Plasma vaspin levels and clinical outcome in incident peritoneal dialysis patients.

BACKGROUND: Vaspin is an adipokine that regulates glucose and lipid metabolism. Plasma vaspin level is increased in chronic kidney disease but decreased in hemodialysis patients. However, plasma vaspin level in peritoneal dialysis (PD) patients, as well as its prognostic role, has not been studied. METHODS: We recruited 146 incident PD patients. Their baseline plasma vaspin levels, body anthropometry, the profile of insulin resistance, bioimpedance spectroscopy parameters, dialysis adequacy, and nutritional indices were measured. They were followed for up to 5 years for survival analysis. RESULTS: The average age was 58.4 ± 11.8 years; 96 patients (65.8%) were men, and 90 (61.6%) had diabetes. The median vaspin level was 0.18 ng/dL (interquartile range [IQR] 0.11 to 0.30 ng/dL). Plasma vaspin level did not have a significant correlation with adipose tissue mass or baseline insulin level. However, plasma vaspin level had a modest correlation with the change in insulin resistance, as represented by the HOMA-IR index, in non-diabetic patients (r = -0.358, p = 0.048). Although the plasma vaspin level quartile did not have a significant association with patient survival in the entire cohort, it had a significant interaction with diabetic status (p < 0.001). In nondiabetic patients, plasma vaspin level quartile was an independent predictor of patient survival after adjusting for confounding clinical factors (adjusted hazard ratio 2.038, 95% confidence interval 1.191-3.487, p = 0.009), while the result for diabetic patients was not significant. CONCLUSIONS: Plasma vaspin level quartile had a significant association with patient survival in non-diabetic PD patients. Baseline plasma vaspin level also had a modest inverse correlation with the subsequent change in the severity of insulin resistance, but the exact biological role of vaspin deserves further studies.

Circulating endotoxin and inflammation: associations with fitness, physical activity and the effect of a 6-month programme of cycling exercise during haemodialysis.

BACKGROUND: Intradialytic cycling (IDC) may provide cardiovascular benefits to individuals receiving haemodialysis, but the exact mechanism behind these improvements remains unclear. The primary aim of this study was to investigate the effect of a 6-month programme of IDC on circulating endotoxin (secondary analysis from the CYCLE-HD trial). Secondary aims were to investigate changes in circulating cytokines [interleukin-6 (IL-6), IL-10, tumour necrosis factor-α, C-reactive protein (CRP) and the IL-6:IL-10 ratio] and their associations with physical activity, fitness and cardiovascular outcomes. METHODS: Participants were randomized to either a 6-month programme of IDC (thrice weekly, moderate intensity cycling at a rating of perceived exertion of 12-14) in addition to usual care (n = 46) or usual care only (control group; n = 46). Outcome measures were obtained at baseline and then again at 6 months. RESULTS: There was no significant (P = 0.137) difference in circulating endotoxin between groups at 6 months (IDC group: 0.34 ± 0.08 EU/mL; control group: 0.37 ± 0.07 EU/mL). There were no significant between-group differences in any circulating cytokine following the 6-month programme of IDC. Higher levels of physical activity and fitness were associated with lower levels of endotoxin, IL-6, CRP and IL-6:IL-10 ratio. CONCLUSIONS: Our data show no change in circulating endotoxin or cytokines following a 6-month programme of IDC. However, higher levels of physical activity outside of haemodialysis were associated with lower levels of inflammation.

Adipose expression of miR-130b and miR-17-5p with wasting, cardiovascular event and mortality in advanced chronic kidney disease patients.

