Reclassification of chronic kidney disease patients for end-stage renal disease risk by proteinuria indexed to estimated glomerular filtration rate: multicentre prospective study in nephrology clinics.

BACKGROUND: In non-dialysis chronic kidney disease (CKD), absolute proteinuria (Uprot) depends on the extent of kidney damage and residual glomerular filtration rate (GFR). We therefore evaluated, as compared with Uprot, the strength of association of proteinuria indexed to estimated GFR (eGFR) with end-stage renal disease (ESRD) risk. METHODS: In a multi-cohort prospective study in 3957 CKD patients of Stages G3-G5 referred to nephrology clinics, we tested two multivariable Cox models for ESRD risk, with either Uprot (g/24 h) or filtration-adjusted proteinuria (F-Uprot) calculated as Uprot/eGFR ×100. RESULTS: Mean ± SD age was 67 ± 14 years, males 60%, diabetics 29%, cardiovascular disease (CVD) 34%, eGFR 32 ± 13 mL/min/1.73 m2, median (interquartile range) Uprot 0.41 (0.12-1.29) g/24 h and F-Uprot 1.41 (0.36-4.93) g/24 h per 100 mL/min/1.73 m2 eGFR. Over a median follow-up of 44 months, 862 patients reached ESRD. At competing risk analysis, ESRD risk progressively increased when F-Uprot was 1.0-4.9 and ≥5.0 versus <1.0 g/24 h per 100 mL/min/1.73 m2 eGFR in Stages G3a-G4 (P < 0.001) and Stage G5 (P = 0.002). Multivariable Cox analysis showed that Uprot predicts ESRD in Stages G3a-G4 while in G5 the effect was not significant; conversely, F-Uprot significantly predicted ESRD at all stages. The F-Uprot model allowed a significantly better prediction versus the Uprot model according to Akaike information criterion. Net reclassification improvement was 12.2% (95% confidence interval 4.2-21.1), with higher reclassification in elderly, diabetes and CVD, as well as in diabetic nephropathy and glomerulonephritis, and in CKD Stages G4 and G5. CONCLUSIONS: In patients referred to nephrology clinics, F-Uprot predicts ESRD at all stages of overt CKD and improves, as compared with Uprot, reclassification of patients for renal risk, especially in more advanced and complicated disease.

Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease.

Background: Protein carbamylation is one of the non-enzymatic reactions involved in protein molecular ageing. We sought to investigate the relationship between urea levels and protein carbamylation, and whether a Mediterranean diet (MD) and a very low protein diet (VLPD) reduce protein carbamylation through reduction in urea levels in patients with chronic kidney disease (CKD). Methods: This is a prospective, randomized, crossover controlled trial that investigated 60 patients with CKD grades 3B-4 (46 males, mean age of 67 years). The enrolled CKD patients were randomly assigned (1:1) to two different nutritional treatment arms: (i) 3 months of free diet (FD), 6 months of VLPD, 3 months of FD and 6 months of MD; and (ii) 3 months of FD, 6 months of MD, 3 months of FD and 6 months of VLPD. Blood levels of lysine (Lys) and homocitrulline (Hcit) and their ratio were used as markers of cyanate levels. Due to a lack of pre-existing data on the potential effects of different dietary regimens and in light of the exploratory nature of the study, no formal sample size estimation was carried out. Results: At study completion, lower diastolic blood pressure and decreased serum levels of urea, sodium, phosphorus and parathyroid hormone, but higher serum levels of bicarbonate and haemoglobin, were noted with MD and VLPD. When compared with FD, both MD and VLPD were also associated with a decrease in serum Hcit levels and Hcit/Lys ratios (P < 0.001). Notably, reductions in urea levels correlated with substantial reductions in Hcit levels (R2 = 0.16 and 0.17 for VLPD and MD, respectively). Conclusion: In conclusion, nutritional treatments that significantly decrease serum levels of urea are associated with reduced protein carbamylation.

Correction of metabolic acidosis improves insulin resistance in chronic kidney disease.

