Differential effects of peritoneal and hemodialysis on circulating regulatory T cells one month post initiation of renal replacement therapy.

Backgroundː Chronic kidney disease stage G5 (CKD G5) patients show an activated but impaired immune system. One function of the FOXP3+ regulatory T (Treg) cells is to preserve tolerance to self while maintaining the ability to fight infectious agents. The aim of this pilot study is to evaluate longitudinal changes in Treg cells before and 1 month after the first dialysis treatment. Materials and methodsː CKD G5 patients not yet on dialysis were enrolled and started on hemodialysis (HD) or peritoneal dialysis (PD). Tregs were analyzed by flow cytometry at two time points: T0 (before the first dialysis treatment) and T1 (1 month after the first dialysis session). Wilcoxon test for dependent samples was used to compare the mean percentage difference between T0 and T1: Δ% = 100 × [(T1 - T0) / T0]. Resultsː 21 patients were enrolled: 8 on HD and 13 on PD. The proportion of total lymphocytes (low side scatter lymphocyte gate) and T lymphocytes (in the CD3+CD4+ gate) did not change significantly 1 month after the start of dialysis in both groups. Treg cells (as CD25+FOXP3+, FOXP3+, or CD25+CD127-), analyzed as percentage of the lymphocyte gate, showed a significant increase post PD (CD25+FOXP3+: median = 35.92; p = 0.0425; FOXP3+: median = 30.85; p = 0.0479 and CD25+CD127-: median = 23.71; p = 0.0215). The same populations, did not change 1 month after the first dialysis session. Conclusionː Our study is the first to evaluate longitudinal effects of dialysis on Treg cells in uremia and suggests that PD was more effective in increasing Treg levels 1 month post initiation of dialysis and may contribute to improvement of inflammatory status. Thus, PD may contribute to better outcomes for patients with renal dysfunction, also maintaining homeostasis of peritoneal and renal tissues.

Increased Levels of sRAGE in Diabetic CKD-G5D Patients: A Potential Protective Mechanism against AGE-Related Upregulation of Fibroblast Growth Factor 23 and Inflammation.

Advanced glycation end products (AGEs) may induce cardiac remodeling in kidney disease by promoting fibroblast growth factor 23 (FGF-23) expression. Since AGEs are increased in diabetes mellitus (DM), our first aim was to evaluate the existence of any potential association between AGEs, FGF-23, inflammation, and increased cardiovascular risk in DM patients on dialysis (CKD-G5D). Secondarily, we explored the potential role of the soluble receptor for AGEs (sRAGE) as a marker of heart failure. Levels of glycated albumin (GA), sRAGE, c-terminal FGF-23 (cFGF-23), brain natriuretic peptide (BNP), and inflammatory mediators were compared between DM and non-DM CKD-G5D patients. The levels of sRAGE, cFGF-23, BNP, and proinflammatory markers were over the ranges of normality in both DM and non-DM groups. Only GA and sRAGE levels were increased in DM compared to non-DM patients. Plasma levels of sRAGE and CRP were the only independent predictors of BNP concentration. In conclusion, in DM CKD-G5D patients, sRAGE appeared to be a marker of cardiac remodeling. Indeed, its increase could be a potential protective mechanism against the increased risk of cardiovascular complications related to AGEs and inflammation. The causal relationship between sRAGE and cardiovascular risk in these patients needs to be further confirmed by mechanistic studies.