BACKGROUND: There are limited data on the association of adipose microRNA expression with body composition and adverse clinical outcomes in patients with advanced chronic kidney disease (CKD). We aimed to evaluate the association of adipose miR-130b and miR-17-5p expressions with body composition, functional state, cardiovascular outcome and mortality in incident dialysis patients. METHODS: We performed a single-center prospective cohort study. Patients who were planned for peritoneal dialysis were recruited. miR-130b and miR-17-5p expressions were measured from subcutaneous and pre-peritoneal fat tissue obtained during peritoneal dialysis catheter insertion. Body composition and physical function were assessed by bioimpedance spectroscopy and Clinical Frailty Scale. Primary outcome was 2-year survival. Secondary outcomes were 2-year technique survival and major adverse cardiovascular event (MACE) rate. RESULTS: Adipose expression of miR-130b and miR-17-5p correlated with parameters of muscle mass including intracellular water (miR-130b: r = 0.191, P = 0.02; miR-17-5p: r = 0.211, P = 0.013) and lean tissue mass (miR-17-5p: r = 0.176, P = 0.04; miR-17-5p: r = 0.176, P = 0.004). miR-130b expression predicted frailty significantly (P = 0.017). Adipose miR-17-5p expression predicted 2-year all-cause survival (P = 0.020) and technique survival (P = 0.036), while miR-130b expression predicted incidence of MACE (P = 0.015). CONCLUSIONS: Adipose miR-130b and miR-17-5p expressions correlated with body composition parameters, frailty, and predicted cardiovascular events and mortality in advanced CKD patients.

Urinary miRNA profile for the diagnosis of IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Urinary micro-RNA (miRNA) level is increasingly reported to as non-invasive markers of various kidney diseases. We aim to identify urinary miRNA targets for the diagnosis of IgAN. METHODS: In the development cohort, we performed complete miRNA profiling of urinary sediment in 22 patients with IgAN and 11 healthy controls (CTL). Potential miRNA targets were quantified by a separate validation cohort of 33 IgAN patients and 9 healthy controls. RESULTS: In the development cohort, we identified 39 miRNA targets that have significantly different expression between IgAN and CTL (14 up-regulated, and 25 down-regulated). Among the 8 miRNA targets chosen for validation study, urinary miR-204, miR-431 and miR-555 remained significantly reduced, and urinary miR-150 level was significantly increased in the IgAN as compared to CTL. The area-under-curve of the receiver operating characteristic (ROC) curve for urinary mi-204 level for the diagnosis of IgAN was 0.976, and the diagnostic performance of combining additional miRNA targets was not further improved. At the cut-off 1.70 unit, the sensitivity and specificity of urinary miR-204 was 100 and 55.5%, respectively, for diagnosing IgAN. CONCLUSIONS: Urinary miR-150, miR-204, miR-431 and miR-555 levels are significantly different between IgAN and healthy controls; urinary miR-204 level alone has the best diagnostic accuracy.

Urinary mitochondrial DNA level as a biomarker of tissue injury in non-diabetic chronic kidney diseases.

BACKGROUND: Urinary mitochondrial DNA (mtDNA) fragment level has been proposed as a biomarker of chronic kidney disease (CKD). In this study, we determine the relation between urinary mtDNA level and rate of renal function deterioration in non-diabetic CKD. METHODS: We recruited 102 non-diabetic CKD patients (43 with kidney biopsy that showed non-specific nephrosclerosis). Urinary mtDNA level was measured and compared to baseline clinical and pathological parameters. The patients were followed 48.3 ± 31.8 months for renal events (need of dialysis or over 30% reduction in estimated glomerular filtration rate [eGFR]). RESULTS: The median urinary mtDNA level was 1519.42 (inter-quartile range 511.81-3073.03) million copy/mmol creatinine. There were significant correlations between urinary mtDNA level and baseline eGFR (r = 0.429, p < 0.001), proteinuria (r = 0.368, p < 0.001), severity of glomerulosclerosis (r = - 0.537, p < 0.001), and tubulointerstitial fibrosis (r = - 0.374, p = 0.014). The overall rate of eGFR decline was - 2.18 ± 5.94 ml/min/1.73m2 per year. There was no significant correlation between the rate of eGFR decline and urinary mtDNA level. By univariate analysis, urinary mtDNA level predicts dialysis-free survival, but the result became insignificant after adjusting for clinical and histological confounding factors. CONCLUSION: Urinary mtDNA levels have no significant association with the rate of renal function decline in non-diabetic CKD, although the levels correlate with baseline renal function, proteinuria, and the severity of histological damage. Urinary mtDNA level may be a surrogate marker of permanent renal damage in non-diabetic CKD.

Plasma Mitochondrial DNA Level is a Prognostic Marker in Peritoneal Dialysis Patients.

