The Effects of Two Kinds of Dietary Interventions on Serum Metabolic Profiles in Haemodialysis Patients.

The goal of this study was to evaluate the effects of two kinds of 24-week dietary interventions in haemodialysis patients, a traditional nutritional intervention without a meal before dialysis (HG1) and implementation of a nutritional intervention with a meal served just before dialysis (HG2), in terms of analysing the differences in the serum metabolic profiles and finding biomarkers of dietary efficacy. These studies were performed in two homogenous groups of patients (n = 35 in both groups). Among the metabolites with the highest statistical significance between HG1 and HG2 after the end of the study, 21 substances were putatively annotated, which had potential significance in both of the most relevant metabolic pathways and those related to diet. After the 24 weeks of the dietary intervention, the main differences between the metabolomic profiles in the HG2 vs. HG1 groups were related to the higher signal intensities from amino acid metabolites: indole-3-carboxaldehyde, 5-(hydroxymethyl-2-furoyl)glycine, homocitrulline, 4-(glutamylamino)butanoate, tryptophol, gamma-glutamylthreonine, and isovalerylglycine. These metabolites are intermediates in the metabolic pathways of the necessary amino acids (Trp, Tyr, Phe, Leu, Ile, Val, Liz, and amino acids of the urea cycle) and are also diet-related intermediates (4-guanidinobutanoic acid, indole-3-carboxyaldehyde, homocitrulline, and isovalerylglycine).

Effects of the Malnutrition-Eat Additional Meal (MEAM) Diet on the Serum Levels of Albumin and C-Reactive Protein in Hemodialysis Patients.

The main objective of this project was to evaluate the efficiency of two kinds of nutritional intervention implemented in hemodialysis patients for 24 weeks (traditional nutritional intervention without a meal served before dialysis for group HG1, and nutritional intervention involving a meal served before dialysis for group HG2), and their impact on nutritional status and serum concentrations of C-reactive protein (CRP). Nutritional status and serum biochemical parameters were analyzed in the control group (CG, n = 70) and in two homogeneous groups of patients, HG1 (n = 35) and HG2 (n = 35). There was an interesting trend in both groups of patients connected with increased intake, mainly of energy and protein. In HG1, the greatest increase in energy intake was observed on Sundays, and in HG2 on the days with dialysis. In HG2, after 24 weeks of the nutritional intervention, an increase in serum albumin (p = 0.0157) and a decrease in CRP concentration (p = 0.0306) were observed, whereas in HG1 there was a decrease in serum albumin concentration (p = 0.0043) with no significant change in CRP concentration. The nutritional intervention applied, called the Malnutrition-Eat Additional Meal (MEAM) diet with an easily digestible meal served before dialysis, was aimed at improving the patients' nutritional status and the obtained results indicate the need not only for substantial reeducation of hemodialysis patients in the area of their diet, but also for undertaking further research and discussions on the possibility of ensuring adequate meals for hemodialysis patients before the dialysis procedure.

A potential link between AQP3 and SLC14A1 gene expression level and clinical parameters of maintenance hemodialysis patients.

BACKGROUND: The transport of water and urea through the erythrocyte membrane is facilitated by aquaporins such as aquaglyceroporin (AQP3), and type B urea transporters (UT-B). As they may play an important role in osmotic balance of maintenance hemodialysis (HD) patients, the aim of the present study was to determine whether any relationship exists between the expression of their genes and the biochemical / clinical parameters in HD patients. METHODS: AQP3 and UT-B (SLC14A1) gene expression was evaluated using RT-qPCR analysis in 76 HD patients and 35 participants with no kidney failure. RESULTS: The HD group demonstrated significantly higher median expression of AQP3 and UT-B (Z = 2.16; P = 0.03 and Z = 8.82; p < 0.0001, respectively) than controls. AQP3 negatively correlated with pre-dialysis urea serum concentration (R = -0.22; P = 0.049) and sodium gradient (R = -0.31; P = 0.04); however, no significant UT-B correlations were observed. Regarding the cause of end-stage kidney disease, AQP3 expression positively correlated with erythropoietin dosages in the chronic glomerulonephritis (GN) subgroup (R = 0.6; P = 0.003), but negatively in the diabetic nephropathy subgroup (R = -0.59; P = 0.004). UT-B positively correlated with inter-dialytic weight gain% in the GN subgroup (R = 0.47; P = 0.03). CONCLUSION: Maintenance hemodialysis seems significantly modify AQP3 and UT-B expression but their link to clinical and biochemical parameters needs further large-scale evaluation.

Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies.

Rationale & Objective: Chronic kidney disease-associated pruritus (CKD-aP) in patients treated by hemodialysis (HD) impairs quality of life (QoL). Difelikefalin, a selective κ-opioid receptor agonist, decreased the intensity of CKD-aP in patients undergoing HD. This pooled analysis evaluated difelikefalin's efficacy and the itch-related QoL overall and in subgroups defined by demographics or disease characteristics. Study Design: In KALM-1 and KALM-2, participants were randomized (1:1) to receive intravenous difelikefalin or placebo 3 times/wk for 12 weeks, followed by a 52-week open-label extension. Setting & Participants: Adults with moderate to severe CKD-aP treated by HD in North America, Europe, and the Asia-Pacific region. Intervention: Intravenous difelikefalin at 0.5 mcg/kg or placebo. Outcomes: Itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]) and itch-related QoL (Skindex-10 and 5-D Itch questionnaires). Results: 851 participants were randomized (difelikefalin, n = 426; placebo, n = 425). This pooled analysis demonstrated early     (week 1), sustained difelikefalin efficacy, with significantly greater achievement of ≥3-point WI-NRS reduction with difelikefalin (51.1%) versus placebo (35.2%; P < 0.001). Achievement of a ≥4-point WI-NRS reduction was significantly greater with difelikefalin (38.7%) versus placebo (23.4%; P < 0.001). Difelikefalin reduced itch intensity in subgroups based on age, sex, anti-itch medication use, the presence of specific medical conditions, and gabapentin or pregabalin use. More participants receiving difelikefalin versus placebo achieved clinically meaningful decreases of ≥15 points on the Skindex-10 scale (55.5% vs 40.5%, respectively; P < 0.001) and ≥5 points on the 5-D Itch scale (52.1% vs 42.3%, respectively; P = 0.01), with sustained 5-D Itch effects up to 64 weeks. Limitations: Subgroup samples were small. The WI-NRS, Skindex-10, and 5-D Itch are not used in routine clinical care of dialysis patients; therefore, findings may not reflect the real-world effectiveness of difelikefalin. Conclusions: Difelikefalin demonstrated rapid, sustained efficacy, with consistent results in diverse populations of patients treated by HD. Funding: Cara Therapeutics, Inc. Trial Registration: The KALM-1 trial is registered as NCT03422653 and the KALM-2 trial is registered as NCT03636269.

Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study.

INTRODUCTION: Patients with hepatocyte nuclear factor-1 beta (HNF1B) mutations present a variable phenotype with two main symptoms: maturity onset diabetes of the young (MODY) and polycystic kidney disease (PKD). OBJECTIVES: Identification of serum metabolites specific for HNF1Bmut and evaluation of their role in disease pathogenesis. METHODS: We recruited patients with HNF1Bmut (N = 10), HNF1Amut (N = 10), PKD: non-dialyzed and dialyzed (N = 8 and N = 13); and healthy controls (N = 12). Serum fingerprinting was performed by LC-QTOF-MS. Selected metabolite was validated by ELISA (enzyme-linked immunosorbent assay) measurements and then biologically connected with HNF1B by in silico analysis. HepG2 were stimulated with lysophosphatidic acid (LPA) and HNF1B gene was knocked down (kd) by small interfering RNA. Transcriptomic analysis with microarrays and western blot measurements were performed. RESULTS: Serum levels of six metabolites including: arachidonic acid, hydroxyeicosatetraenoic acid, linoleamide and three LPA (18:1, 18:2 and 20:4), had AUC (the area under the curve) > 0.9 (HNF1Bmut vs comparative groups). The increased level of LPA was confirmed by ELISA measurements. In HepG2HNF1Bkd cells LPA stimulation lead to downregulation of many pathways associated with cell cycle, lipid metabolism, and upregulation of steroid hormone metabolism and Wnt signaling. Also, increased intracellular protein level of autotaxin was detected in the cells. GSK-3alpha/beta protein level and its phosphorylated ratio were differentially affected by LPA stimulation in HNF1Bkd and control cells. CONCLUSIONS: LPA is elevated in sera of patients with HNF1Bmut. LPA contributes to the pathogenesis of HNF1B-MODY by affecting Wnt/GSK-3 signaling.