Copeptin levels and kidney function in ADPKD: case-control study.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Studies have suggested a possible prognostic role of copeptin in determining the rate of progressive kidney function decline in ADPKD patients. However, it remains unresolved whether the changes in copeptin levels are specific for ADPKD or merely reflect a decline in glomerular filtration rate (GFR) regardless of the etiology of chronic kidney disease (CKD). METHODS: We performed a case-control study in ADPKD and non-ADPKD (control) patients. Patients were categorized based on the GFR-category (G-stage, KDIGO). We evaluated urea, creatinine, cystatin C, and copeptin in plasma and correlated these levels with estimated glomerular filtration rate (eGFR) (CKD-EPI). All p-values were two sided, and p < 0.05 was considered as statistically significant. RESULTS: We enrolled 112 ADPKD and 112 control patients. The median copeptin level was 10.72 (interquartile range (IQR) 5.21 - 26.21) pmol/L in the ADPKD group and 12.32 (IQR 4.47 - 30.73) pmol/L in the control group. The median copeptin level increased according to the G-stage in a progressive fashion and remained statistically significant across all G-stages and in both groups. Copeptin levels were not significantly different between ADPKD and control groups. We found a significant inverse correlation between copeptin level and eGFR (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) in the ADPKD, r = -0.81 (p < 0.001), and in the control group, r = -0.76 (p < 0.001). CONCLUSIONS: Copeptin levels seem to be strongly correlated with renal function rather than the presence of ADPKD. Further prospective studies need to evaluate its role as a prognostic marker in the early stage of CKD for ADPKD progression.

The Influence of Hemodialysis on T Regulatory Cells: A Meta-Analysis and Systematic Review.

AIMS: The study aimed to determine whether the available literature supports a positive or negative influence of dialysis on regulatory T-cells (Tregs). METHODS: We performed a systematic search and a meta-analysis. Mean differences in Tregs number of chronic kidney disease stages G5 on dialysis patients (CKD G5D) and healthy controls (HCs) were compared. Random effects model was applied. The software used was general package for meta-analysis (version 4.3-0, depends R (≥2.9.1)). RESULTS: Five studies were included in the meta-analysis. The mean difference in percentage of Tregs on CD4+ T-cells between CKD G5D and HCs was not statistically different. Moreover, CKD GFR stages G5 not on dialysis (CKD G5) versus HC (p = 0.002; mean difference in Treg percentage was -2.47% in CKD G5 vs. HC) and CKD G5 versus CKD G5D (not significant). CONCLUSION: This meta-analysis demonstrates an association between the uremic state and lower Tregs, and supports the hypothesis that hemodialysis alter Tregs. Our findings highlight the need for new clinical studies. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=449242.

Cardiac surgery-associated acute kidney injury.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy.

Effect of percutaneous ventricular assist devices on renal function.

Ventricular assist devices (VADs) are used to improve the systemic circulation and to decrease ventricular loading in patients with hemodynamic instability that is refractory to pharmacologic therapies. During an acute critical event, percutaneous devices are preferred because of their rapid deployment, since implantable devices require more extensive procedures. Implantable devices are used for patients with established end-stage heart failure as a bridge to heart transplantation, recovery or destination therapy. This report reviews mechanical principles and clinical studies regarding percutaneous VAD to address their potential renal effects. Since the focus of this study is set on devices that are dedicated to cardiac support only, extracorporeal membrane oxygenation systems are not included.

Relationship between Residual Urine Output and Type of Dialysis with FGF23 Levels.

Several studies investigated the role of fibroblast growth factor 23 (FGF23) in the regulation of renal phosphate excretion in chronic kidney disease (CKD). However, patients with residual urine output (UO) seem to control their serum phosphorus levels better. Our aim was to determine whether FGF23 levels are influenced by dialysis modality and UO. We performed a cross-sectional study in hemodialysis (HD) and peritoneal dialysis (PD) patients. The C-terminal FGF23 (cFGF23) levels were determined in plasma with a two-site enzyme-linked immunosorbent assay. The UO collection referred to an mL/day measurement. All p values were two-sided, and the statistical significance was set at p < 0.05. We enrolled 133 patients (58 HD, 75 PD, UO 70%). The median cFGF23 was significantly higher in HD vs. PD patients (p = 0.0017) and not significantly higher in patients without UO (p = 0.12). We found a negative correlation between cFGF23 and the UO volume (p = 0.0250), but the correlation was not significant when considering the type of dialysis treatment. Phosphorus (ß = 0.21677; p = 0.0007), type of dialysis (ß = −0.68392; p = 0.0003), and creatinine (ß = 0.08130; p = 0.0133) were significant and independent predictors of cFGF23 levels. In conclusion, cFGF23 was significantly higher in HD than in PD patients. We found a significant negative correlation between cFGF23 and the residual UO volume, but the correlation was not significant considering the type of dialysis. Our study reveals that dialysis modality is an independent predictor of FGF23 levels. In particular, PD is associated with lower FGF23 levels than HD.