BACKGROUND/AIMS: Circulating bacterial DNA fragment is related to systemic inflammatory state in peritoneal dialysis (PD) patients. We hypothesize that circulating mitochondrial DNA, which has a similar structure with bacterial DNA, correlates with systemic inflammatory state and predicts cardiovascular event in new PD patients. METHODS: We measured plasma mitochondrial DNA level by quantitative polymerase chain reaction (PCR) in 197 new PD patients and 150 patients with chronic kidney disease. PD patients were followed for 24 months for the development of cardiovascular event, hospitalization, and patient survival. RESULTS: There was a stepwise increase in plasma mitochondrial DNA level with worsening renal function. The average plasma mitochondrial DNA level was 18.0 ± 1.2 PCR cycles. Plasma mitochondrial DNA level correlated with serum CRP level (r = -0.538, p < 0.0001). At 24 months, the event-free survival was 67.4%, 66.4%, 63.4% and 44.2% for plasma mitochondrial DNA level quartiles I, II, III and IV, respectively (p = 0.049). After adjusting for confounders, plasma mitochondrial DNA level, malnutrition-inflammation score, and baseline arterial pulse wave velocity were independent predictors of composite cardiovascular end-point; each doubling in plasma mitochondrial DNA level confers 16.0% (95% confidence interval, 2.5 - 31.3%, p = 0.001) excess in risk. Plasma mitochondrial DNA also correlated with the number of hospital admission (r = -0.218, p = 0.002) and duration of hospitalization for cardiovascular reasons (r = -0.232, p = 0.001). CONCLUSION: Plasma mitochondrial DNA level significantly correlates with systemic inflammatory state, and is a strong predictor of cardiovascular event as well as the need of hospitalization in new PD patients.

Dialysate bacterial endotoxin as a prognostic indicator of peritoneal dialysis related peritonitis.

Peritonitis is the major complication of peritoneal dialysis (PD). The aim of our present study is to explore the prognostic value of endotoxin level in PD effluent for the prediction of treatment failure in PD-related peritonitis. We studied 325 peritonitis episodes in 223 patients. PD effluent (PDE) was collected every 5 days for endotoxin level and leukocyte count. Patients were followed for relapsing or recurrent peritonitis. We found 20 episodes (6.2%) had primary treatment failure; 41 (12.6%) developed relapsing, 19 (5.8%) had recurrent, and 22 (6.8%) had repeat episodes. Endotoxin was detectable in the PDE of 19 episodes (24.4%) caused by Gram negative organisms, 4 episodes (6.8%) of mixed bacterial growth, and none of the culture negative episodes or those by Gram positive organisms. For episodes caused by Gram negative bacteria, a detectable endotoxin level in PDE on day 5 had a sensitivity and specificity of 66.7% and 83.3%, respectively, for predicting primary treatment failure. In contrast, PDE leukocyte count > 1000 per mm3 on day 5 had a sensitivity and specificity of 88.9% and 89.1%, respectively; the addition of PDE endotoxin assay did not improve the sensitivity or specificity. We conclude that detectable endotoxin in PDE 5 days after antibiotic therapy might predict primary treatment failure in peritonitis episodes caused by Gram negative organisms. However, the sensitivity and specificity of PDE endotoxin assay was inferior to PDE leukocyte count.

Gut permeability, circulating bacterial fragments and measures of congestion in peritoneal dialysis.

Background: Limited data exist on the association between gut permeability, circulating bacterial fragment and volume overload in peritoneal dialysis (PD) patients. We measured circulating bacterial fragments, N-terminal pro B-type natriuretic peptide (NT-proBNP), calprotectin and zonulin levels, and evaluate their association with the clinical outcomes in PD patients. Methods: This was a single-center prospective study on 108 consecutive incident PD patients. Plasma endotoxin and bacterial DNA, and serum NT-proBNP, calprotectin and zonulin levels were measured. Primary outcomes were technique and patient survival, secondary outcomes were hospitalization data. Results: There was no significant correlation between plasma endotoxin and bacterial DNA, and serum NT-proBNP, calprotectin and zonulin levels. The Homeostatic Model Assessment for Insulin Resistance (HOMA)-2ß index, which represents insulin resistance, positively correlated with plasma bacterial DNA (r = 0.421, P < .001) and calprotectin levels (r = 0.362, P = .003), while serum NT-proBNP level correlated with the severity of volume overload and residual renal function. Serum NT-proBNP level was associated with technique survival even after adjusting for confounding factors [adjusted hazard ratio (aHR) 1.030, 95% confidence interval 1.009-1.051]. NT-proBNP level was also associated with patient survival by univariate analysis, but the association became insignificant after adjusting for confounding factors (aHR 1.010, P = .073). Similarly, NT-proBNP correlated with the number of hospitalizations and duration of hospitalization by univariate analysis, but the association became insignificant after adjusting for confounding factors. Conclusion: There was no correlation between markers of gut permeability, circulating bacterial fragments and measures of congestion in PD patients. Bacterial fragments levels and gut permeability are both associated with insulin resistance. Serum NT-proBNP level is associated with the severity of volume overload and technique survival. Further studies are required to delineate the mechanism of high circulating bacterial fragment levels in PD patients.