Serum microRNA profiles in patients with autosomal dominant polycystic kidney disease show systematic dysregulation partially reversible by hemodialysis.

INTRODUCTION: The impact of autosomal dominant polycystic kidney disease (ADPKD) on serum microRNAs (miRNA) is unknown. MATERIAL AND METHODS: For profiling experiment we recruited 30 patients from three equinumerous groups: controls, ADPKD and ADPKD on hemodialysis. From the last group extra samples were collected for in pre-/postdialysis analysis. Additionally, 23 healthy volunteers were used for selected biomarker verification. Real-time PCR arrays were used for quantification of 752 miRNAs. Validation of selected miRNAs was performed in total RNA extracted from the serum and the exosomal fraction in pre-/postdialysis samples. RESULTS: In total, 37 significant circulating miRNAs were found to differ between ADPKD patients and controls. In validation, 3 miRNAs with the highest fold change in comparison of dialyzed vs non-dialyzed patients (miR-532-3p, miR-320b, miR-144-5p) were not significantly altered by hemodialysis and from the top down-regulated ones, miR-27a-3p was significantly lower after dialysis in both total and exosomal fractions, miR-20a-5p was down-regulated in the exosomal fraction and miR-16-5p was unaltered by hemodialysis. MiR-16-5p was selected as the best circulating biomarker of ADPKD. Circulating representatives of the miR-17 family sharing the same seed region (miR-20a-5p, miR-93-5p and miR-106a-5p) showed significantly lower expression among dialyzed vs. non-dialyzed patients and their exosomal fraction dropped after hemodialysis. CONCLUSIONS: The serum miRNAs among ADPKD patients differ substantially depending on the stage of CKD. The exosomal fraction of miRNA was more affected by dialysis than the total one. There was a common pattern of down-regulation for circulating miR-17 family members sharing the same seed region.

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

The Maintenance Immunosuppression Scheme Influences Early C4d Urinary Excretion in Kidney Graft Recipients but Does Not Affect the Long-term Graft Survival.

C4d urinary excretion varies according to the risk of graft rejection or progression of chronic allograft nephropathy. The most common maintenance immunosuppression (IS) schemes include cyclosporine (CSA) or tacrolimus (TAC) with azathiopryne (AZA) or mycophenolate mophetil (MMF). The chosen IS may influence kidney transplant outcomes and possibly modify urinary C4d. The aim of the study was to determine whether early C4d urinary excretion varies in patients after kidney allograft transplantation (KTx) regarding administered IS and if these factors may help to predict long-term KTx outcomes. The study involved 185 patients who underwent KTx. The urinary specimens were assessed by enzyme-linked immunosorbent assay test for C4d excretion. To increase the objectivity, C4d excretion was divided by urinary creatinine excretion (ng/mgCr). The study population was grouped according to the IS scheme, that is, CSA + AZA, CSA + MMF, and TAC + MMF. At baseline, the greatest C4d urinary excretion was noticed in patients treated with CSA + AZA, 199.5 ± 175.9 ng/mL (5.3 ± 7.1 ng/mgCr) and the lowest in those in whom tacrolimus and mycophenolate mophetil was administered, 166.6 ± 186.3 ng/mL (3.9 ± 6.2 ng/mgCr). In the CSA + MMF group, C4d excretion was 195.6 ± 200.3 ng/mL (5.0 ± 6.6 ng/mgCr). Statistically significant differences were seen only between the CSA + AZA and TAC + MMF groups, analysis of variance P < 0.05 (P < 0.01 for C4d/urinary creatinine ratio). No statistically significant differences were found in graft survival rates between different immunosuppressive regimens. Although early C4d measurements vary in patients after kidney allograft transplantation regarding administered IS, this IS dependant variation does not seem to affect the long-term graft survival.

A Taurolidine-Citrate-Heparin Lock Solution Effectively Eradicates Pathogens From the Catheter Biofilm in Hemodialysis Patients.