Gene Polymorphism in Five Target Genes of Immunosuppressive Therapy and Risk of Development of Preeclampsia.

Pregnancy can be considered as an allogeneic transplant and preeclampsia can be seen as a failure of the acceptance mechanisms of this transplant as occurs in acute organ transplant rejection. Some genetic polymorphisms may be involved in its pathogenesis. Since the kidney is one of the organs mainly involved in preeclampsia, our study attempted to determine the frequencies of single nucleotide polymorphisms of DNA (SNP) in 3 genes (adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1)/multi drug reactivity 1 (MDR1) gene, interleukin 10 gene and tumor necrosis factor α gene) which are targets of immunosuppressive therapies and related to acute renal rejection. The study was an observational, monocentric, case-control study. We enrolled 20 women with severe preeclampsia and 10 women age-matched with regular pregnancy. Continuous variables were compared by the Student's t-test for independent variables or using the Mann-Whitney test depending on their distribution. We used Fisher test to compare categorical variables between cases and controls, while we used logistic regression model to evaluate which risk factor was associated with preeclampsia. Although there was no statistically significant difference between the two groups, we found different percentages of two of the polymorphisms considered (rs1045642 and rs2032582 in the gene ABCB1). Despite these results, our work may be helpful for future research to better understand the pathogenesis of preeclampsia.

Neutrophil gelatinase-associated lipocalin does not predict acute kidney injury in heart failure.

BACKGROUND: Acute cardiorenal syndrome type 1 (CRS-1) is defined by a rapid cardiac dysfunction leading to acute kidney injury (AKI). Neutrophil gelatinase-associated lipocalin (NGAL) is expressed on the surface of human neutrophils and epithelial cells, such as renal tubule cells, and its serum (sNGAL) and urinary have been used to predict AKI in different clinical settings. AIM: To characterize CRS-1 in a cohort of patients with acute heart diseases, evaluating the potentiality of sNGAL as an early marker of CRS-1. METHODS: We performed a retrospective cohort, multi-centre study. From January 2010 to December 2011, we recruited 202 adult patients admitted to the coronary intensive care unit (CICU) with a diagnosis of acute heart failure or acute coronary syndrome. We monitored the renal function to evaluate CRS-1 development and measured sNGAL levels within 24 h and after 72 h of CICU admission. RESULTS: Overall, enrolled patients were hemodynamically stable with a mean arterial pressure of 92 (82-107) mmHg, 55/202 (27.2%) of the patients developed CRS-1, but none of them required dialysis. Neither the NGAL delta value (AUC 0.40, 95%CI: 0.25-0.55) nor the NGAL peak (AUC 0.45, 95%CI: 0.36-0.54) or NGAL cut-off (≥ 140 ng/mL) values were statistically significant between the two groups (CRS-1 vs no-CRS1 patients). The area under the ROC curve for the prediction of CRS-1 was 0.40 (95%CI: 0.25-0.55) for the delta NGAL value and 0.45 (95%CI: 0.36-0.54) for the NGAL peak value. Finally, in multivariate analysis, the risk of developing CRS-1 was correlated with age > 60 years, urea nitrogen at admission and 24 h-urine output (AUC 0.83, SE = 60.5% SP = 93%), while sNGAL was not significantly correlated. CONCLUSION: In our population, sNGAL does not predict CRS-1, probably as a consequence of the mild renal injury and the low severity of heart disease. So, these data might suggest that patient selection should be taken into account when considering the utility of NGAL measurement as a biomarker of kidney damage.