Omentin-1 Levels and Outcomes in Incident Peritoneal Dialysis Patients.

Rationale & Objective: Omentin-1 is an adipokine with anti-inflammatory and cardioprotective properties. The objective of this study was to determine the prognostic role of plasma omentin-1 levels in incident peritoneal dialysis (PD) patients. Study Design: Retrospective analysis of prospective cohort. Setting & Participants: 152 incident PD patients. Predictors: Plasma omentin-1 level, adipose tissue omentin-1 messenger RNA (mRNA) expression. Outcomes: Patient survival, technique survival, hospital admission, and duration of stay. Analytical Approach: Time-to-event survival analyses; linear regression for hospitalization. Results: The mean age was 58.4 ± 11.7 years; 102 were men, and 92 had diabetes. There was no significant correlation between plasma omentin-1 level and its adipose tissue mRNA expression. A higher plasma omentin-1 level quartile was not associated with patient survival (P = 0.92) or technique survival (P = 0.83) but had a modest correlation with a lower number of hospital admissions (P = 0.07) and shorter duration of hospital stay (P = 0.04). In adjusted models using multivariable linear regression, a higher plasma omentin-1 level quartile remained significantly associated with fewer hospital admissions (ß, -0.13; 95% CI, -0.26 to -0.002; P = 0.05) and shorter hospitalization duration (ß, -0.20; 95% CI, -0.38 to -0.02; P = 0.03). Limitations: Observational study with baseline measures only. Conclusions: Plasma omentin-1 level was not associated with patient survival, technique survival, or peritonitis, but higher plasma omentin-1 levels were associated with fewer hospital admissions and shorter duration of hospitalization among incident PD patients.

Circulating and Adipose Tissue Adiponectin Level and Outcomes in Incident Peritoneal Dialysis Patients.

Rationale & Objective: Cardiovascular disease is the major cause of mortality and morbidity in peritoneal dialysis (PD) patients. Adiponectin, a key adipokine, is related to obesity and insulin resistance. We determined the clinical and prognostic value of plasma adiponectin level and its adipose tissue messenger RNA (mRNA) expression in new PD patients. Study Design: Retrospective analysis of a prospective observational study. Setting & Participants: 152 new PD patients from a single center; 6 adults undergoing abdominal surgeries without kidney disease served as controls. Predictors: Plasma adiponectin level and its adipose tissue mRNA expression. Outcomes: Body build and composition, patient and technique survival. Analytical Approach: Adiponectin level and mRNA expression were grouped in quartiles for correlation analysis for body build and Cox regression for survival analysis. Results: The median plasma adiponectin level was 31.98 µg/mL (IQR, 16.81-49.49 µg/mL), and adiponectin mRNA expression in adipose tissue was 1.65 times higher than in controls (IQR, 0.98-2.63). There was a modest but statistically significant correlation between plasma adiponectin and its adipose tissue mRNA expression (r = 0.40, P < 0.001). Plasma adiponectin level inversely correlated with body mass index, waist-hip ratio, mid-arm circumference, adipose tissue mass, plasma triglyceride (r = -0.39, -0.38, -0.41, -0.38, and -0.30, respectively; P < 0.001 for all), as well as serum insulin level (r = -0.24, P = 0.005). Similar correlations were present but less marked with adipose tissue adiponectin mRNA level. Neither plasma adiponectin level nor adipose tissue adiponectin mRNA level predicted patient or technique survival. Limitations: Observational study, single center, single baseline measurement. Conclusions: Plasma adiponectin level correlated with the degree of adiposity in new PD patients. However, neither plasma adiponectin level nor its adipose tissue mRNA expression was an independent prognostic indicator in kidney failure patients newly started on PD.

