Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation.

Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress.

Pro-Inflammatory Effects of Indoxyl Sulfate in Mice: Impairment of Intestinal Homeostasis and Immune Response.

The intestines are recognized as the main source of chronic inflammation in chronic kidney disease (CKD) and, among other cells, macrophages are involved in modulating this process as well as in the impaired immune response which also occurs in CKD patients. In this study, we evaluated the effect of Indoxyl Sulfate (IS), a protein bound uremic toxin poorly eliminated by hemodialysis, on inflammatory, oxidative stress and pro-apoptotic parameters, at the intestinal level in mice, on intestinal epithelial cells (IEC-6) and on primary murine peritoneal macrophages. C57BL/6J mice were treated with IS (800 mg/kg i.p.) for 3 or 6 h and histopathological analysis showed that IS induced intestinal inflammation and increased cyclooxygenase-2 (COX-2), nitrotyrosine and Bax expression in intestinal tissue. In IEC-6 cells, IS (125-1000 µM) increased tumor necrosis factor-α levels, COX-2 and inducible nitric oxide synthase expression and nitrotyrosine formation. Moreover, IS increased pro-oxidant, pro-inflammatory and pro-apoptotic parameters in peritoneal macrophages from IS-treated mice. Also, the serum concentration of IS and pro-inflammatory levels of cytokines resulted increased in IS-treated mice. Our results indicate that IS significantly contributes to affect intestinal homeostasis, immune response, and to induce a systemic pro-inflammatory state thus highlighting its potential role as therapeutic target in CKD patients.

Dietary satisfaction and quality of life in chronic kidney disease patients on low-protein diets: a multicentre study with long-term outcome data (TOrino-Pisa study).

BACKGROUND: Concerns about adherence and quality of life (QoL) limit the diffusion of low-protein diets (LPDs) as a way to slow chronic kidney disease (CKD) progression and postpone dialysis. The aim of this multicentre study is to assess dietary satisfaction in stable CKD patients. METHODS: This was a multicentre cross-sectional study with long-term follow-up data. Prevalent patients on LPD for at least 6 months were selected in four Italian centres. QoL was assessed using the World Health Organization Quality of Life questionnaire, and diet satisfaction with the Modification of Diet in Renal Disease satisfaction questionnaire. Comorbidity was assessed by Charlson Comorbidity Index, estimated glomerular filtration rate (eGFR) was calculated by the CKD Epidemiology Collaboration equation and protein intake by Maroni-Mitch formula. Survival was analysed with Kaplan-Meier curves and Cox Proportional Hazard Model. RESULTS: Four hundred and twenty-two CKD Stages 3-5 patients were enrolled. Over 95% were on moderately restricted diets (0.6 g/kg/day). Compliance was good (protein intake: 0.59 g/kg/day at baseline, 0.72 at the end of follow-up). Median dietary satisfaction was 4 on a 1-5 scale. QoL was not affected by the type of diet, but was influenced by age, comorbidity and setting of care. Two years later, at the end of follow-up, 66.6% of the patients were still on a diet; the main causes of discontinuation were dialysis and death. The dropout rate was low (5.5%); in Cox analysis, patient and renal survival were influenced by age and eGFR, but not by QoL, setting of care or type of diet. CONCLUSIONS: LPDs are compatible with high dietary satisfaction and minimal dropout, at least in patients who are able to follow such a diet for at least 6 months.

Inflammation and Oxidative Stress in Chronic Kidney Disease-Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites.

Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.

Phosphate levels in patients treated with low-flux haemodialysis, pre-dilution haemofiltration and haemodiafiltration: post hoc analysis of a multicentre, randomized and controlled trial.