Catheter-related bacteremia (CRB) is a typical complication of hemodialysis catheter use. Catheter lumen colonization by pathogens is regarded as a direct cause of CRB. Once settled, the catheter biofilm increases the risk of developing infection, thus necessitating insertion replacement and antibiotic treatment. The study assessed the self-sufficient efficacy of taurolidine-citrate-heparin lock solution in eradicating catheter biofilm bacteria and keeping it sterile in patients on hemodialysis. Twenty-nine chronic patients on hemodialysis with tunneled and nontunneled catheters locked with a heparin filling (the mean time of heparin lock use -30.1 ± 2.0 days) and subsequently converted to a taurolidine-citrate-heparin filling were included. Peripheral vein and catheter lumen blood cultures were obtained before the filling change and after taurolidine-citrate-heparin lock use (mean time 33.8 ± 7.6 days). Twenty-four participants with tunneled and nontunneled catheters locked with taurolidine-citrate-heparin filling served as the control group. During the heparin-locking period, CRB was diagnosed in 3 cases (only nontunneled catheters). The catheter blood cultures findings were positive in 23 patients (10 temporary and 13 permanent catheters), whereas both the catheter and peripheral vein blood cultures were sterile in 3 of 29 subjects (only permanent catheters). Irrespective of catheter type (tunneled or nontunneled), repeated culture revealed no pathogens in any of the 23 patients with initial positive catheter blood culture, after the use of taurolidine-citrate-heparin filling. No positive blood culture was noted in the control group. The taurolidine-citrate-heparin lock solution effectively eradicated pathogens from nontunneled and tunneled catheter biofilms and helped to maintain catheter lumen sterility.

Macrophage migration inhibitory factor urinary excretion revisited ­ MIF a potent predictor of the immunosuppressive treatment outcomes in patients with proliferative primary glomerulonephritis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine that shares many activities with other pro-inflammatory cytokines in primary glomerulonephritis (GN). This study assesses the influence of immunosuppressive treatment on serum and urine MIF in patients with proliferative (PGN) and non-proliferative (NPGN) glomerulonephritis, and evaluates the potential of MIF in predicting outcomes. METHODS: Eighty-four patients (45 males and 39 females) with primary GN were included. Urinary excretion of MIF (ng/mg of urinary creatinine) was measured both pre- and post-treatment with combined steroids and cyclophosphamide. After a 12-month follow-up, the patients were retrospectively divided into four subgroups: responders of proliferative GN (R-PGN), non-responders of proliferative GN (NR-PGN), responders of non-proliferative GN (R-NPGN) and non-responders of non-proliferative GN (NR-NPGN). RESULTS: The median pre-treatment urinary MIF values were higher in PGN than in NPGN (3.6 versus 2.2; ANOVA P = 0.039). The highest pre-treatment urinary excretion of MIF was observed in NR-PGN (median 6.1), which was significantly higher than other subgroups (ANOVA P < 0.05). The treatment significantly reduced MIF urinary excretion only in R-PGN (P < 0.01). In NR-PGN, pre- (5.9 ± 2.9 pg/mgCr) and post-treatment mean MIF excretion (4.9 ± 2.3 pg/mgCr) exceeded the calculated cut off value (3.3 pg/mgCr). CONCLUSION: MIF urinary excretion appears to be a prognostic marker of therapy outcomes only in proliferative glomerulonephritis, in which lower urinary MIF may be linked with good prognosis, whereas a higher MIF urinary excretion value was a marker of unfavorable therapy outcomes. In Non-Responders, urinary MIF measurements may help to reconsider the choice of the immunosuppressive regimen at early stages of the treatment and act as an impulse to search for new therapeutic strategies.

[The early C4d urinary excretion and long-term kidney graft survival in patients treated with tacrolimus and mycophenolate mophetil]. / Wczesne wydalanie z moczem C4d a odlegle przezycie przeszczepu nerki u chorych leczonych takrolimusem i mykofenolanem mofetylu.