Urinary mi-106a for the diagnosis of IgA nephropathy: Liquid biopsy for kidney disease.

BACKGROUND: Urinary micro-RNA (miRNA) level may serve as non-invasive disease markers for immunoglobulin A nephropathy (IgAN), but urinary miRNA targets identified in previous studies may represent kidney scarring rather than being specific for IgAN. We aim to identify urinary miRNA targets for the diagnosis of IgAN by including hypertensive nephrosclerosis (HTN) as a control group. Methods In the development cohort, we performed complete miRNA profiling of urinary sediment in 33 patients with IgAN, 9 with HTN, and 9 healthy controls (CTL). Potential miRNA targets were quantified by a separate validation cohort of 72 IgAN, 34 HTN, and 20 healthy controls. Results In the development cohort, we identified 6 miRNA targets with urinary levels significantly increased in IgAN as compared to both HTN and CTL. In the validation study, all 6 miRNA targets remained increased than the other groups, although the result of miR-345 did not reach statistical significance. The area-under-curve of the receiver operating characteristic (ROC) curve for urinary mi-106a level for the diagnosis of IgAN was 0.742 (p < 0.0001), and the diagnostic performance was not further improved by having additional miRNA targets. At the cut-off ≥ 800 copy per 1000 copies of housekeeping gene, urinary miR-106a has 100% sensitivity and 14.8% specificity in detecting IgA nephropathy. Conclusions We identified 6 miRNA targets whose urinary levels are significantly elevated in IgAN, and urinary miR-106a level has an excellent sensitivity for the identification of IgAN. Further validation studies are needed to confirm its role in disease screening.

Adipose and Plasma microRNAs miR-221 and 222 Associate with Obesity, Insulin Resistance, and New Onset Diabetes after Peritoneal Dialysis.

BACKGROUND: The correlation between microRNA, obesity, and glycemic intolerance in patients on peritoneal dialysis (PD) is unknown. We aimed to measure the adipose and plasma miR-221 and -222 levels, and to evaluate their association with adiposity, glucose intolerance, and new onset diabetes mellitus (NODM) after the commencement of PD. METHODS: We prospectively recruited incident adult PD patients. miR-221 and -222 were measured from adipose tissue and plasma obtained during PD catheter insertion. These patients were followed for 24 months, and the outcomes were changes in adiposity, insulin resistance, and NODM after PD. RESULTS: One hundred and sixty-five patients were recruited. Patients with pre-existing DM had higher adipose miR-221 (1.1 ± 1.2 vs. 0.7 ± 0.9-fold, p = 0.02) and -222 (1.9 ± 2.0 vs. 1.2 ± 1.3-fold, p = 0.01). High adipose miR-221 and -222 levels were associated with a greater increase in waist circumference (miR-221: beta 1.82, 95% CI 0.57-3.07, p = 0.005; miR-222: beta 1.35, 95% CI 0.08-2.63, p = 0.038), Homeostatic Model Assessment for Insulin Resistance (HOMA) index (miR-221: beta 8.16, 95% CI 2.80-13.53, p = 0.003; miR-222: beta 6.59, 95% CI 1.13-12.05, p = 0.018), and insulin requirements (miR-221: beta 0.05, 95% CI 0.006-0.09, p = 0.02; miR-222: beta 0.06, 95% CI 0.02-0.11, p = 0.002) after PD. The plasma miR-222 level predicted the onset of NODM (OR 8.25, 95% CI 1.35-50.5, p = 0.02). CONCLUSION: miR-221 and -222 are associated with the progression of obesity, insulin resistance, and NODM after PD.

Adipose and serum zinc alpha-2-glycoprotein (ZAG) expressions predict longitudinal change of adiposity, wasting and predict survival in dialysis patients.