BACKGROUND: Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial. METHODS: This analysis was performed in the database of a multicentre, open label and randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: on-line pre-dilution HF (36 patients) or on-line pre-dilution haemodiafiltration (40 patients). RESULTS: CTs did not affect P (P = 0.526), calcium (Ca) (P = 0.849) and parathyroid hormone levels (P = 0.622). P levels were associated with the use of phosphate binders including aluminium-based phosphate binders (P < 0.001) and sevelamer (P < 0.001), pre-dialysis bicarbonate levels (P < 0.001) and pre-dialysis blood K levels (P < 0.001). On multivariate analysis (generalized linear model), serum P was again largely unassociated with CTs (P = 0.631). Notably, participating centres were by far the strongest independent correlate of serum P, explaining 45.3% of the variance of serum P over the trial and this association was confirmed at multivariate analysis. Bicarbonate (P < 0.001) and, to a weaker extent, serum K (P = 0.032) were independently related to serum P. CONCLUSIONS: In comparison with low-flux HD, CTs did not significantly affect serum P levels. Participating centres were the main source of P variability during the trial followed by treatment with phosphate binders, serum bicarbonate and, to a weak extent, serum potassium levels (ClinicalTrials.gov Identifier: NCT011583309).

Impact of BMI on cardiovascular events, renal function, and coronary artery calcification.

BACKGROUND/AIMS: High BMI increases the risk of cardiovascular events (CVEs) in the general population. Conflicting results have been reported on the role of BMI on CVEs and on decline of renal function in patients with chronic kidney disease not on dialysis (CKD). This study evaluates the impact of BMI on CVEs, dialysis initiation, and coronary artery calcification (CAC) in CKD patients. METHODS: CKD patients were divided in normal-BMI and high-BMI patients. CVEs, initiation of dialysis, and extent and progression of CAC were assessed. Univariate and multivariable analysis were performed (adjustment variables: age, diabetes, hypertension, gender, CKD stage, serum concentration of hemoglobin, parathyroid hormone, calcium, phosphorus, albumin, C-reactive protein, LDL-cholesterol, total calcium score, 24-hour proteinuria). Patients were followed to the first event (CVE, dialysis) or for 2 years. RESULTS: 471 patients were evaluated. A CVE occurred in 13.5 and 21.3% (p < 0.05) of normal-BMI and high-BMI patients, respectively. High BMI did not increase the risk for CVEs in univariate (HR: 1.86; 95% CI: 0.97-3.54; p = 0.06) or multivariable analysis (HR: 1.36; 95% CI: 0.57-3.14; p = 0.50). High BMI did not increase the risk for initiation of dialysis in univariate (HR: 0.96; 95% CI: 0.58-1.60; p = 0.9) or multivariable analysis (HR: 1.77; 95% CI: 0.82-3.81; p = 0.14). Adding the interaction term (between BMI and glomerular filtration rate) to other variables, the risk of dialysis initiation significantly increased (HR: 3.06; 95% CI: 1.31-7.18; p = 0.01) in high-BMI patients. High BMI was not a predictor of CAC extent or progression. CONCLUSIONS: High BMI was not a predictor of CVEs. High BMI increased the risk for dialysis initiation, but high BMI was not associated to CAC extent and progression. The presence of confounders may underestimate the impact of high BMI on dialysis initiation.

History of Sleep Disorders in Chronic Kidney Disease: First Approach.

OBJECTIVES: In this study, we examined the history of sleep disorders in chronic kidney disease, 60 years after the advent of hemodialysis and renal transplant of genetically nonrelated organs, which have spurred a critical mass of data. MATERIALS AND METHODS: We analyzed selected literature on sleep disorders in chronic kidney disease from 1959 onward. RESULTS: Sleep disturbances are present in the general population. They cause loss of renal function and progressive nephron loss. Insomnia, sleep apnea, restless leg syndrome, and periodic limb movements represent sleep disturbances in chronic kidney disease. These symptoms manifest early in chronic kidney disease and are a rule in patients on dialysis and kidney transplant recipients. Sleep disturbances cause fatigue, excessive daily sleepiness, impaired daytime function, impaired health-related quality of life, increased morbidity, and increased mortality. CONCLUSIONS: Sleep disorders affect most patients with chronic kidney disease. No ascertained pharmacological therapy exists, and even a successful transplant does not totally restore a refreshing sleep. Longer nocturnal hemodialysis is of benefit. Sleep apnea may be cured with continuous positive airway pressure.