UNLABELLED: The C4d urinary excretion seems to increase with the risk of graft rejection or progression of chronic allograft nephropathy although its impact on long-term kidney transplant (KTx) outcomes remains unclear. Presently the most common maintenance immunosuppression schemes (IS) includes corticosteroids and cyclosporine or tacrolimus (Tac) with mycophenolane mophetil (MMF), and Tac combined with MMF is regarded to be superior to other schemes. The aim of the study was to determine whether the initial (1-3 months post KTx) level of C4d urinary excretion may help to predict long-term kidney allograft transplantation outcomes in patients treated with Tac+MMF as maintenance IS. MATERIAL AND METHODS: The study involved 66 patients who had undergone kidney allograft transplantation. The urine specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion (ng/mgCr). The study population was grouped according the calculated Roc curve (the cut off value of the urinary C4d excretion 13.1 ng/mgCr; AUC 0.93; 95% CI 0.74-0.95) into LC4d and HC4d, C4d below or above 13.1 ng/mgCr. RESULTS: The mean C4d urinary excretion was 166.6 +/- 186.3 ng/mL (3.9 +/- 6.2 ng/mgCr), in LC4d and HC4d 34.8 +/- 102.2 ng/mL (1.1 +/- 6.4 ng/mgCr) and 347.3 +/- 255.7ng/mL (19.2 +/- 5.9 ng/mgCr), respectively. In accord with the division of study population, the statistically significant differences were seen between LC4d and HC4d in urinary C4d excretion Z = 4.4; p = 0.019 (Z = 4.9, p = 0.011 for excretion calculated per urinary creatinine). Kaplan-Meier curve analysis demonstrated a higher graft survival rate in LC4d than in HC4d group (p = 0.048 by log-rank) in ten years follow-up. CONCLUSIONS: In patients treated with tacrolimus and mycophenolate mophetil as a maintenance immunosuppression, the lower C4d urinary excretion in the early post-transplant period seems to be a low significance prognostic marker of a better long-term kidney allograft transplantation outcome.

Absence of C4d urinary excretion in the early post-transplant period is associated with improved long-term kidney graft survival.

INTRODUCTION: C4d urinary excretion varies according to the risk of graft rejection or progression of chronic allograft nephropathy, but its influence on long-term kidney transplant (KTx) outcomes remains unclear. The aim of the study was to determine whether the initial (1-3 months post KTx) level of C4d urinary excretion may help to predict long-term kidney allograft transplantation outcomes. MATERIALS AND METHODS: The study involved 185 patients who had undergone KTx. The urinary specimens taken from the morning urine portion were assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment, all measurements were divided by urinary creatinine excretion (ng/mgCr). The study population was grouped according to the C4d excretion cut-off value into low (LC4d, 109 participants) and high (HC4d, 76 participants) C4d excretion groups. Additionally a subgroup with absence of C4d in the urine (ZC4d, 26 patients) was formed. RESULTS: The calculated Roc curve indicated the cut off value of the urinary C4d excretion as 12.4ng/mgCr (AUC 0.77; 95%CI 0.73-0.95). The mean C4d urinary excretions in LC4d and HC4d were 1.9±3.27 and 20.6±4.6ng/mgCr, respectively, whereas after exclusion of ZC4d subgroup, the mean C4d was 14.9±6.3ng/mgCr in the remainder. Kaplan-Meier curve analysis demonstrated a slightly higher graft survival rate (GSR) in LC4d than in HC4d group (p=0.04 by log-rank). The subsequent analysis showed the highest GSR in ZC4d subgroup (p=0.0006 by log-rank). CONCLUSION: Although lower C4d urinary excretion in the early post-transplant period seems to be associated with better long-term kidney allograft transplantation outcomes, only its absence in the urine appears to be a solid predictor of improved graft survival.

Sodium gradient, xerostomia, thirst and inter-dialytic excessive weight gain: a possible relationship with hyposalivation in patients on maintenance hemodialysis.