There were limited data on adipose and serum zinc alpha-2-glycoprotein (ZAG) expression and its association with body composition in patients with advanced chronic kidney disease (CKD). This study aimed to quantify adipose and serum ZAG expression and evaluate their association with body composition and its longitudinal change, together with mortality in incident dialysis patients. We performed a single-center prospective cohort study. Patients who were planned for peritoneal dialysis were recruited. ZAG levels were measured from serum sample, subcutaneous and pre-peritoneal fat tissue obtained during peritoneal dialysis catheter insertion. Body composition and functional state were evaluated by bioimpedance spectroscopy and Clinical Frailty Scale respectively at baseline and were repeated 1 year later. Primary outcome was 2-year survival. Secondary outcomes were longitudinal changes of body composition. At baseline, the average adipose and serum ZAG expression was 13.4 ± 130.0-fold and 74.7 ± 20.9 µg/ml respectively. Both adipose and serum ZAG expressions independently predicted adipose tissue mass (ATM) (p = 0.001, p = 0.008, respectively). At 1 year, ATM increased by 3.3 ± 7.4 kg (p < 0.001) while lean tissue mass (LTM) remained similar (p = 0.5). Adipose but not serum ZAG level predicted change in ATM (p = 0.007) and LTM (p = 0.01). Serum ZAG level predicted overall survival (p = 0.005) and risk of infection-related death (p = 0.045) after adjusting for confounders. In conclusion, adipose and serum ZAG levels negatively correlated with adiposity and predicted its longitudinal change of fat and lean tissue mass, whilst serum ZAG predicted survival independent of body mass in advanced CKD patient.

Expression of ACE and ACE2 in patients with hypertensive nephrosclerosis.

BACKGROUND: The interplay between intrarenal angiotensin-converting enzyme (ACE) and type 2 ACE (ACE2) might play important roles in the pathogenesis of hypertensive nephrosclerosis (HTN), but human data are limited. METHODS: Renal biopsy specimens of 41 patients with HTN and 10 transplant donors as controls (CTL) were studied. The glomerular and tubulointerstitial mRNA expression of ACE and ACE2 was measured by laser microdissection and real-time quantitative polymerase chain reaction. The corresponding protein level was determined by immunohistochemistry. RESULTS: Neither the glomerular nor tubulointerstitial mRNA expression of ACE or ACE2 correlated with the corresponding protein level by immunohistochemistry. The tubulointerstitial levels of ACE and ACE2 were significantly lower in HTN than CTL, while the glomerular ACE and ACE2 levels were similar between the groups. The tubulointersitial ACE and ACE2 levels significantly correlated with the estimated glomerular filtration rate (GFR) and inversely with the degree of histological damage. The glomerular ACE and ACE2 levels significantly correlated with the rate of GFR decline. The ratio of glomerular ACE and ACE2 level correlated with the estimated GFR and the degree of glomerulosclerosis. CONCLUSION: Our results suggest that intrarenal ACE and ACE2 may play an important role in the pathogenesis and progression of HTN. Studies based on the mRNA expression of ACE and ACE2 should be cautiously interpreted.

Exploring the Link Between Hepatic Perfusion and Endotoxemia in Hemodialysis.

INTRODUCTION: The liver receives gut-derived endotoxin via the portal vein, clearing it before it enters systemic circulation. Hemodialysis negatively impacts the perfusion and function of multiple organs systems. Dialysate cooling reduces hemodialysis-induced circulatory stress and protects organs from ischemic injury. This study examined how hemodialysis disrupts liver hemodynamics and function, its effect on endotoxemia, and the potential protective effect of dialysate cooling. METHODS: Fifteen patients were randomized to receive either standard (36.5°C dialysate temperature) or cooled (35.0°C) hemodialysis first in a two-visit crossover trial. We applied computed tomography (CT) liver perfusion imaging to patients before, 3 hours into and after each hemodialysis session. We measured hepatic perfusion and perfusion heterogeneity. Hepatic function was measured by indocyanine green (ICG) clearance. Endotoxin levels in blood throughout dialysis were also measured. RESULTS: During hemodialysis, overall liver perfusion did not significantly change, but portal vein perfusion trended towards increasing (P = 0.14) and perfusion heterogeneity significantly increased (P = 0.038). In addition, ICG clearance decreased significantly during hemodialysis (P = 0.016), and endotoxin levels trended towards increasing during hemodialysis (P = 0.15) and increased significantly after hemodialysis (P = 0.037). Applying dialysate cooling trended towards abrogating these changes but did not reach statistical significance compared to standard hemodialysis. CONCLUSION: Hemodialysis redistributes liver perfusion, attenuates hepatic function, and results in endotoxemia. Higher endotoxin levels in end-stage renal disease (ESRD) patients may result from the combination of decreased hepatic clearance function and increasing fraction of liver perfusion coming from toxin-laden portal vein during hemodialysis. The protective potential of dialysate cooling should be explored further in future research studies.