Predictors of haemoglobin levels and resistance to erythropoiesis-stimulating agents in patients treated with low-flux haemodialysis, haemofiltration and haemodiafiltration: results of a multicentre randomized and controlled trial.

BACKGROUND: Predictors of haemoglobin (Hb) levels and resistance to erythropoiesis-stimulating agents (ESAs) in dialysis patients have not yet been clearly defined. Some mainly uncontrolled studies suggest that online haemodiafiltration (HDF) may have a beneficial effect on Hb, whereas no data are available concerning online haemofiltration (HF). The objectives of this study were to evaluate the effects of convective treatments (CTs) on Hb levels and ESA resistance in comparison with low-flux haemodialysis (HD) and to evaluate the predictors of these outcomes. METHODS: Primary multivariate analysis was made of a pre-specified secondary outcome of a multicentre, open-label, randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: online pre-dilution HF (36 patients) or online pre-dilution HDF (40 patients). RESULTS: CTs did not affect Hb levels (P = 0.596) or ESA resistance (P = 0.984). Hb correlated with polycystic kidney disease (P = 0.001), C-reactive protein (P = 0.025), ferritin (P = 0.018), ESA dose (P < 0.001) and total cholesterol (P = 0.021). The participating centres were the main source of Hb variability (partial eta(2) 0.313, P < 0.001). ESA resistance directly correlated with serum ferritin (P = 0.030) and beta2 microglobulin (P = 0.065); participating centres were again a major source of variance (partial eta(2) 0.367, P < 0.001). Transferrin saturation did not predict either outcome variables (P = 0.277 and P = 0.170). CONCLUSIONS: In comparison with low-flux HD, CTs did not significantly improve Hb levels or ESA resistance. The main sources of variability were participating centres, ESA dose and the underlying disease.

Hemofiltration and hemodiafiltration reduce intradialytic hypotension in ESRD.

Symptomatic intradialytic hypotension is a common complication of hemodialysis (HD). The application of convective therapies to the outpatient setting may improve outcomes, including intradialytic hypotension. In this multicenter, open-label, randomized controlled study, we randomly assigned 146 long-term dialysis patients to HD (n = 70), online predilution hemofiltration (HF; n = 36), or online predilution hemodiafiltration (HDF; n = 40). The primary end point was the frequency of intradialytic symptomatic hypotension (ISH). Compared with the run-in period, the frequency of sessions with ISH during the evaluation period increased for HD (7.1 to 7.9%) and decreased for both HF (9.8 to 8.0%) and HDF (10.6 to 5.2%) (P < 0.001). Mean predialysis systolic BP increased by 4.2 mmHg among those who were assigned to HDF compared with decreases of 0.6 and 1.8 mmHg among those who were assigned to HD and HF, respectively (P = 0.038). Multivariate logistic regression demonstrated significant risk reductions in ISH for both HF (odds ratio 0.69; 95% confidence interval 0.51 to 0.92) and HDF (odds ratio 0.46, 95% confidence interval 0.33 to 0.63). There was a trend toward higher dropout for those who were assigned to HF (P = 0.107). In conclusion, compared with conventional HD, convective therapies (HDF and HF) reduce ISH in long-term dialysis patients.

Vascular Calcification Progression Modulates the Risk Associated with Vascular Calcification Burden in Incident to Dialysis Patients.