PURPOSE: The aim of the study was to assess whether hyposalivation is linked with increased thirst sensation and weight gain in hemodialysis (HD) patients and whether there is any connection between hyposalivation and sodium balance. METHODS: One hundred and eleven participants (64 males and 47 females) receiving maintenance hemodialysis, mean age 59.1 ± 13.6 years old, were involved in the study. All participants completed a survey evaluating thirst intensity (DTI) and xerostomia inventory (XI). In addition, pre-dialysis sodium concentration and inter-dialytic weight gain (IWG) were assessed. The division into no-hyposalivation and hyposalivation groups was based on an unstimulated whole saliva (UWS) flow rate. RESULTS: Hyposalivation, UWS below 0.1 mL/min, was reported in 28.8% of HD patients. In these participants, IWG was higher than in patients with UWS > 0.1 mL/min (3.65 ± 1.78 vs 3.0 ± 1.4; p = 0.042), as well as the pre-dialysis sodium gradient (3.22 ± 2.1 vs 1.6 ± 2.8; p = 0.031). The mean XI and DTI scores did not differ between study groups. In the hyposalivation group, pre-dialysis sodium serum gradient negatively correlated with saliva outflow (ρ = -0.61, p = 0.019) and positively with IWG (ρ = 0.49, p = 0.022). IWG correlated with XI (ρ = 0.622, p = 0.016) in hyposalivation group and with DTI in no-hyposalivation group (ρ = 0.386, p = 0.033). CONCLUSIONS: Hyposalivation significantly correlates with IWG; however, its influence on thirst and self-reported mouth dryness seems to be weaker than expected. Additionally, hyposalivation was found to be associated with an elevated pre-dialysis sodium gradient.

[The influence of pre-transplantation dialysis modality on late C4d urinary excretion in kidney graft recipients]. / Wplyw przedtransplantacyjnej metody dializoterapii na pózne wydalanie z moczem skladnika dopelniacza C4d u chorych po przeszczepie nerki.

INTRODUCTION: The C4d deposits as well as its urinary excretion are markers of the humoral acute kidney graft rejection. The pre-transplant dialysis modality influences on the post-transplant outcomes and it is possible that it may modify C4d urinary excretion. AIM: The aim of the study was the assessment of the pre-transplant dialysis modality on late C4d urinary excretion. MATERIAL AND METHODS: The study comprised 185 patients who underwent kidney allograft transplantation (KTx). The urinary specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion. The study population was grouped according the pre-transplant dialysis modality i.e. hemo- and peritoneal dialysis RESULTS: In the study the C4d urinary excretion in patients treated with hemodialysis was higher than in peritoneal dialysis, irrespectively whether in direct measurements 221.1 ± 239.9 ng/ml vs 156.4 ± 188.7 ng/ml (p < 0.05) or when calculated per urinary creatinine 5.2 ± 7.1 ng/mgCr i 3.4 ± 7.9 ng/mgr (p < 0.05). CONCLUSIONS: Pre-transplant dialysis modality influences late C4d urinary excretion.

[The assessment of C4d urinary excretion in early and late post kidney transplant periods]. / Ocena wydalania z moczem skladnika dopelniacza C4d we wczesnym i póznym okresie po transplantacji nerki.

INTRODUCTION: Recent data describes the involvement of compliment elements in humoral kidney graft rejection. The C4d deposits in peritubular capilars are the marker of compliment activity and the element of humoral acute graft rejection. The aim of the study was the assessment of C4d urinary excretion in early and late post-kidney transplant periods. MATERIAL AND METHODS: The study comprised 185 patients who underwent kidney allograft transplantation (KTx). The urinary specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion. The study population was grouped according the post-transplant time i.e. <1 and >1 year after KTx. RESULTS: In the study the C4d urinary excretion in patients <1 year and >1 year post kidney transplantation were 4.6 ± 7.5 and 5.3 ± 7.9 ng/mgCr, respectively. The mean C4d excretion was 4.8 ± 7.6 ng/mgCr. The values did not differ significantly. The direct assessment of C4d excretion (not divided per creatinuria) were also comparable in the study groups (207.2 ± 261.8 ng/ml and 212.9 ± 249.3 ng/ml, respectively). CONCLUSIONS: C4d urinary excretion did not depend on post-transplant time.

[The influence of maintenance immunosuppression scheme on D4d urinary excretion in kidney graft recipients]. / Wplyw wyboru podtrzymujacego schematu immunosupresji na wydalanie z moczem skladnika dopelniacza C4d u chorych po przeszczepie nerki.

