinib treatment suppressed xanthine oxidase activity, which mediates uric acid production, and preserved expression of organic anion transporters 1 and 3, which promotes uric acid excretion in the kidney of hyperuricemic rats. Thus, blocking EGFR can attenuate development of HN via suppression of TGF-β1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body.     

Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease

BackgroundIn the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes.MethodsAdults with eGFR of 25–75 ml/min per 1.73 m² and urinary albumin-to-creatinine ratio of 200–5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin’s effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m²) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death.ResultsA total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval [95% CI]: −2 to 47%) reduction in the primary composite endpoint, and 29% (−2 to 51%), 17% (−53 to 55%), and 32% (−21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest.ConclusionsAmong patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.     

Iron Sucrose Accelerates Early Atherogenesis by Increasing Superoxide Production and Upregulating Adhesion Molecules in CKD

High-dose intravenous iron supplementation is associated with adverse cardiovascular outcomes in patients with CKD, but the underlying mechanism is unknown. Our study investigated the causative role of iron sucrose in leukocyte–endothelium interactions, an index of early atherogenesis, and subsequent atherosclerosis in the mouse remnant kidney model. We found that expression levels of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and adhesion of U937 cells increased in iron-treated human aortic endothelial cells through upregulated NADPH oxidase (NOx) and NF-κB signaling. We then measured mononuclear–endothelial adhesion and atherosclerotic lesions of the proximal aorta in male C57BL/6 mice with subtotal nephrectomy, male apolipoprotein E–deficient (ApoE^−/−) mice with uninephrectomy, and sham-operated mice subjected to saline or parenteral iron loading. Iron sucrose significantly increased tissue superoxide production, expression of tissue cell adhesion molecules, and endothelial adhesiveness in mice with subtotal nephrectomy. Moreover, iron sucrose exacerbated atherosclerosis in the aorta of ApoE^−/− mice with uninephrectomy. In patients with CKD, intravenous iron sucrose increased circulating mononuclear superoxide production, expression of soluble adhesion molecules, and mononuclear–endothelial adhesion compared with healthy subjects or untreated patients. In summary, iron sucrose aggravated endothelial dysfunction through NOx/NF-κB/CAM signaling, increased mononuclear–endothelial adhesion, and exacerbated atherosclerosis in mice with remnant kidneys. These results suggest a novel causative role for therapeutic iron in cardiovascular complications in patients with CKD.Anemia is frequently encountered and associated with cardiovascular (CV) outcomes in patients with CKD.¹ Correcting anemia usually requires erythropoiesis-stimulating agents (ESAs). The use of intravenous iron with ESA is required for optimal management of anemia in CKD patients.² The reasons for intravenous iron therapy are that it helps reduce ESA requirements and increases hemoglobin levels.³ As a major transition metal, excess iron is a potent pro-oxidant capable of redox cycling. Rooyakkers et al.⁴ have disclosed that intravenous iron administration generates bioactive iron, increases reactive oxygen species (ROS) in plasma, and reduces forearm flow-mediated dilatation in healthy individuals. A cross-sectional study has shown an interrelation among administered annual intravenous iron dose, carotid intima media thickness, and generation of advanced oxidation products of proteins in patients under maintenance hemodialysis (HD).⁵ Recently, our study⁶ and a study by Kalantar-Zadeh et al.⁷ have suggested that high-dose intravenous iron supplementation is associated with adverse CV outcomes and increased mortality in HD patients. However, the underlying mechanisms of this association have not been fully elucidated.The molecular link between iron and endothelial damage and subsequent formation of atherosclerosis in vivo remains to be clarified. Pang et al.⁸ have shown colocalization of ferritin and iron in human atherosclerotic lesions, implicating the pathologic evidence of iron in the development of atherosclerosis. Our previous study⁹ has disclosed that iron deposition is closely associated with the progression of atherosclerosis in apolipoprotein E–deficient (ApoE^−/−) mice. Restrictions in dietary iron intake to ApoE^−/− mice led to a significant reduction in atherosclerotic lesion formation through decrease of LDL oxidation.⁹ In contrast, Kirk et al.¹⁰ have found that elevated serum tissue levels of iron induced by a 2% carbonyl iron diet were not atherogenic in ApoE^−/− mice. Dietary iron overload caused a 30% rise in plasma triglyceride and cholesterol but reduced the severity of atherosclerosis by 50%. Using a rat CKD model, Lim and Vaziri¹¹ showed that intravenous iron dextran administration induced oxidative stress in the aorta and heart but failed to show an impact on atherosclerotic lesions. Therefore, the contention that iron participates in endothelial dysfunction and subsequent atherosclerosis in CKD animal models remains to be confirmed.In initiating atherosclerosis, cell adhesion molecules, such as intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are upregulated on the endothelial cell surface to mediate the adhesion of circulating mononuclear cells (MNCs) to endothelial cells and the migration of MNCs to the subendothelial space. During disease progression, ROSs serve as common intracellular messengers for redox-sensitive pathways and play a role in the development of vascular disease.¹² Because renal dysfunction is associated with higher oxidative stress and because iron provokes ROS production in vivo,^5,13 we postulated that iron accelerates atherogenesis by increasing the adhesion of MNCs to endothelial cells and the development of atherosclerotic lesions in CKD.Therefore, first, we conducted an in vitro assay of MNC–endothelial cell adhesion to investigate the signaling cascade in iron sucrose-treated human aortic endothelial cells (HAECs). Second, a novel MNC–endothelial cell adhesion assay, an index of early atherogenesis, was carried out in subtotal nephrectomized (SNx) C57BL/6 mice to assess the in vivo effects of parenteral iron sucrose on endothelial damage. Third, uninephrectomized (UNx) ApoE^−/− mice were examined to assess the chronic cumulative effects of parenteral iron sucrose on the progression of atherosclerotic lesions. Fourth, a human study was performed to validate whether intravenous iron sucrose could promote circulating MNCs in ROS production and endothelial adhesiveness of circulating MNCs in CKD patients undergoing HD.     