Acute rejection in kidney transplantation and the evaluation of associated polymorphisms (SNPs): the importance of sample size.

Background Acute rejection (AR) is one of the most frequent complications after kidney transplantation (KT). Scientific evidence reports that some single-nucleotide polymorphisms (SNPs) located in genes involved in the immune response and in the pharmacokinetics and pharmacodynamics of immunosuppressive drugs are associated with rejection in renal transplant patients. The aim of this study was to evaluate some SNPs located in six genes: interleukin-10 (IL-10), tumor necrosis factor (TNF), adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1), uridine diphosphate glucuronosyltransferase family 1 member A9 (UGT1A9), inosine monophosphate dehydrogenase 1 (IMPDH1) and IMPDH2. Methods We enrolled cases with at least one AR after KT and two groups of controls: patients without any AR after KT and healthy blood donors. Genetic analysis on DNA was performed. The heterozygosity (HET) was determined and the Hardy-Weinberg equilibrium (HWE) test was performed for each SNP. The sample size was calculated using the QUANTO program and the genetic associations were calculated using the SAS program (SAS Institute Inc., Cary, NC, USA). Results In our previous preliminary study (sample size was not reached for cases), the results showed that patients with the C allele in the SNP rs1045642 and the A allele in the SNP rs2032582 of the ABCB1 gene had more frequent AR. In contrast, with the achievement of sample size, the trend of the previous data was not confirmed. Conclusions Our study highlights a fundamental aspect of scientific research that is generally presumed, i.e. the sample size of groups enrolled for a scientific study. We believe that our study will make a significant contribution to the scientific community in the discussion of the importance of the analysis and the achievement of sample size to evaluate the associations between SNPs and the studied event.

The Role of NGAL in Peritoneal Dialysis Effluent in Early Diagnosis of Peritonitis: Case-Control Study in Peritoneal Dialysis Patients.

BACKGROUND: Peritoneal dialysis (PD) is frequently complicated by high rates of peritonitis, which result in hospitalization, technique failure, transfer to hemodialysis, and increased mortality. Early diagnosis, and identification of contributing factors are essential components to increasing effectiveness of care. In previous reports, neutrophil gelatinase-associated lipocalin (NGAL), a lipocalin which is a key player in innate immunity and rapidly detectable in peritoneal dialysis effluent (PDE), has been demonstrated to be a useful tool in the early diagnosis of peritonitis. This study investigates predictive value of PDE NGAL concentration as a prognostic indicator for PD-related peritonitis. METHODS: A case-control study with 182 PD patients was conducted. Plasma and PDE were analyzed for the following biomarkers: C-reactive protein (CRP), blood procalcitonin (PCT), leucocytes and NGAL in PDE. The cases consisted of patients with suspected peritonitis, while controls were the patients who came to our ambulatory clinic for routine visits without any sign of peritonitis. The episodes of peritonitis were defined in agreement with International Society for Peritoneal Dialysis guidelines. Continuous variables were presented as the median values and interquartile range (IQR). Mann-Whitney U test was used to compare continuous variables. Univariate and multivariate logistic regression were used to evaluate the association of biomarkers with peritonitis. Receiver operating characteristic (ROC) curve analysis was used to calculate area under curve (AUC) for biomarkers. Finally we evaluated sensitivity, and specificity for each biomarker. All statistical analyses were performed with SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). RESULTS: During the 19-month study, of the 182 patients, 80 had a clinical diagnosis of peritonitis. C-reactive protein levels (p < 0.001), PCT (p < 0.001), NGAL in PDE (p < 0.001), and white blood cells (WBC) in PDE (p < 0.001) were all significantly different in patients with and without peritonitis. In univariate analysis, CRP (odds ratio [OR] 1,339; p = 0.001), PCT (OR 2,473; p < 0,001), WBC in PDE (OR 3,986; p < 0,001), and NGAL in PDE (OR 36.75 p < 0.001) were significantly associated with episodes of peritonitis. In multivariate regression analysis, only WBC (OR 24.84; p = 0,012), and peritoneal NGAL levels (OR 136.6; p = 0,01) were independent predictors of peritonitis events. Moreover, AUC for NGAL in peritoneal effluent was 0,936 (p < 0.001) while AUC for CRP, PCT, and WBC count in peritoneal effluent were 0,704 (p = 0.001), 0.762 (p = 0.039), 0,975 (p < 0.001), respectively. Finally, combined WBC and peritoneal NGAL test increased the specificity (= 96%) of the single test. CONCLUSIONS: These results identify NGAL in peritoneal effluent as a reliable marker of peritonitis episodes in PD patients. Collectively, our findings demonstrate that the use of peritoneal NGAL cooperatively with current clinical diagnostic tools as a prognostic indicator, presents a valuable diagnostic tool in PD-associated peritonitis.