INTRODUCTION: The C4d urinary excretion varies according to the risk of graft rejection or progression of chronic allograft nephropathy. The most common maintenance immunosuppression (IS) schemes includes cyclosporine (CSA) ortacrolimus (TAC with azathiopryne (AZA) or mycophenolane mophetil (MMF). The chosen IS may influence on the kidney transplant outcomes and possibly modify C4d urinary secretion. The aim of the study was to assess whether IS scheme may influence on C4d urinary excretion. MATERIAL AND METHODS: The study involved 185 patients who underwent kidney allograft transplantation (KTx).The urinary specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion (ng/mg Ucr). The study population was grouped according the IS scheme, i.e., CSA+AZA, CSA+MMF and TAC+MMF. RESULTS: The highest C4d urinary excretion was noticed in patients treated with CSA+AZA--210 +/- 229 ng/ml (5.1 +/- 7.9 ng/mg Ucr) and the lowest in those in whom tacrolimus and mycophenolane mophetil was administered -198?188 ng/ml (4.4 +/- 7.1 ng/mg Ucr). In CSA+MMF group C4d excretion was 207?256 ng/ml (4.7 +/- 7.7 ng/mg Ucr). The statistically significant differences were seen only between CSA+AZA and TAC+MMF groups--ANOVA p<0.05 (p<0.01 for excretion calculated per Ucr). CONCLUSIONS: C4d urinary excretion in kidney graft recipients depends on immunosuppression scheme and is the lowest in patients treated with tacrolimus and mycophenolane mophetil.

S-Fas urinary excretion helps to predict the immunosuppressive treatment outcomes in patients with proliferative primary glomerulonephritis.

Deregulation of soluble apoptosis stimulating fragment (sFas) plays an important role in glomerulonephritis (GN). The study assed the influence of immunosuppressive treatment on serum and urine sFas in patients with proliferative (PGN) and non-proliferative (NPGN) GN, and evaluated the potential of sFas measurements in predicting outcomes. Eighty-four patients with GN (45 males and 39 females) were included. Serum concentration (ng/mL) and urinary excretion (ng/mg of urinary creatinine) of sFas were measured before and after the treatment. After 12 months of therapy with steroids and cyclophosphamide, patients were divided into two subgroups according to the treatment results: Responders (R) and Non-Responders (NR). The sFas urinary excretion was reduced after treatment in both PGN and NPGN (from 17.12 ± 15 to 5.3 ± 4.2, P = 0.008 and from 10.11 ± 6.1 to 3.4 ± 3.0, P = 0.039; respectively) whereas the sFas serum concentration remained unchanged. In PGN, pre-treatment urinary sFas concentration was significantly lower in the Responders than in Non-Responders (2.3 ± 3.1 vs 19.4 ± 14.1, P = 0.003), and was lower still than in both R (P = 0.044) and NR (P = 0.042) subgroups with NPGN. The immunosuppressive treatment reduced sFas urinary excretion in proliferative and non-proliferative GN and results suggest that the lower urinary sFas may be linked with favorable therapy outcomes in patients with PGN.

Predictive value of conjointly examined IL-1ra, TNF-R I, TNF-R II, and RANTES in patients with primary glomerulonephritis.

Interleukin-1 receptor antagonist (IL-1ra), tumor necrosis factor soluble receptors (sTNF-R) type I and II, and regulated upon activation, normal T-cell expressed and secreted (RANTES) play an important role in the modulation of primary glomerulonephritis (GN) course. The aim of the study was to assess whether pre-treatment measurements of IL-1ra, sTNF-R, and RANTES assessed conjointly may be useful as predicting factors in patients with GN. In 84 patients (45 males and 39 female) serum concentration (pg/mL) and urinary excretion (pg/mgCr) of cytokines were measured. After 12 months of therapy with steroids and cyclophosphamide the patients were divided into two subgroups: Responders (R) and Non-Responders (NR) according to the treatment results. The urinary IL-1ra, TNF-RI and RII were significantly higher in R than NR (1,732 vs 646 with P < 0.001, 13.1 vs 6.3 with P = 0.005, and 33.6 vs 14.4 with P = 0.012). The urinary RANTES excretion was increased in NR (79.6 vs 28.5; P < 0.001). The multivariable analysis showed that if conjointly assessed, only urinary IL-1ra, TNF-R I and R II, RANTES with 85% probability pointed the feature remission (R). In conclusion, the urinary excretion of IL-1ra, TNF-R I and R II, and RANTES examined conjointly are effective in predicting favorable response to immunosuppressive treatment in patients with GN.

The effect of IL-2, IL-12 and IL15 on the function of natural killer cells in children suffering from type 1 diabetes mellitus.

