Phyllis Mei-Shan Cheng

PREDICTORS OF RESIDUAL RENAL FUNCTION DECLINE IN PATIENTS UNDERGOING CONTINUOUS AMBULATORY PERITONEAL DIALYSIS

♦ Background: Residual renal function (RRF) is an important prognostic indicator in continuous ambulatory peritoneal dialysis (CAPD) patients. We determined the predictors of RRF loss in a cohort of incident CAPD patients. ♦ Methods: We reviewed the record of 645 incident CAPD patients. RRF loss is represented by the slope of decline of residual glomerular filtration rate (GFR) as well as the time to anuria. ♦ Results: The average rate of residual GFR decline was -0.083 ± 0.094 mL/min/month. The rate of residual GFR decline was faster with a higher proteinuria (r = -0.506, p < 0.0001) and baseline residual GFR (r = -0.560, p < 0.0001). Multivariate analysis showed that proteinuria, baseline residual GFR, and the use of diuretics were independent predictors of residual GFR decline. Cox proportional hazard model showed that proteinuria, glucose exposure, and the number of peritonitis episodes were independent predictors of progression to anuria, while a higher baseline GFR was protective. Each 1 g/day of proteinuria is associated with a 13.2% increase in the risk of progressing to anuria, each 10 g/day higher glucose exposure is associated with a 2.5% increase in risk, while each peritonitis episode confers a 3.8% increase in risk. ♦ Conclusions: Our study shows that factors predicting the loss of residual solute clearance and urine output are different. Proteinuria, baseline residual GFR, and the use of diuretics are independently related to the rate of RRF decline in CAPD patients, while proteinuria, glucose exposure, and the number of peritonitis episodes are independent predictors for the development of anuria. The role of anti-proteinuric therapy and measures to prevent peritonitis episodes in the preservation of RRF should be tested in future studies.

Circulating bacterial-derived DNA fragments as a marker of systemic inflammation in peritoneal dialysis

BACKGROUND Endotoxemia is common in peritoneal dialysis (PD) patients, and circulating lipopolysaccharide (LPS) level is related to the degree of systemic inflammation and atherosclerosis. We hypothesize that circulating bacterial DNA, another microbial component, correlates with the degree of systemic inflammation and predicts the survival of new PD patients. METHODS We measured the plasma bacterial DNA level in the archive blood samples of 300 consecutive new PD patients. The result was compared with serum C-reactive protein (CRP) level, patient survival and peritonitis-free survival. RESULTS The average age was 57.8 ± 12.1 years, average plasma bacterial DNA level 34.3 ± 1.3 cycles and average follow-up 37.9 ± 22.2 months. The plasma bacterial DNA level correlated with serum CRP (r = 0.565, P < 0.001) and LPS levels (r = 0.224, P = 0.029). At 36 months, the patient survival were 77.5, 78.3, 74.6 and 65.2% for plasma bacterial DNA level quartiles I, II, III and IV, respectively (log-rank test, P = 0.034). By multivariate analysis with the Cox proportional hazard model to adjust for confounders, the plasma bacterial DNA level had no independent effect. Similarly, peritonitis-free survival were 60.6, 59.8, 60.3 and 50.4% for plasma bacterial DNA level quartiles I, II, III and IV, respectively, at 36 months (P = 0.020), and the difference was not significant after adjusting for confounding factors. CONCLUSION We found that the plasma bacterial DNA level correlated with the degree of systemic inflammatory state in PD patients. Although plasma bacterial DNA level seems to predict patient survival and peritonitis-free survival, the association disappears after adjusting for confounding factors. Further prospective studies are needed to delineate the role of plasma bacterial DNA as a prognostic marker of renal failure patients.

Effect of using ultrapure dialysate for hemodialysis on the level of circulating bacterial fragment in renal failure patients.