BACKGROUND: Correction of metabolic acidosis (MA) with nutritional therapy or bicarbonate administration is widely used in chronic kidney disease (CKD) patients. However, it is unknown whether these interventions reduce insulin resistance (IR) in diabetic patients with CKD. We sought to evaluate the effect of MA correction on endogenous insulin action in diabetic type 2 (DM2) CKD patients. METHODS: A total of 145 CKD subjects (83 men e 62 women) with DM2 treated with oral antidiabetic drugs were included in the study and followed up to 1 year. All patients were randomly assigned 1:1 to either open-label (A) oral bicarbonate to achieve serum bicarbonate levels of 24-28 mmol/L (treatment group) or (B) no treatment (control group). The Homeostatic model assessment (HOMA) index was used to evaluate IR at study inception and conclusion. Parametric and non-parametric tests as well as linear regression were used. RESULTS: At baseline no differences in demographic and clinical characteristics between the two groups was observed. Average dose of bicarbonate in the treatment group was 0.7 ± 0.2 mmol/kg. Treated patients showed a better metabolic control as confirmed by lower insulin levels (13.4 ± 5.2 vs 19.9 ± 6.3; for treated and control subjects respectively; p < 0.001), Homa-IR (5.9[5.0-7.0] vs 6.3[5.3-8.2]; p = 0.01) and need for oral antidiabetic drugs. The serum bicarbonate and HOMA-IR relationship was non-linear and the largest HOMA-IR reduction was noted for serum bicarbonate levels between 24 and 28 mmol/l. Adjustment for confounders, suggests that serum bicarbonate rather than treatment drives the effect on HOMA-IR. CONCLUSIONS: Serum bicarbonate is related to IR and the largest HOMA-IR reduction is noted for serum bicarbonate between 24 and 28 mmol/l. Treatment with bicarbonate influences IR. However, changes in serum bicarbonate explains the effect of treatment on HOMA index. Future efforts are required to validate these results in diabetic and non-diabetic CKD patients. TRIAL REGISTRATION: The trial was registered at www.clinicaltrial.gov (Use of Bicarbonate in Chronic Renal Insufficiency (UBI) study - NCT01640119 ).

Low-protein diets for chronic kidney disease patients: the Italian experience.

BACKGROUND: Nutritional treatment has always represented a major feature of CKD management. Over the decades, the use of nutritional treatment in CKD patients has been marked by several goals. The first of these include the attainment of metabolic and fluid control together with the prevention and correction of signs, symptoms and complications of advanced CKD. The aim of this first stage is the prevention of malnutrition and a delay in the commencement of dialysis. Subsequently, nutritional manipulations have also been applied in association with other therapeutic interventions in an attempt to control several cardiovascular risk factors associated with CKD and to improve the patient's overall outcome. Over time and in reference to multiple aims, the modalities of nutritional treatment have been focused not only on protein intake but also on other nutrients. DISCUSSION: This paper describes the pathophysiological basis and rationale of nutritional treatment in CKD and also provides a report on extensive experience in the field of renal diets in Italy, with special attention given to approaches in clinical practice and management. Italian nephrologists have a longstanding tradition in implementing low protein diets in the treatment of CKD patients, with the principle objective of alleviating uremic symptoms, improving nutritional status and also a possibility of slowing down the progression of CKD or delaying the start of dialysis. A renewed interest in this field is based on the aim of implementing a wider nutritional therapy other than only reducing the protein intake, paying careful attention to factors such as energy intake, the quality of proteins and phosphate and sodium intakes, making today's low-protein diet program much more ambitious than previous. The motivation was the reduction in progression of renal insufficiency through reduction of proteinuria, a better control of blood pressure values and also through correction of metabolic acidosis. One major goal of the flexible and innovative Italian approach to the low-protein diet in CKD patients is the improvement of patient adherence, a crucial factor in the successful implementation of a low-protein diet program.

High-tone external muscle stimulation in patients with acute kidney injury (AKI): beneficial effects on NO metabolism, asymmetric dimethylarginine, and endothelin-1.