Background: It is estimated that chronic kidney disease (CKD) accounts globally for 5 to 10 million deaths annually, mainly due to cardiovascular (CV) diseases. Traditional as well as non-traditional CV risk factors such as vascular calcification are believed to drive this disproportionate risk burden. We aimed to investigate the association of coronary artery calcification (CAC) progression with all-cause mortality in patients new to hemodialysis (HD). Methods: Post hoc analysis of the Independent study (NCT00710788). At study inception and after 12 months of follow-up, 414 patients underwent computed tomography imaging for quantification of CAC via the Agatston methods. The square root method was used to assess CAC progression (CACP), and survival analyses were used to test its association with mortality. Results: Over a median follow-up of 36 months, 106 patients died from all causes. Expired patients were older, more likely to be diabetic or to have experienced an atherosclerotic CV event, and exhibited a significantly greater CAC burden (p = 0.002). Survival analyses confirmed an independent association of CAC burden (hazard ratio: 1.29; 95% confidence interval: 1.17-1.44) and CACP (HR: 5.16; 2.61-10.21) with all-cause mortality. CACP mitigated the risk associated with CAC burden (p = 0.002), and adjustment for calcium-free phosphate binder attenuated the strength of the link between CACP and mortality. Conclusions: CAC burden and CACP predict mortality in incident to dialysis patients. However, CACP reduced the risk associated with baseline CAC, and calcium-free phosphate binders attenuated the association of CACP and outcomes, suggesting that CACP modulation may improve survival in this population. Future endeavors are needed to confirm whether drugs or kidney transplantation may attenuate CACP and improve survival in HD patients.

Ketoanalogs' Effects on Intestinal Microbiota Modulation and Uremic Toxins Serum Levels in Chronic Kidney Disease (Medika2 Study).

Nutritional therapy (NT) is a therapeutic option in the conservative treatment of chronic kidney disease (CKD) patients to delay the start of dialysis. The aim of this study was to evaluate the specific effect of ketoanalogs (KA)-supplemented diets for gut microbiota modulation. In a previous study we observed that the Mediterranean diet (MD) and a KA-supplemented very-low-protein diet (VLPD) modulated beneficially gut microbiota, reducing indoxyl- and p-cresyl-sulfate (IS, PCS) serum levels, and ameliorating the intestinal permeability in CKD patients. In the current study, we added a third diet regimen consisting of KA-supplemented MD. Forty-three patients with CKD grades 3B-4 continuing the crossover clinical trial were assigned to six months of KA-supplemented MD (MD + KA). Compared to MD, KA-supplementation in MD + KA determined (i) a decrease of Clostridiaceae, Methanobacteriaceae, Prevotellaceae, and Lactobacillaceae while Bacteroidaceae and Lachnospiraceae increased; (ii) a reduction of total and free IS and PCS compared to a free diet (FD)-more than the MD, but not as effectively as the VLPD. These results further clarify the driving role of urea levels in regulating gut integrity status and demonstrating that the reduction of azotemia produced by KA-supplemented VLPD was more effective than KA-supplemented MD in gut microbiota modulation mainly due to the effect of the drastic reduction of protein intake rather than the effect of KA.

Predictive Value of Measures of Vascular Calcification Burden and Progression for Risk of Death in Incident to Dialysis Patients.

BACKGROUND: Vascular calcification (VC) is a marker of cardiovascular (CV) disease and various methods allow for presence and extension assessment in different arterial districts. Nevertheless, it is currently unclear which one of these methods for VC evaluation best predict outcome and if this piece of information adds to the predictive value of traditional CV risk factors in patients receiving hemodialysis (HD). METHODS: data of 184 of the 466 patients followed in the Independent study (NCT00710788) were post hoc examined to assess the association three concurrent measures of vascular calcification and all-cause survival. Specifically, coronary artery calcification (CAC) was determined by the Agatston and the volume score while abdominal aorta calcification was determined by plain X-ray of the lumbar spine (Kauppila score (KS)). Survival and regression models as well as metrics of risk recalculation were used to test the association of VC and outcome beyond the Framingham risk score. RESULTS: Middle-age (62.6(15.8) years) men (51%) and women (49%) starting HD were analyzed. Over 36 (median 36; interquartile range: 8-36) months of follow-up 69 patients expired. Each measure of VC (CAC or KS) predicted all-cause mortality independently factors commonly associated with all-cause survival (p < 0.001). Far more importantly, each measurement of VC significantly improved risk prediction and patient reclassification (p < 0.001) beyond traditional cardiovascular risk factors. CONCLUSIONS: Overall, presence and extension of VC, irrespective of the arterial site, predict risk of all-cause of death in patients starting hemodialysis. Of note, both CAC and KS increase risk stratification beyond traditional CV risk factors. However, future efforts are needed to assess whether a risk-based approach encompassing VC screening to guide HD patient management improves survival.