Uremic toxins: some thoughts on acrolein and spermine

Chronic kidney disease (CKD) is characterized by the progressive reduction of glomerular filtration rate and subsequent retention of organic waste compounds called uremic toxins. While patients with CKD are at a higher risk of premature death due to cardiovascular complications, this increased risk cannot be completely explained by classical cardiovascular risk factors such as hypertension, diabetes mellitus, and obesity. Instead, recent research suggests that uremic toxins may play a key role in explaining this marked increase in cardiovascular mortality in patients with CKD. While spermine, a tetra-amine, has previously been hypothesized to act as an uremic toxin, the following review presents a summary of recent literature that casts doubt on this assertion. Instead, acrolein, an oxidative product of spermine and the triamine spermidine, is likely responsible for the toxic effects previously attributed to spermine.     

POOR NUTRITIONAL STATUS AND INFLAMMATION: Linking Oxidative Stress and Inflammation in Kidney Disease: Which is the Chicken and Which is the Egg?

For end-stage renal disease (ESRD) patients, cardiovascular disease remains the single most common cause of excess morbidity and mortality. Furthermore, although the prevalence of traditional cardiovascular risk factors is high in the dialysis population, the extent and severity of associated cardiovascular morbidity and mortality remain disproportionate to traditional risk factor profiles. Consequently, considerable effort has been focused on "nontraditional" risk factors for cardiovascular events in this patient population. Among the examined nontraditional risk factors, increased oxidative stress as well as increased acute phase inflammation are postulated to be important contributors to uremic cardiovascular risk. Additional important uremic cardiovascular risk factors include malnutrition and endothelial dysfunction, both of which may be directly linked to the processes that cause increased oxidative stress and inflammation in uremia. In this context I review available data linking the pathogenesis of oxidative stress to acute phase inflammation and uremia. I also review data suggesting that oxidative stress in uremia directly contributes to the development of acute phase inflammation and that patients with higher levels of inflammation have higher levels of oxidative stress biomarkers. Similarly I review emerging data on the potential effects of antioxidant therapy on inflammatory biomarkers, as well as data suggesting that strategies to lower acute phase inflammation may also improve biomarkers of oxidative stress. Theoretical constructs evaluating the linkage of oxidative stress and inflammation in uremia and their contribution to the pathogenesis of atherosclerosis are suggested.     