Background: Cardiovascular disease is the major cause of mortality and morbidity in dialysis patients. Recently, circulating endotoxin is found to associate with the systemic inflammatory state and cardiovascular disease of dialysis patients. Previous studies showed that the use of ultrapure dialysate for hemodialysis could reduce the exposure to exogenous endotoxin. We studied the effect of using ultrapure dialysate for hemodialysis on circulating endotoxin and bacterial DNA fragment levels and vascular stiffness. Methods: This is an open-labeled prospective study of 25 patients (14 male). Circulating endotoxin and bacterial DNA level, vascular stiffness as represented by arterial pulse wave velocity (PWV), nutrition and hydration status were monitored before and repeatedly throughout 12 months after the use of ultrapure dialysate for hemodialysis. Results: The average age was 58.9 ± 10.2 years; 21 patients completed the study. Within 4 weeks of conversion to ultrapure dialysate for hemodialysis, the plasma endotoxin level fell from 0.302 ± 0.083 to 0.209 ± 0.044 EU/ml (p < 0.0001) and then remained static, while serum bacterial DNA level remained similar. Furthermore, the time-averaged plasma endotoxin level during the study period significantly correlated with serum C-reactive protein level (r = 0.483, p = 0.017), carotid-femoral PWV (r = 0.455, p = 0.033), and malnutrition inflammation score (r = 0.461, p = 0.031). The time-averaged serum bacterial DNA level significantly correlated with malnutrition inflammation score (r = 0.550, p = 0.008) and inversely with subjective global assessment score (r = -0.543, p = 0.009), but not with PWV. Conclusions: In hemodialysis patients, circulating endotoxin level is associated with vascular stiffness and systemic inflammation. Using ultrapure dialysate for hemodialysis effectively reduces circulating endotoxin level in hemodialysis patients. The long-term benefit of using ultrapure dialysate for hemodialysis requires further study.

Circulating bacterial-derived DNA fragment level is a strong predictor of cardiovascular disease in peritoneal dialysis patients.

Background Circulating bacterial DNA fragment is related to systemic inflammatory state in peritoneal dialysis (PD) patients. We hypothesize that plasma bacterial DNA level predicts cardiovascular events in new PD patients. Methods We measured plasma bacterial DNA level in 191 new PD patients, who were then followed for at least a year for the development of cardiovascular event, hospitalization, and patient survival. Results The average age was 59.3 ± 11.8 years; plasma bacterial DNA level 34.9 ± 1.5 cycles; average follow up 23.2 ± 9.7 months. At 24 months, the event-free survival was 86.1%, 69.8%, 55.4% and 30.8% for plasma bacterial DNA level quartiles I, II, III and IV, respectively (p < 0.0001). After adjusting for confounders, plasma bacterial DNA level, baseline residual renal function and malnutrition-inflammation score were independent predictors of composite cardiovascular end-point; each doubling in plasma bacterial DNA level confers a 26.9% (95% confidence interval, 13.0 – 42.5%) excess in risk. Plasma bacterial DNA also correlated with the number of hospital admission (r = -0.379, p < 0.0001) and duration of hospitalization for cardiovascular reasons (r = -0.386, p < 0.0001). Plasma bacterial DNA level did not correlate with baseline arterial pulse wave velocity (PWV), but with the change in carotid-radial PWV in one year (r = -0.238, p = 0.005). Conclusions Circulating bacterial DNA fragment level is a strong predictor of cardiovascular event, need of hospitalization, as well as the progressive change in arterial stiffness in new PD patients.

The Effect of Neutral Peritoneal Dialysis Solution with Low Glucose-Degradation-Product on the Fluid Status and Body Composition--A Randomized Control Trial.

Background Previous studies report conflicting results on the benefit of peritoneal dialysis (PD) patients treated with low glucose degradation product (GDP) solution. The effects of low GDP solution on body fluid status and arterial pulse wave velocity (PWV) have not been studied. Methods We randomly assigned 68 incident PD patients to low GDP (Intervention Group) or conventional solutions (Control Group); 4 dropped off before they received the assigned treatment. Patients were followed for 52 weeks for changes in ultrafiltration, residual renal function, body fluid status and arterial PWV. Result After 52 weeks, Intervention Group had higher overhydration (3.1 ± 2.6 vs 1.9 ± 2.2 L, p = 0.045) and extracellular water volume (17.7 ± 3.9 vs 15.8 ± 3.1 L, p = 0.034) than Control Group. There was no significant difference in PWV between groups. There was no significant difference in residual renal function between the Groups. Intervention Group had lower ultrafiltration volume than Control Group at 4 weeks (0.45 ± .0.61 vs 0.90 ± 0.79 L/day, p = 0.013), but the difference became insignificant at later time points. Intervention Group had lower serum CRP levels than Control Group (4.17 ± 0.77 vs 4.91 ± 0.95 mg/dL, p < 0.0001). Conclusion Incident PD patients treated with low GDP solution have less severe systemic inflammation but trends of less ultrafiltration, and more fluid accumulation. However, the effects on ultrafiltration and fluid accumulation disappear with time. The long term effect of low GDP solution requires further study. Trial Registration ClinicalTrials.gov NCT00966615

Urinary mitochondrial DNA level is an indicator of intra-renal mitochondrial depletion and renal scarring in diabetic nephropathy