Current Management of Hyperkalemia in Non-Dialysis CKD: Longitudinal Study of Patients Receiving Stable Nephrology Care.

BACKGROUND: No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. METHODS: We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). RESULTS: We studied 562 patients (age 66.2 ± 14.5 y; 61% males; eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was "absent" in 50.7%, "resolving" in 15.6%, "new onset" in 16.6%, and "persistent" in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p < 0.0001), K-binders (from 2.0 to 7.7%, p < 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p < 0.001); these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR < 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). CONCLUSIONS: This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.

New evidence of direct oral anticoagulation therapy on cardiac valve calcifications, renal preservation and inflammatory modulation.

BACKGROUND: Rivaroxaban is a direct inhibitor of activated Factor X (FXa), an anti-inflammatory protein exerting a protective effect on the cardiac valve and vascular endothelium. We compare the effect of Warfarin and Rivaroxaban on inflammation biomarkers and their contribution to heart valve calcification progression and renal preservation in a population of atrial fibrillation (AF) patients with chronic kidney disease (CKD) stage 3b - 4. METHODS: This was an observational, multicenter, prospective study enrolling 347 consecutive CKD stage 3b - 4 patients newly diagnosed with AF: 247 were treated with Rivaroxaban and 100 with Warfarin. Every 12 months, we measured creatinine levels and cardiac valve calcification via standard trans-thoracic echocardiogram, while plasma levels of inflammatory mediators were quantified by ELISA at baseline and after 24 months. RESULTS: Over a follow-up of 24 months, long-term treatment with Rivaroxaban was associated with a significative reduction of cytokines. Patients treated with Rivaroxaban experienced a more frequent stabilization/regression of valve calcifications comparing with patients treated with Warfarin. Rivaroxaban use was related with an improvement in kidney function in 87.4% of patients, while in those treated with Warfarin was reported a worsening of renal clearance in 98% of cases. Patients taking Rivaroxaban experienced lower adverse events (3.2% vs 49%, p-value <0.001). CONCLUSIONS: Our findings suggest that Rivaroxaban compared to Warfarin is associated with lower levels of serum markers of inflammation. The inhibition of FXa may exert an anti-inflammatory effect contributing to reduce the risk of cardiac valve calcification progression and worsening of renal function.

Vascular calcification and QT interval in incident hemodialysis patients.

This study proposes [corrected] to evaluate the impact of different phosphate binders on the slowing of [corrected]cardiovascular calcification [corrected] and QT dispersion in incident haemodialysis patients with a follow-up of [corrected] 36 months. This is to be a [corrected] randomized, multicenter, perspective, [corrected] interventional study. Inclusion criteria are age over 18 years and being an [corrected] incident patient [corrected] on hemodialysis. Exclusion criteria are congenital prolongation of QT segment syndrome, QT-c >440 ms, bradycardia <50 beats per minute, symptomatic [corrected] arrhythmia or any other significant heart problems; electrolyte imbalances [corrected] (especially hypokalemia, hypomagnesemia or [corrected] hypocalcemia); abnormal liver function tests and [corrected] hypothyroidism. An informed consent will be taken at study entry. The patients will be randomized to 2 cohorts: [corrected] 180 patients in the sevelamer [corrected] group and 180 patients in calcium-binder phosphate group. Related vascular calcification mortality is the principal end point [corrected] and will be evaluated at 36 months.

Microbiota issue in CKD: how promising are gut-targeted approaches?