Polymerase chain reaction/electrospray ionization-mass spectrometry (PCR/ESI-MS) is not suitable for rapid bacterial identification in peritoneal dialysis effluent.

BACKGROUND: Peritoneal dialysis (PD)-related peritonitis is a serious complication of PD, but routine microbiological culture is slow and could not identify the organism in 15% cases. We examine the accuracy of polymerase chain reaction/electrospray ionization-mass spectrometry (PCR/ESI-MS), a PCR-based method developed for the direct detection of bacteria in blood, for rapid identification of microorganisms from PD effluent. METHODS: We recruited 73 consecutive patients with PD-related peritonitis. Dialysis effluent was collected for routine bacterial culture, PCR/ESI-MS, and bacterial DNA quantification before initiation of antibiotic therapy. RESULTS: By digital PCR with universal bacterial primers, bacterial DNA was detectable in all PD effluent specimens. For the entire cohort, taking standard bacterial culture as the gold standard, the PCR/ESI-MS assay correctly identified 34.3% of the causative organisms, failed to identify any organism in 52.1% cases, and identified a different organism in 8.2% cases. For the 14 episodes of peritonitis that were culture negative by conventional bacterial culture, the PCR/ESI-MS assay identified an organism in only four cases. The detection rate of the IRIDICA BAC BSI assay was not affected by the use of biocompatible PD solution or concomitant exit-site infection. CONCLUSIONS: The PCR/ESI-MS assay could not identify the causative organism in over 50% of the PD effluent samples in patients with PD-related peritonitis and should be not used for such purpose. The reason for the poor performance needs further investigation.

Prognostic significance of peritoneal dialysis effluent mitochondrial DNA level.

BACKGROUND: Mitochondrial DNA (mtDNA) resembles bacterial DNA and potentially triggers local and systemic inflammation. We evaluate the prognostic implications of PD effluent mtDNA level in peritoneal dialysis (PD) patients. METHODS: We measured mtDNA in the PD effluent (PDE) sediment and supernatant of 168 incident PD patients. All patients were followed for hospitalization, technique and overall survival. RESULTS: The median PD effluent supernatant and sediment mtDNA levels were 255.4 unit (interquartile range [IQR] 157.5-451.3) and 201.6 unit (IQR 147.8-267.3), respectively. Serum C-reactive protein level closely with PDE sediment mtDNA level (r = 0.471, p < 0.001) and less with supernatant mtDNA level (r = 0.156, p = 0.044). PDE supernatant mtDNA level correlates with dialysate-to-plasma creatinine ratio at 4 h (D/P4) (r = 0.361, p < 0.001) but not with any clinical outcome. PDE sediment mtDNA was an independent predictor of technique survival (p = 0.011) and the duration of hospitalization (p = 0.044) after adjusting for clinical confounding factors. CONCLUSIONS: PDE sediment mtDNA level significantly correlated with systemic inflammation, while PDE supernatant mtDNA level correlated with peritoneal transport. PDE sediment mtDNA level also independently predicted technique survival and duration of hospitalization. The mechanism of the different implications between PDE sediment and supernatant mtDNA levels deserves further investigations.

Kidney microRNA-21 Expression and Kidney Function in IgA Nephropathy.