INTRODUCTION: The immunologic reaction of pancreatic islets destruction leads to the occurrence of type 1 diabetes mellitus (T1D). The autoreactive lymphocytes play the pivotal role in this process although mechanisms regulating the lymphocyte migration and infiltration of Langerhans islets have not been fully understood yet. The in vitro studies showed natural killer (NK) cells potency to initiate pancreatic islets cell lyses. Many authors postulate that NK cells may be involved in this reaction. AIM OF THE STUDY: The aim of the study was to evaluate the effect of IL-2, IL-12 and IL-15 stimulation on peripheral blood NK cells in children suffering from type 1 diabetes mellitus in comparison to healthy controls. MATERIAL AND METHODS: Fifteen children with type 1 diabetes and 10 healthy adults were examined. NK cells were isolated by the magnetic cell separation system (MACS). For activation, NK cells were cultured with IL-2, IL-12 and IL-15 for 24 hours. The production of IFN-γ and IL-10 by NK cells was measured using commercial ELISA kits. FACS analysis of cell surface antigens--CD16, CD56, NKG2D and CD137 was performed using LSR II flow cytometer. RESULTS: In children with T1D the IFN-γ median concentration in supernatant obtained from NK cells culture was 16.831 ng/ml (inter quartile range 5.566-25.509) and did not statistically differ from median IFN-γ concentration in the control group--14.810 ng/ml (7.022-18.785), p = 0.76. In contrast, the IL-10 median concentration was statistically higher in T1D patients 7.87 pg/ml (1.32-11.37) than in healthy participants--1.41 pg/ml (1.05-4.81), p = 0.01. The median (inter-quartile range) percentage of NK NKG2D(+) was found in 0.42% (0.28-0.76) cells of TID patients versus 0.72% (0.53-1.08) in the controls (p = 0.05). There was no difference between -T1D group and the control group in regard to NK cells expressing CD137 - 6.58% (3.38-12.4) versus 6.85% (2.94-10.8); p = 0.8. CONCLUSIONS: The observed activity of NK cells after in vitro stimulation by IL2, IL-12 and IL15 in children suffering from type 1 diabetes mellitus indicates the tendency for supporting the inhibition of autoimmunological reaction by increased IL10 synthesis and increased number of NK cells with surface NKG2D receptors.

The dual blockade of the renin-angiotensin system in hemodialysis patients requires decreased dialysate sodium concentration.

PURPOSE: The study evaluated whether the dual blockade of the renin-angiotensin system may influence the sodium balance in hemodialysis. METHODS: The study involved 148 hemodialysis patients (male 85, female 63), mean age 59.6 ± 12.9 years. Participants were randomly selected to receive either angiotensin-converting enzyme inhibitor (ACEI)--subgroup A--or dual blockade ACEI and angiotensin receptor blocker (ARB)--subgroup AA. RESULTS: At baseline, in the A versus AA subgroups, the pre-dialysis sodium concentrations (mmol/l) were 137.7 ± 0.5 versus 137.9 ± 0.8, the sodium gradients 2.6 ± 0.5 versus 2.9 ± 0.4, interdialytic weight gain (IWG) (kg) 3.1 ± 0.2 versus 3.0 ± 0.3, and thirst inventory score (points) 18.1 ± 1.0 versus 19.0 ± 1.7, respectively. After 3 months of therapy, a decrease in sodium concentration to 134.5 ± 0.5 and the increase of its gradient to 5.5 ± 0.5 were noted in the AA subgroup. An elevation of mean interdialytic weight gain to 3.47 ± 0.2 and thirst score to 21.3 ± 2.1 was observed. No significant changes in subgroup A were found. One month of the dialysate sodium concentration being lowered from 140 mmol/l to 138 mmol/l was associated with reduced serum sodium concentration and gradient, decreased IWG and restored moderate thirst score in the AA subgroup (137.5 ± 0.6 and 2.9 ± 0.6, 3.0 ± 0.5 and 19.2 ± 1.3, respectively). CONCLUSIONS: The dual blockade of the renin-angiotensin system affects sodium balance, increasing the sodium gradient, thus elevating thirst sensation and enhancing interdialytic weight gain. In maintenance hemodialysis patients treated with both ACEI and ARB, lowered dialysate sodium levels should be prescribed.