Mitochondrial Ca²âº uptake induces cyclic AMP generation in the matrix and modulates organelle ATP levels.

While the role of mitochondrial Ca²âº homeostasis in cell pathophysiology is widely accepted, the possibility that cAMP regulates mitochondrial functions has only recently received experimental support. The site of cAMP production, its targets, and its functions in the organelles remain uncertain. Using a variety of genetic/pharmacological tools, we here demonstrate that the mitochondrial inner membrane is impermeable to cytosolic cAMP, while an autonomous cAMP signaling toolkit is expressed in the matrix. We demonstrate that rises in matrix Ca²âº powerfully stimulate cAMP increases within mitochondria and that matrix cAMP levels regulate their ATP synthesizing efficiency. In cardiomyocyte cultures, mitochondrial cAMP can be increased by treatments that augment the frequency and amplitude of Ca²âº oscillations within the cytosol and organelles, revealing that mitochondria can integrate an oscillatory Ca²âº signal to increase cAMP in their matrix. The present data reveal the existence, within mitochondria, of a hitherto unknown crosstalk between Ca²âº and cAMP.

Cardiac surgery-associated acute kidney injury.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy.

Bioimpedance and brain natriuretic peptide in peritoneal dialysis patients.

Assessment of ideal body weight in peritoneal dialysis (PD) patients is important for clinical practice. Fluid overload may produce hypertension, reduced arterial distensibility, left ventricular hypertrophy. All these are risk factors for mortality in PD patients: cardio- and cerebrovascular events are the main causes of morbidity and mortality in PD population. Nowadays, a clear and widely accepted definition of ideal body weight in PD patients does not exist. Probably the ideal body weight is the weight at which the extra cellular volume is normal. Many different tools have been used to assess the hydration status in dialysis patients. Ultrasonic evaluation of inferior vena cava diameter only assesses intravascular volume, and is also influenced by diastolic dysfunction and is thus a reflection of preload and not of tissue hydration. Direct measurement of extra cellular and total body water by dilution methods is considered as the golden standard, but these techniques are laborious and expensive. Parameters, such as brain natriuretic peptide (BNP) or NT-proBNP can reflect changes in hydration status and may help the nephrologist to estimate it. Natriuretic peptides are influenced both by preload and ventricular abnormalities and in patients with renal failure accumulation can occur. Bioimpedance is an accurate, reproducible, not expensive and not invasive technique that permits a good evaluation of hydration status in PD and can drive the nephrologist in his clinical choices. Clinical evaluation, strict control of body weight, diuresis, sodium and fluids intakes, bioimpedance monitoring and serum levels of natriuretic peptides may all together help us to maintain the PD patient euvolemic.