OBJECTIVES: The aim of this study was to assess potential effects of high-tone external muscle stimulation (HTEMS) on parameters of endothelial dysfunction (ED) in patients with acute kidney injury (AKI). BACKGROUND: The bad outcome of AKI patients is markedly influenced by ED, microinflammation, oxidative stress and protein hypercatabolism. Recently, we have shown that intradialytic application of HTMS was associated with a faster resolution of AKI. Here, we investigated in the same cohort of patients whether parameters of ED such as nitric oxide (NO), asymmetric-dimethylarginine (ADMA), and endothelin 1 (ET-1) are modulated by HTEMS as compared to non-HTEMS-treated AKI patients. METHODS: In a post-hoc study we analyzed plasma samples of the 34 AKI patients stage 5, of whom 17 underwent intradialytic HTEMS treatment while the other 17 served as AKI dialysis controls. Measurements included plasma nitrate and nitrite (NOx), ADMA, ET-1 and were performed before and on days 3, 7, 14, 21, and 28 after start of daily dialysis. Additional 16 healthy volunteers served as controls. RESULTS: Initially, in both AKI groups NOx levels were markedly lower and ADMA and ET-1 levels were higher compared to the healthy controls. After initiation of daily hemodialysis the HTEMS group showed a faster improvement of NOx and ET-1 (after 1 week) and ADMA levels (after 2 weeks) compared to the No- HTEMS group. After 2 weeks, all parameters of the HTEMS group were not different from healthy controls, while the No-HTEMSAKI group needed 3 - 4 weeks. CONCLUSION: Our findings suggest for the first time that in AKI patients, application of HTEMS is associated with a faster normalization of lowered NOx and elevated ADMA and ET-1 plasma levels. We hypothesize that the more rapid amelioration of these parameters in the HTEMS group contributed to the accelerated recovery of AKI. With regard to the small study groups with different causes of AKI, investigations in a greater number of AKI patients is required.

Antiplatelet therapy to prevent hemodialysis vascular access failure: systematic review and meta-analysis.

BACKGROUND: Hemodialysis vascular access failure occurs often and increases morbidity for people on hemodialysis therapy. Antiplatelet agents may prevent hemodialysis vascular access failure, but potentially may be hazardous in people with end-stage kidney disease who have impaired hemostasis. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials. SETTING & POPULATION: Adults on long-term hemodialysis therapy. SELECTION CRITERIA: Trials evaluating hemodialysis vascular access outcomes identified by searches in Cochrane CENTRAL and Renal Group Trial Registers and Embase, without language restriction. INTERVENTION: Antiplatelet therapy. OUTCOMES: Hemodialysis vascular access failure (thrombosis or loss of patency), failure to attain vascular access suitable for dialysis, need for intervention to attain patency or assist maturation, major bleeding, minor bleeding, and antiplatelet treatment withdrawal. Treatment effects were summarized as RRs with 95% CIs using random-effects meta-analysis. RESULTS: 21 eligible trials (4,826 participants) comparing antiplatelet treatment with placebo or no treatment were included. 12 trials (3,118 participants) started antiplatelet therapy around the time of dialysis vascular access surgery and continued treatment for approximately 6 months. Antiplatelet treatment reduced fistula failure (thrombosis or loss of patency) by one-half (6 trials, 1,222 participants; RR, 0.49; 95% CI, 0.30-0.81) but had uncertain effects on graft patency and attaining fistula or graft function suitable for dialysis. Overall, antiplatelet treatment had uncertain effects on major bleeding. LIMITATIONS: Unclear or high risk of bias in most trials and few trial data, particularly for antiplatelet effects on graft function and vascular access suitability for dialysis. CONCLUSIONS: Antiplatelet treatment protects fistula from thrombosis or loss of patency, but has little or no effect on graft patency and uncertain effects on vascular access maturation for dialysis and major bleeding. Interventions that demonstrably improve vascular access suitability for dialysis are needed.

Antiplatelet agents for chronic kidney disease.