Background Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic nephropathy (DN). We study the relation between urinary and intra-renal mitochondrial deoxyribonucleic acid (mtDNA) levels and renal dysfunction in DN. Methods We recruited 92 patients with biopsy-proven DN. Urinary sediment, urinary supernatant and intra-renal mtDNA levels were measured and compared with baseline renal biopsy, kidney scarring and renal function decline in the subsequent 24 months. Results mtDNA could be detected in all urine supernatant, urine sediment and renal biopsy specimens. There was a modest but statistically significant inverse correlation between urinary supernatant and intra-renal mtDNA levels (r = -0.453, P = 0.012). Urinary supernatant mtDNA level had modest but statistically significant correlations, inversely with estimated glomerular filtration rate (r = -0.214, P = 0.04), and positively with interstitial fibrosis (r = 0.300, P = 0.005). Intra-renal mtDNA had significant inverse correlation with interstitial fibrosis (r = -0.537, P = 0.003). However, there was no significant relation between renal function decline and urinary supernatant, urinary sediment or intra-renal mtDNA levels. Conclusions mtDNA is readily detectable in urinary supernatant and kidney tissue, and their levels correlate with renal function and scarring in DN. Further studies are needed to determine the accuracy of urinary supernatant mtDNA level as a prognostic indicator of DN, as well as its role in other kidney diseases.

Frailty in Chinese Peritoneal Dialysis Patients: Prevalence and Prognostic Significance.

Background/Aims: Previous studies showed that frailty is prevalent in both pre-dialysis and dialysis patients. However, the prevalence and prognostic implication of frailty in Chinese peritoneal dialysis (PD) patients remain unknown. Methods: We used a validated questionnaire to determine the Frailty Score of 193 unselected prevalent PD patients. All patients were then followed for 2 years for their need of hospitalization and mortality. Results: Amongst the 193 patients, 134 (69.4%) met the criteria of being frail. Frailty Score significantly correlated with Charlsons comorbidity score (r = 0.40, p < 0.0001), Malnutrition Inflammation Score (r = 0.59, p < 0.0001), and inversely with Subjective Global Assessment score (r = -0.44, p < 0.0001). Frailty was closely associated with the need of hospitalization. Patients with nil, mild, moderate, and severe frailty required 2.4 ± 6.0, 1.6 ± 1.6, 2.7 ± 2.5, 5.2 ± 4.8 hospital admissions per year, respectively (p < 0.0001), and they stayed in hospital for 6.4 ± 9.2, 5.3 ± 6.2, 10.0 ± 10.4, 12.9 ± 20.1 days per hospital admission, respectively (p < 0.0001). However, Frailty Score was not an independent predictor of patient or technique survival. Conclusions: Frailty is prevalent among Chinese PD patients. Frail PD patients have a high risk of requiring hospitalization and their hospital stay tends to be prolonged. Early identification may allow timely intervention to prevent adverse health outcomes in this group of patients.

Effect of cinacalcet treatment on vascular arterial stiffness among peritoneal dialysis patients with secondary hyperparathyroidism

Although calcimimetics cinacalcet can reduce parathyroid hormone level and control secondary hyperparathyroidism in end‐stage renal disease patients, risk of vascular calcification remains high. Whether cinacalcet can further reduce vascular damage or arterial stiffness is unknown.

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.

Peritoneal dialysis effluent miR-21 and miR-589 levels correlate with longitudinal change in peritoneal transport characteristics.

BACKGROUND The role of microRNA (miRNA) in peritoneal fibrosis and longitudinal change in transport is uncertain. METHODS We studied 80 new peritoneal dialysis (PD) patients. Peritoneal transport was determined by standard peritoneal equilibration test (PET) of creatinine at baseline. Based on published literature, PD effluent levels of 10 miRNA targets were quantified. PET and miRNA quantification were repeated one year later in 46 patients. RESULTS Baseline PD effluent levels of all targets tested had modest but significant correlation with peritoneal transport parameters. PD effluent miR-21 and miR-589 levels correlated with dialysate-to-plasma creatinine concentration at 4h (D/P4) at baseline (r=0.377, p=0.001 and r=0.237, p=0.037, respectively) and after one year of PD (r=0.362, p=0.014 and r=0.402, p=0.007). The change in PD effluent -21 and miR-589 levels over one year correlated with the corresponding change in D/P4 (r=0.470, p=0.001 and r=0.479, p=0.002). The number of peritonitis episodes during follow up significantly correlated with the change in PD effluent miR-21 (r=0.387, p=0.009) and miR-589 (r=0.336, p=0.027) levels. There was no significant correlation between PD effluent miRNA level and ultrafiltration volume. CONCLUSION Amongst the 10 miRNA targets tested, miR-21 and miR-589 showed consistently significant relation with peritoneal transport. Further studies are needed to delineate their mechanisms of regulating peritoneal transport.