The Soluble VEGF Receptor sFlt1 Contributes to Endothelial Dysfunction in CKD

Endothelial dysfunction contributes to the increased cardiovascular risk that accompanies CKD. We hypothesized that the soluble VEGF receptor 1 (sFlt-1), a VEGF antagonist, plays a role in endothelial dysfunction and decreased angiogenesis in CKD. We enrolled 130 patients with CKD stages 3 to 5 and 56 age- and gender-matched control patients. Plasma sFlt-1 levels were higher in patients with CKD and, after multivariate regression analyses, exclusively associated with renal function and levels of vWF, a marker of endothelial dysfunction. Compared with serum from control patients, both recombinant sFlt-1 and serum from patients with CKD had antiangiogenic activity in the chick chorioallantoic membrane (CAM) assay, induced endothelial cell apoptosis in vitro, and decreased nitric oxide generation in two different endothelial cell lines. Pretreating the sera with an antibody against sFlt-1 abrogated all of these effects. Furthermore, we observed increased sFlt1 levels in 5/6-nephrectomized rats compared with sham-operated animals. Finally, using real-time PCR and ELISA, we identified monocytes as a possible source of increased sFlt-1 in patients with CKD. Our findings show that excess sFlt-1 associates with endothelial dysfunction in CKD and suggest that increased sFlt-1 may predict cardiovascular risk in CKD.Chronic kidney disease (CKD) is a prevalent health problem associated with increased cardiovascular morbidity and mortality. It is now well established that the impairment of renal function is independently associated with endothelial dysfunction and that endothelial dysfunction is involved in this renal function–associated cardiovascular mortality.¹ In addition, the functional changes in vascular endothelium observed in patients with CKD are associated with increased atherosclerosis, ischemic heart disease, and vascular stiffening.^2,3 Moreover, animal models of uremic disease generally present decreased angiogenesis and arteriogenesis, i.e., the formation of new vessels from pre-existing ones and opening of collateral vessels in the heart, kidney, and hind-limb.^4–6Hypertension and shear stress, inflammation, diabetes-associated factors such as advanced glycated end products, and uremic toxins are some of the prevalent risk factors of endothelial dysfunction in CKD.^7–9 However, other unknown risk factors may be present.Soluble vascular endothelial growth factor (VEGF) receptor 1, also known as soluble Flt-1 (sFlt-1), is a splice variant of the VEGF receptor lacking the transmembrane and cytoplasmic domains. As a potent antagonist of VEGF, sFlt-1 specifically binds VEGF. It is known to regulate its action negatively on two levels: first, it binds and sequesters VEGF in the circulation; second, by occupying the VEGF receptor, it prevents VEGF occupancy and subsequent signal transduction.¹⁰ Of note, VEGF is a well-known promoter of angiogenesis and an endogenous regulator of endothelial integrity. Anti-VEGF compounds, such as sFlt-1, have been found to cause endothelial dysfunction, decrease angiogenesis, impair capillary repair, and increase proteinuria.¹¹ Furthermore, sFlt-1 has been described as a risk factor for pre-eclampsia, the major renal complication of pregnancy.¹² Endothelial cells, monocytes, and placenta are the major sources of sFlt-1.^13,14Serum sFlt-1 levels have not been determined in patients with CKD yet. Because these patients are characterized by endothelial dysfunction and impaired angiogenesis, we speculated that sFlt-1 levels might be increased in these patients, ultimately constituting a novel cardiovascular risk factor in CKD. The aim of this study was to investigate this hypothesis and to study possible mechanisms of sFlt-1–induced effects on endothelial function.     

Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=−0.59, P<0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P<0.001; for Klotho: r=−0.49, P<0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal–regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.     

Effects of oral alkali drug therapy on clinical outcomes in pre-dialysis chronic kidney disease patients: a systematic review and meta-analysis

BackgroundMetabolic acidosis accelerates the progression of chronic kidney disease (CKD) and increases the mortality rate. Whether oral alkali drug therapy benefits pre-dialysis CKD patients is controversial. We performed a meta-analysis of the effects of oral alkali drug therapy on major clinical outcomes in pre-dialysis CKD patients.MethodsWe systematically searched MEDLINE using the Ovid, EMBASE, and Cochrane Library databases without language restriction. We included all eligible clinical studies that involved pre-dialysis CKD adults and compared those who received oral alkali drug therapy with controls.ResultsA total of 18 eligible studies, including 14 randomized controlled trials and 4 cohort studies reported in 19 publications with 3695 participants, were included. Oral alkali drug therapy led to a 55% reduction in renal failure events (relative risk [RR]: 0.45; 95% confidence interval [CI]: 0.25–0.82), a rate of decline in the estimated glomerular filtration rate (eGFR) of 2.59 mL/min/1.73 m² per year (95% CI, 0.88–4.31). There was no significant effect on decline in eGFR events (RR: 0.34; 95% CI: 0.09–1.23), proteinuria (standardized mean difference: −0.32; 95% CI: −1.08 to 0.43), all-cause mortality events (RR: 0.90; 95% CI: 0.40–2.02) and cardiovascular (CV) events (RR: 1.03; 95% CI: 0.32–3.37) compared with the control groups.ConclusionBased on the available and low-to-moderate certainty evidence, oral alkali drug therapy might potentially reduce the risk of kidney failure events, but no benefit in reducing all-cause mortality events, CV events, decline in eGFR and porteninuria.     