In chronic kidney disease (CKD), the progressive decline in the renal excretory function leads to accumulation of urea and toxins in the blood. The CKD-associated dysbiosis of gut microbiota further contributes to uremia by increasing intestinal toxins production. Gut microbiota is involved in a complex network of human organs, mediated by microbial metabolites: in CKD, gut-heart and gut-brain axes may have a role in increased cardiovascular risk and neuropsychiatric disorders. While the cardiovascular toxicity of some microbial molecules is well known, their presumptive neurotoxicity needs to be confirmed by specific studies. In this review, we describe gut-heart and gut-brain axes in CKD, with an overview of the experimental and human studies characterizing CKD-associated gut microbiota, and we discuss the benefits coming from new approaches aimed at gut manipulation. Microbiota metabolism is emerging as a modifiable non-traditional risk factor in nephrology. In order to take advantage of this issue, it is necessary to consider the microbiota manipulation as part of the nutritional management of CKD. Integrating the low-protein nutritional approach with prebiotic, probiotic and synbiotic supplementation is a promising tool to control disease progression and comorbidities, though an extensive validation in large-scale clinical trials is still required.

Cardiac valve calcification and use of anticoagulants: Preliminary observation of a potentially modifiable risk factor.

AIMS: Direct oral anticoagulant (DOAC) has been recently introduced in the clinical practice. Rather than interfering with vitamin K-dependent posttranscriptional modification of various proteins, DOACs selectively inhibit factors involved in the coagulation cascade. In particular, in contrast with Warfarin, Rivaroxabn does not interfere with activation of matrix Gla Protein (MGP), a potent vascular calcification Inhibitor. We herein sought to investigate the impact of Rivaroxaban and Warfarin on cardiac valve calcifications in a cohort of moderate-to advanced CKD patients. METHODS AND RESULTS: This is a multicenter, observational, retrospective, longitudinal study. Consecutive CKD stage 3b - 4 (according to KDIGO guidelines) patients from 8 cardiologic outpatient clinics were enrolled between May 2015 and October 2017. All patients received anticoagulation (100 Warfarin vs 247 Rivaroxaban) as part of their non-valvular atrial fibrillation management. Cardiac valve calcification was evaluated via standard trans-thoracic echocardiogram. 347 patients (mean age: 66 years; mean eGFR: 37 ml/min/1.73 m2) were studied. Over a mean follow-up period of 16 months, Rivaroxaban compared to Warfarin reduced both mitral and aortic valve calcifications (p < 0.001) independently of the degree of calcifications at baseline and potential confounders. Notably, Rivaroxaban use was also associated with a significant reduction in C reactive protein (CRP) (p < 0.001) during follow-up. CONCLUSION: This study generates the hypothesis that the use of Rivaroxaban associates with a reduction of cardiac valve calcification deposition and progression as compared to Warfarin, in a cohort of CKD stage 3b-4 patients. Future endeavors are needed to confirm and to establish the mechanisms responsible for these findings.

Fractional Excretion of Phosphate (FeP) Is Associated with End-Stage Renal Disease Patients with CKD 3b and 5.

Background: The perturbation of phosphate homeostasis portends unfavorable outcomes in chronic kidney disease (CKD). However, the absence of randomized clinical trials (RCT) fuels the discussion of whether phosphate or some other phosphorous-related factor(s) such as fibroblast growth factor 23 (FGF-23) mediates the cardiovascular and systemic toxicity. We herein test whether the fractional excretion of phosphate (FeP) as a marker of renal stress to excrete phosphorous predicts unfavorable outcomes in CKD patients. Methods: Retrospective, cross-sectional observational study. For current analysis, an historical cohort of 407 records of CKD stage 3b-5 patients attending between January 2010 and October 2015 at the Nephrology Unit of Solofra (AV), Italy were utilized. Demographic, clinical, laboratory, and outcome data were identified through the subjects' medical records. We tested whether quartiles of FeP are associated with the risk of CKD progression or all causes of death. Parametric as well as non-parametric tests, linear and logistic regression, as well as survival analysis were utilized. Results: Overall, we investigated middle-age (mean 66.0, standard deviation 12.3 years) men and women (male 43%) with CKD stage 3b to 5 (creatinine clearance 32.0 (13.3) mL/min). Older age, lower diastolic blood pressure, poor renal function, as well as higher serum phosphate were associated with FeP. Patients with higher FeP were at an increased risk of starting dialysis or dying (hazard ratio 2.40; 95% confidence interval (1.44, 3.99)). Notably, when the two endpoints were analyzed separately, FeP was associated with renal but not all-cause survival. Conclusion: FeP is associated with ESRD, but not all-cause mortality risk in a large cohort of moderate to advanced CKD patients. Future efforts are required to validate FeP as a marker of nephron stress and risk factor for CKD progression in this high-risk population.