BACKGROUND: Antiplatelet agents are widely used to prevent cardiovascular events. The risks and benefits of antiplatelet treatment may be different in people with chronic kidney disease (CKD) for whom occlusive atherosclerotic events are less prevalent, and bleeding hazards might be increased. OBJECTIVES: To summarise the effects of antiplatelet treatment (antiplatelet agent versus control or other antiplatelet agent) for the prevention of cardiovascular and adverse kidney outcomes in individuals with CKD. SEARCH METHODS: In January 2011 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cochrane Renal Group's Specialised Register without language restriction. SELECTION CRITERIA: We selected randomised controlled trials of any antiplatelet treatment versus placebo or no treatment, or direct head-to-head antiplatelet agent studies in people with CKD. Studies were included if they enrolled participants with CKD, or included people in broader at-risk populations in which data for subgroups with CKD could be disaggregated. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from primary study reports and any available supplementary information for study population, interventions, outcomes, and risks of bias. Risk ratios (RR) and 95% confidence intervals (CI) were calculated from numbers of events and numbers of participants at risk which were extracted from each included study. The reported RRs were extracted where crude event rates were not provided. Data was pooled using the random-effects model. MAIN RESULTS: We included 50 studies, enrolling 27,139 participants; 44 studies (21,460 participants) compared an antiplatelet agent with placebo or no treatment, and six studies (5679 participants) directly compared one antiplatelet agent with another. Compared to placebo or no treatment, antiplatelet agents reduced the risk of myocardial infarction (17 studies; RR 0.87, 95% CI 0.76 to 0.99), but not all-cause mortality (30 studies; RR 0.93, 95% CI 0.81 to 1.06), cardiovascular mortality (19 studies; RR 0.89, 95% CI 0.70 to 1.12) or stroke (11 studies; RR 1.00, 95% CI 0.58 to 1.72). Antiplatelet agents increased the risk of major (27 studies; RR 1.33, 95% CI 1.10 to 1.65) and minor bleeding (18 studies; RR 1.49, 95% CI 1.12 to 1.97). In terms of dialysis access outcomes, antiplatelet agents reduced access thrombosis or patency failure but had no effect on suitability for dialysis. Meta-regression analysis indicated no differences in the relative benefit or harms of treatment (risk of all-cause mortality, myocardial infarction, or major bleeding) by type of antiplatelet agent or stage of CKD. Limited data were available for direct head-to-head comparisons of antiplatelet drugs, treatment in kidney transplant recipients, primary prevention, or risk of ESKD. AUTHORS' CONCLUSIONS: Antiplatelet agents reduce myocardial infarction but increase major bleeding. Risks may outweigh harms among people with low annual risks of cardiovascular events, including those with early stages of CKD who do not have clinically-evident occlusive cardiovascular disease.

Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease.

BACKGROUND AND OBJECTIVES: High levels of indoxyl sulfate (IS) are associated with chronic kidney disease (CKD) progression and increased mortality in CKD patients. The aim of this pilot study was to assess whether a very low protein diet (VLPD; 0.3 g/kg bw/day), with a consequent low phosphorus intake, would reduce IS serum levels compared to a low protein diet (LPD; 0.6 g/kg bw/day) in CKD patients not yet on dialysis. MATERIAL AND METHODS: This is a post hoc analysis of a preceding cross-over study aimed to analyze FGF23 during VLPD. Here we performed a prospective randomized controlled crossover study in which 32 patients were randomized to receive either a VLPD (0.3 g/kg bw/day) supplemented with ketoanalogues during the first week and an LPD during the second week (group A, n = 16), or an LPD during the first week and a VLPD during the second week (group B, n = 16 patients). IS serum levels were measured at baseline and at the end of each study period. We compared them to 24 hemodialysis patients (HD) and 14 healthy subjects (control). RESULTS: IS serum concentration was significantly higher in the HD (43.4 ± 12.3 µM) and CKD (11.1 ± 6.6 µM) groups compared to the control group (2.9 ± 1.1 µM; p < 0.001). IS levels also correlated with creatinine values in CKD patients (R(2) = 0.42; p < 0.0001). After only 1 week of a VLPD, even preceded by an LPD, CKD patients showed a significant reduction of IS serum levels (37%). CONCLUSIONS: VLPD supplemented with ketoanalogues reduced IS serum levels in CKD patients not yet on dialysis.

Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Antiplatelet agents are used to prevent cardiovascular events; however, treatment effects may differ in persons with chronic kidney disease (CKD) because atherosclerotic disease is less prevalent, whereas bleeding hazards may be increased in this population. PURPOSE: To summarize the effects of antiplatelet treatment on cardiovascular events, mortality, and bleeding in persons with CKD. DATA SOURCES: Embase and Cochrane databases through November 2011 without language restriction. STUDY SELECTION: Randomized trials that included adults with CKD and compared antiplatelet agents with standard care, placebo, or no treatment. DATA EXTRACTION: Data for populations, interventions, outcomes, and risk for bias were extracted. Quality of evidence for treatment effects on myocardial infarction, death, and bleeding was summarized by using Grading of Recommendations Assessment, Development, and Evaluation guidelines. DATA SYNTHESIS: Nine trials (all post hoc subgroup analyses for CKD) involving 9969 persons who had acute coronary syndromes or were undergoing percutaneous coronary intervention and 31 trials involving 11,701 persons with stable or no cardiovascular disease were identified. Low-quality evidence has found that in persons with acute coronary syndromes, glycoprotein IIb/IIIa inhibitors or clopidogrel plus standard care compared with standard care alone had little or no effect on all-cause or cardiovascular mortality or on myocardial infarction but increased serious bleeding. Compared with placebo or no treatment in persons with stable or no cardiovascular disease, antiplatelet agents prevented myocardial infarction but had uncertain effects on mortality and increased minor bleeding according to generally low-quality evidence. LIMITATIONS: Data for antiplatelet agents in persons with CKD are frequently derived from post hoc analyses of trials of broader populations. Definitions for bleeding outcomes and trial duration were heterogeneous. CONCLUSION: Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards. PRIMARY FUNDING SOURCE: None.

Blood pressure variability and outcomes in chronic kidney disease.

BACKGROUND: We investigated the effects of visit-to-visit systolic blood pressure variability (SBPV) on both mortality and dialysis inception in a cohort of chronic kidney disease (CKD) patients not requiring dialysis therapy. Furthermore, we also explored the carry-over effect of visit-to-visit SBPV on mortality after dialysis initiation. METHODS: We conducted a longitudinal retrospective, observational, multi-centre study in three tertiary care nephrology outpatient clinics. All the ambulatory CKD patients admitted to the outpatient clinics from 1 January 2004 to 31 December 2005 were screened for study eligibility. We selected all consecutive patients older than 18 years of age with a mean estimated glomerular filtration rate of <60 mL/min/m(2), free from cardiovascular disease. SBPV was defined as the ratio of the SD to the mean SBP of five values recorded during a run-in phase of 4-5 months. Data on dialysis inception and mortality were recorded through 31 December 2010. RESULTS: Overall, we selected a cohort of 374 elderly (median age: 79 years) subjects. A total of 232 (62%) and 103 (29%) patients were male and had diabetes, respectively. A significant association between SBPV and the risk of death but not of CKD progression to dialysis was noted at univariate and after multivariable adjustments (hazard ratio for all-cause mortality per 1% increase in SBPV: 1.05; 95% confidence interval: 1.02-1.09; P = 0.001). Notably, no lethal event was recorded after dialysis initiation. CONCLUSIONS: Current findings suggest that SBPV may be of use for risk stratification in CKD patients.

Effect of a low- versus moderate-protein diet on progression of CKD: follow-up of a randomized controlled trial.