Electrocardiographic Measures and Prediction of Cardiovascular and Noncardiovascular Death in CKD

Limited studies have assessed the resting 12-lead electrocardiogram (ECG) as a screening test in intermediate risk populations. We evaluated whether a panel of common ECG parameters are independent predictors of mortality risk in a prospective cohort of participants with CKD. The Chronic Renal Insufficiency Cohort (CRIC) study enrolled 3939 participants with eGFR<70 ml/min per 1.73 m² from June 2003 to September 2008. Over a median follow-up of 7.5 years, 750 participants died. After adjudicating the initial 497 deaths, we identified 256 cardiovascular and 241 noncardiovascular deaths. ECG metrics were independent risk markers for cardiovascular death (hazard ratio, 95% confidence interval): PR interval ≥200 ms (1.62, 1.19–2.19); QRS interval 100–119 ms (1.64, 1.20–2.25) and ≥120 ms (1.75, 1.17–2.62); corrected QT (QTc) interval ≥450 ms in men or ≥460 ms in women (1.72, 1.19–2.49); and heart rate 60–90 beats per minute (1.21, 0.89–1.63) and ≥90 beats per minute (2.35, 1.03–5.33). Most ECG measures were stronger markers of risk for cardiovascular death than for all-cause mortality or noncardiovascular death. Adding these intervals to a comprehensive model of cardiorenal risk factors increased the C-statistic for cardiovascular death from 0.77 to 0.81 (P<0.001). Furthermore, adding ECG metrics to the model adjusted for standard risk factors resulted in a net reclassification of 12.1% (95% confidence interval 8.1%–16.0%). These data suggest common ECG metrics are independent risk factors for cardiovascular death and enhance the ability to predict death events in a population with CKD.     

Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis–mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.     

Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease

Inflammation is the response of the vasculature or tissues to various stimuli. An acute and chronic pro-inflammatory state exists in patients with chronic kidney disease (CKD), contributing substantially to morbidity and mortality. There are many mediators of inflammation in adults with CKD and end-stage kidney disease (ESKD), including hypoalbuminemia/malnutrition, atherosclerosis, advanced oxidation protein products, the peroxisome proliferators-activated receptor, leptin, the thiobarbituric acid reactive system, asymmetric dimethyl arginine, iron, fetuin-A, and cytokines. Inflammation contributes to the progression of CKD by inducing the release of cytokines and the increased production and activity of adhesion molecules, which together contribute to T cell adhesion and migration into the interstitium, subsequently attracting pro-fibrotic factors. Inflammation in CKD also causes mortality from cardiovascular disease by contributing to the development of vascular calcifications and endothelial dysfunction. Similar to the situation in adults, cardiovascular disease in pediatric CKD is linked to inflammation: abnormal left ventricular wall geometry is positively associated with markers of inflammation. This review focuses on traditional and novel mediators of inflammation in CKD and ESKD, and the deleterious effect inflammation has on the progression of renal and cardiovascular disease.     

Association between atherosclerotic cardiovascular diseases risk and renal outcome in patients with type 2 diabetes mellitus