RATIONALE & OBJECTIVE: Previous studies have suggested that microRNA-21 (miR-21) plays an important role in kidney fibrosis. We examined the relationship between intrarenal miR-21 level and rate of kidney function loss in immunoglobulin A nephropathy (IgAN). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 40 patients with IgAN and 10 with hypertensive nephrosclerosis as controls. PREDICTORS: miR-21 levels in kidney biopsy specimen and urinary sediment, quantified as ratio to the housekeeping gene. OUTCOMES: Kidney event-free survival and rate of kidney function decline. ANALYTIC APPROACH: Time-to-event and correlation analysis. RESULTS: The IgAN group had significantly higher intrarenal miR-21 expression compared with the hypertensive nephrosclerosis group (1.71 [IQR, 0.99-2.77] vs 0.31 [IQR, 0.25-1.32]; P < 0.0001), but urinary miR-21 levels were similar. Intrarenal miR-21 expression had significant but modest correlation with severity of glomerulosclerosis (r = 0.293; P = 0.05) and tubulointerstitial fibrosis (r = 0.341; P = 0.03). Patients with high intrarenal miR-21 expression had significantly higher risk for developing kidney end points compared with those with low expression (log-rank test, P = 0.017). Univariate Cox analysis showed that intrarenal miR-21 expression significantly predicted the development of kidney end points (unadjusted HR, 1.586; 95% CI, 1.179-2.134; P = 0.002). However, the result was just short of statistical significance after adjusting for the severity of histologic damage (P = 0.06). There was also a significant correlation between intrarenal miR-21 expression and the slope of kidney function decline by univariate analysis (r = -0.399; P = 0.02). LIMITATIONS: Small sample size; uncertain cellular origin of miR-21. CONCLUSIONS: We found that intrarenal miR-21 expression is increased in patients with IgAN, modestly correlated with the severity of histologic damage, and predictive of subsequent kidney function loss.

Extended antibiotic therapy for the prevention of relapsing and recurrent peritonitis in peritoneal dialysis patients: a randomized controlled trial.

BACKGROUND: Relapsing and recurrent peritonitis episodes are major causes of technique failure in peritoneal dialysis (PD). We examined the efficacy of extended antibiotic therapy for the prevention of relapsing and recurrent peritonitis. METHODS: From February 2016 to November 2018 we recruited 254 PD patients who fulfilled the diagnostic criteria for PD peritonitis. They were randomized to a standard group, with the duration of intraperitoneal (IP) antibiotic treatment following the International Society for Peritoneal Dialysis (ISPD) guideline according to the causative microorganisms, and an extended group, with 1 extra week of IP antibiotics. The primary endpoint was relapsing, recurrent or repeat peritonitis episodes within 6 months. RESULTS: The primary endpoint developed in 36 and 29 patients of the extended and standard groups, respectively (28.3% versus 22.8%; P = 0.34). The rate of complete cure, without relapsing, recurrent or repeat peritonitis within 6 months, was 63.8 and 69.3% for the extended and standard groups, respectively (P = 0.35). Repeat peritonitis episodes were more common in the extended than the standard group (15.0% versus 5.5%; P = 0.013). CONCLUSIONS: In patients with PD-related peritonitis, extending the antibiotic therapy for 1 extra week beyond the ISPD protocol should not be recommended. Extending the treatment does not reduce the risk of relapsing or recurrent peritonitis episodes but rather is associated with a higher risk of repeat peritonitis episodes.

The width of the basement membrane does not influence clinical presentation or outcome of thin glomerular basement membrane disease with persistent hematuria.

Thin basement membrane disease (TBMD) typically presents with persistent microscopic hematuria, and is usually defined as a glomerular basement membrane (GBM) thickness < 250 nm. Previous studies showed that neither the degree of thinning nor the extent of the abnormality correlate with the patient's clinical presentation or prognosis. To further define this, we enrolled a study group of 41 patients with isolated microscopic hematuria and a normal renal biopsy, except those with a GBM thickness of 250-320 nm, and compared them with 33 patients with traditional TBMD. We found no difference in baseline demographic or clinical parameter between the groups. After follow-up averaging 110 months, there was no significant difference in the risk of detectable or overt proteinuria, hypertension, or impaired renal function between the groups. By the end of the study, only five patients from the study group and four from the TBMD group had no outcome event. By Cox regression analysis, independent predictors of overt proteinuria were male gender, age at biopsy, baseline renal function, proteinuria, and hypertension. Age at biopsy was the only independent predictor for hypertension, and baseline proteinuria was the only independent predictor for impaired renal function. GBM thickness did not predict any outcome event. Hence, lifelong follow-up is advised, as the clinical features and prognosis of these patients with persistent microscopic hematuria and marginally thin GBM are similar to traditional TBMD.