BACKGROUND: Whether low-protein-diet (LPD) as opposed to moderate-protein-diet (MPD) regimens improve the long-term survival of patients with chronic kidney disease (CKD) or induce protein-caloric malnutrition is unknown. STUDY DESIGN: Intention-to-treat analysis of follow-up data from a randomized controlled trial. SETTING & PARTICIPANTS: 423 patients with CKD (stages 4-5) were randomly assigned between January 1999 and January 2003 and followed up until December 2006 or death. The first phase of follow up was from January 1999 to June 2004; additional follow-up was from July 2004 to December 2006. INTERVENTION: LPD versus MPD (protein intake, 0.55 vs 0.80 g/kg/d). OUTCOMES: Protein-caloric malnutrition (defined as the occurrence of 1 of the following: loss of body weight > 5% in 1 month or 7.5% in 3 months or body mass index < 20 kg/m(2) with serum albumin level < 3.2 g/dL and normal C-reactive protein level [<0.5 mg/dL]), dialysis, death, or the composite outcome of dialysis and death. RESULTS: Baseline mean age was 61 years, estimated glomerular filtration rate was 16 mL/min/1.73 m(2), proteinuria had protein excretion of 1.67 g/d, body mass index was 27.1 kg/m(2), protein intake was 0.95 g/kg/d, and there were 57% men. Duration of follow-up was 32 months (median, 30 months; 25th-75th percentiles, 21-39). Average protein intakes were 0.73 +/- 0.04 g/kg/d for the LPD and 0.9 +/- 0.06 g/kg/d for the MPD. 3 patients (0.7%) met criteria for protein-caloric malnutrition. 48 patients died (11%), 83 initiated dialysis therapy (20%), and 113 (27%) reached the composite outcome. In unadjusted Cox survival analyses, effects of the LPD on these outcomes were 1.01 (95% CI, 0.57-1.79), 0.96 (95% CI, 0.62-1.48), and 0.98 (95% CI, 0.68-1.42), respectively. LIMITATIONS: Low event rates for dialysis therapy initiation and death. CONCLUSIONS: Most patients, who were regularly followed up in CKD clinics, were acceptably adherent to the prescribed dietary protein intake restrictions; the LPD and MPD did not lead to protein wasting; and the LPD did not decrease the risk of death or dialysis therapy initiation compared with the MPD.

Setting dialysis start at 6.0 ml/min/1.73 m2 eGFR--a study on safety, quality of life and economic impact.

BACKGROUND: End-stage renal disease care requires enormous economic resources. A timely dialysis start could reduce the costs of the renal replacement therapy (RRT). Our aim was to measure the time to dialysis in CKD patients, with an estimated glomerular filtration rate (eGFR)

[Acute kidney failure in differentiation syndrome: a possible complication during therapy with differentiating agents for acute promyelocytic leukemia. A case report].

Differentiation syndrome (DS), previously known as retinoic acid syndrome or ATRA (all-trans retinoic acid) or ATO (arsenic trioxide) syndrome, is a life-threatening complication of the therapy with differentiating agents in patients with acute promyelocytic leukemia (APL). The latter is a rare subtype of acute myeloid leukemia and represents a hematological emergency. The clinical manifestations of DS, after induction therapy with differentiating agents, include unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, congestive heart failure and acute renal failure. The therapy is based on early intravenous administration of high-dose dexamethasone, in order to counteract the cytokine storm responsible for the DS. Among the supportive measures for the management of DS, furosemide (in 87% of patients) and dialysis (12% of patients) are used to manage acute renal failure, peripheral and pulmonary edema. We describe a case of acute renal failure, treated with haemodialysis, in a young patient with APL and an early and severe DS after induction therapy. This is a rare condition, not well known among nephrologists, where early recognition and treatment are crucial for the prognosis.

Very Low Protein Diet for Patients with Chronic Kidney Disease: Recent Insights.

Use of nutritional therapy (NT) in chronic kidney disease (CKD) patients is still debated among nephrologists, but it represents a fundamental point in the conservative treatment of CKD. It has been used for years and it has new goals today, such as (1) the reduction of edema, diuretics, and blood pressure values with a low sodium-content diet; (2) the dose reduction of phosphate levels and phosphate binders; (3) the administration of bicarbonate with vegetables in order to correct metabolic acidosis and delay CKD progression; (4) the reduction of the number and the doses of drugs and chemical substances; and (5) the lowering of urea levels, the cure of intestinal microbioma, and the reduction of cyanates levels (such as indoxyl-sulphate and p-cresol sulphate), which are the most recent known advantages achievable with NT. In conclusion, NT and especially very low protein diet (VLPD) have several beneficial effects in CKD patients and slows the progression of CKD.

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.

[Protein carbamylation: what it is and why it concerns nephrologists].

Spontaneous urea dissociation in water solution is a prominent source of protein carbamylation in our body. Protein carbamylation is a well-known phenomenon since early seventies. Some years ago, much interest in the diagnostic power of carbamylated protein arouse. Recently the target of the researches focused on its potential cardiovascular pathogenicity. Some authors claimed that this could be a reason for higher cardiovascular mortality in uremic patients. Nutritional therapy, amino acids supplementation and intensive dialysis regimen are some of the therapeutic tools tested to lower the carbamylation burst in this population.