AimsChronic kidney disease (CKD) and diabetes mellitus increase atherosclerotic cardiovascular diseases (ASCVD) risk. However, the association between renal outcome of diabetic kidney disease (DKD) and ASCVD risk is unclear.MethodsThis retrospective study enrolled 218 type 2 diabetic patients with biopsy-proven DKD, and without known cardiovascular diseases. Baseline characteristics were obtained and the 10-year ASCVD risk score was calculated using the Pooled Cohort Equation (PCE). Renal outcome was defined as progression to end-stage renal disease (ESRD). The association between ASCVD risk and renal function and outcome was analyzed with logistic regression and Cox analysis.ResultsAmong all patients, the median 10-year ASCVD risk score was 14.1%. The median of ASCVD risk score in CKD stage 1, 2, 3, and 4 was 10.9%, 12.3%, 16.5%, and 14.8%, respectively (p = 0.268). Compared with patients with lower ASCVD risk (＜14.1%), those with higher ASCVD risk had lower eGFR, higher systolic blood pressure, and more severe renal interstitial inflammation. High ASCVD risk (>14.1%) was an independent indicator of renal dysfunction in multivariable-adjusted logistic analysis (OR, 3.997; 95%CI, 1.385–11.530; p = 0.010), though failed to be an independent risk factor for ESRD in patients with DKD in univariate and multivariate Cox analysis.ConclusionsDKD patients even in CKD stage 1 had comparable ASCVD risk score to patients in CKD stage 2, 3, and 4. Higher ASCVD risk indicated severe renal insufficiency, while no prognostic value of ASVCD risk for renal outcome was observed, which implied macroangiopathy and microangiopathy in patients with DKD were related, but relatively independent.     

Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction

Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium-dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia-specific factors. Several uremic toxins, mostly protein-bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p-cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro-oxidant and pro-inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein-bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.     

Chronic kidney disease stage stratifies short- and long-term outcomes after aortic root replacement

OBJECTIVESChronic kidney disease (CKD) is prevalent in patients undergoing cardiovascular surgery, and it negatively impacts procedural outcomes; however, its influence on the outcomes of aortic surgery has not been well studied. This study aims to elucidate the importance of CKD on the outcomes of aortic root replacement (ARR).Open in a separate windowMETHODSPatients who underwent ARR between 2005 and 2019 were retrospectively reviewed (n = 882). Patients were divided into 3 groups based on the Kidney Disease: Improving Global Outcomes criteria: Group 1 [estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m², n = 421); Group 2 (eGFR = 30–59 ml/min/1.73 m², n = 424); and Group 3 (eGFR < 30 ml/min/1.73 m², n = 37). To reduce potential confounding, a propensity score matching was also performed between Group 1 and the combined group of Group 2 and Group 3. The primary end point was 10-year survival. Secondary end points were in-hospital mortality and perioperative morbidity.RESULTSSevere CKD patients presented with more advanced overall chronic and acute illnesses. Kaplan–Meier analysis showed a significant correlation between CKD stage and 10-year survival (log-rank P < 0.001). The number of events for Group 1 was 15, Group 2 was 49 and Group 3 was 11 in 10 years. Group 3 had significantly higher in-hospital mortality (13.5% vs 3.5% in Group 2 vs 0.7% in Group 1, P < 0.001) and stroke (8.1% vs 7.1% vs 1.2%, P < 0.001) as well as introduction to new dialysis (27.0% vs 5.4% vs 1.7%, P < 0.001). eGFR was shown to be an independent predictor of mortality (hazard ratio, 0.98; 95% confidence interval, 0.96–0.99). Comparison between propensity matched groups showed similar postoperative outcomes, and eGFR was still identified as a predictor of mortality (hazard ratio, 0.97; 95% confidence interval, 0.95–0.99).CONCLUSIONSHigher stage in CKD negatively impacts the long-term survival in patients who are undergoing ARR.     

The Role of Oxidative Stress in Chronic Kidney Disease

New, reliable circulating oxidative stress markers have become available in chronic kidney disease (CKD) patients and have confirmed the long held belief that CKD is a pro-oxidant state. However, several questions related to this state of oxidative stress remain largely unresolved. First, the relative importance of each type of oxidant involved has been insufficiently evaluated. Only two recent studies have addressed this issue, and both suggested that chlorinated stress played a central role. Second, as only few population-based studies are available, the prevalence of oxidative stress among CKD patients remains undetermined. Third, although the link between oxidative stress and inflammation in CKD is emerging as a key process contributing to the genesis of oxidative stress in these patients, its pathogenesis remains poorly defined. Fourth, data favoring the involvement of oxidative stress in uremic toxicity are still limited. Finally, while two recent pilot studies have demonstrated that treatment of CKD patients with antioxidants is able to reduce cardiovascular events, information related to the pharmacokinetic characteristics of antioxidants, as well as their efficacy to prevent oxidative stress, is still limited in this patient group. Thus, although existing data suggest a prominent role of CKD-associated oxidative stress in uremic toxicity, further studies are required to definitively prove this concept.