Nutritional Therapy Modulates Intestinal Microbiota and Reduces Serum Levels of Total and Free Indoxyl Sulfate and P-Cresyl Sulfate in Chronic Kidney Disease (Medika Study).

In chronic kidney disease (CKD), the gut-microbiota metabolites indoxyl sulfate (IS) and p-cresyl sulfate (PCS) progressively accumulate due to their high albumin-binding capacity, leading to clinical complications. In a prospective crossover controlled trial, 60 patients with CKD grades 3B-4 (GFR = 21.6 ± 13.2 mL/min) were randomly assigned to two dietary regimens: (i) 3 months of free diet (FD) (FD is the diet usually used by the patient before being enrolled in the Medika study), 6 months of very low protein diet (VLPD), 3 months of FD and 6 months of Mediterranean diet (MD); (ii) 3 months of FD, 6 months of MD, 3 months of FD, and 6 months of VLPD. VLPD reduced inflammatory Proteobacteria and increased Actinobacteria phyla. MD and VLPD increased some butyrate-forming species of Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Bifidobacteriaceae, and decrease the pathobionts Enterobacteriaceae. The increased level of potential anti-inflammatory Blautia and Faecalibacterium, as well as butyrate-forming Coprococcus and Roseburia species in VLPD was positively associated with dietary intakes and it was negatively correlated with IS and PCS. Compared to FD and MD, VLPD showed a lower amount of some Lactobacillus, Akkermansia, Streptococcus, and Escherichia species. MD and VLPD reduced both the total and free serum IS (MD -36%, -40% and VLPD -69%, -73%, respectively) and PCS (MD -38%, -44% and VLPD -58%, -71%, respectively) compared to FD. VLPD reduced serum D-lactate compared to MD and FD. MD and, to a greater extent, VLPD are effective in the beneficial modulation of gut microbiota, reducing IS and PCS serum levels, and restoring intestinal permeability in CKD patients.

Safety and effectiveness of rivaroxaban and warfarin in moderate-to-advanced CKD: real world data.

BACKGROUND: In recent years, novel anticoagulant drugs have been introduced in the clinical armamentarium and have progressively gained momentum. Although their use is increasing among CKD patients, some skepticism about their risk-benefit ratio still persists. We sought to investigate the safety and effectiveness of rivaroxaban in a cohort of moderate-to-advanced CKD patients. METHODS: This observational, retrospective, longitudinal study involved 347 consecutive CKD stage 3b-4 (according to NKF-KDOQI guidelines) patients enrolled from 8 cardiac outpatient clinics between March 2015 and October 2017. All patients received anticoagulation (100 warfarin vs. 247 rivaroxaban) as part of their non-valvular atrial fibrillation management at the attending physician's discretion. Clinical effectiveness (defined as the occurrence of ischemic stroke, venous thromboembolism, or transient ischemic attack) and safety (intracranial hemorrhage, gastrointestinal or other bleeding) were assessed separately. RESULTS: Over a mean follow-up period of 16 ± 0.3 months, 25 stroke episodes (15 hemorrhagic, and 10 ischemic) occurred in 24 warfarin treated patients vs. none in the rivaroxaban arm. There were 5 vs. 0 episodes of deep venous thrombosis and 8 vs. 2 major episodes of bleeding in the warfarin and rivaroxaban groups, respectively. In contrast, the proportion of minor episodes of bleeding was similar between groups. CONCLUSION: Rivaroxaban seems a safe and effective therapeutic option in CKD stage 3b-4 patients. However, future randomized controlled trials are needed to definitively establish the role of rivaroxaban in CKD patients.