Supplementation of Short-Chain Fatty Acid, Sodium Propionate, in Patients on Maintenance Hemodialysis: Beneficial Effects on Inflammatory Parameters and Gut-Derived Uremic Toxins, A Pilot Study (PLAN Study)

BACKGROUND: In end-stage renal disease (ESRD), gut-derived uremic toxins play a crucial role in the systemic inflammation and oxidative stress promoting the excess morbidity and mortality. The biochemical derangement is in part a consequence of an insufficient generation of short-chain fatty acids (SCFA) due to the dysbiosis of the gut and an insufficient consumption of the fermentable complex carbohydrates. AIM OF THE STUDY: The primary end-point was to evaluate the potential efficacy of SCFA (specifically, sodium propionate (SP)) for patients on maintenance hemodialysis (MHD) on systemic inflammation. Secondary end-points included potential attenuation of oxidative stress markers, insulin resistance and production of gut-derived uremic toxins indoxyl sulfate and p-cresol sulfate, as well as health status after SP supplementation. STUDY DESIGN: We performed a single-center non-randomized pilot study in 20 MHD patients. They received the food additive SP with a daily intake of 2 × 500 mg in the form of capsules for 12 weeks. Pre-dialysis blood samples were taken at the beginning, after six weeks and at the end of the administration period, as well as four weeks after withdrawal of the treatment. RESULTS: The subjects revealed a significant decline of inflammatory parameters C-reactive protein (-46%), interleukin IL-2 (-27%) and IL-17 (-15%). The inflammatory parameters IL-6 and IFN-gamma showed a mild non-significant reduction and the anti-inflammatory cytokine IL-10 increased significantly (+71%). While the concentration of bacterial endotoxins and TNF-α remained unchanged, the gut-derived uremic toxins, indoxyl sulfate (-30%) and p-cresyl sulfate (-50%), revealed a significant decline. The SP supplementation reduced the parameters of oxidative stress malondialdehyde (-32%) and glutathione peroxidase activity (-28%). The serum insulin levels dropped by 30% and the HOMA-index by 32%. The reduction of inflammatory parameters was associated with a lowering of ferritin and a significant increase in transferrin saturation (TSAT). Four weeks after the end of the treatment phase, all improved parameters deteriorated again. Evaluation of the psycho-physical performance with the short form 36 (SF-36) questionnaire showed an enhancement in the self-reported physical functioning, general health, vitality and mental health. The SP supplementation was well tolerated and without important side effects. No patient had left the study due to intolerance to the medication. The SP supplementation in MHD patients reduced pro-inflammatory parameters and oxidative stress and improved insulin resistance and iron metabolism. Furthermore, SP effectively lowered the important gut-derived uremic toxins indoxyl and p-cresol sulfate. These improvements were associated with a better quality of life. Further controlled studies are required in a larger cohort to evaluate the clinical outcome.

A strategy to reduce inflammation and anemia treatment's related costs in dialysis patients.

This is a post-hoc analysis evaluating erythropoiesis stimulating agents' (ESA) related costs while using an additional ultrafilter (Estorclean PLUS) to produce ultrapure dialysis water located within the fluid pathway after the treatment with reverse osmosis and before the dialysis machine. Twenty-nine patients (19 treated with epoetin alfa and 10 with darboepoetin alfa) were included in the analysis. We showed to gain savings of 210 € per patient (35 € per patient each month) with epoetin alfa during the experimental period of 6 months, compared to the control period and of 545 € per patient (90 € per patient each month) with darboepoetin alfa. Estorclean PLUS had a cost of 600 € (25 € per month per each patient) and was used for 6 months. Intravenous iron therapy with sodium ferrigluconate had a cost of 0,545 €/62,5 mg. In conclusion, during the experimental period with the use of Estorclean, we obtained global savings of 11 € per patient per month with epoetin alfa and 30 € per patient per month with darboepoetin alfa to treat anemia in dialysis patients.