Clinical And Genetic Risk Factors Of Higher Peritoneal Solute Transport In Peritoneal Dialysis Patients

Peritoneal dialysis is one of major renal replacement treatment for patients with end-stage renal disease.In peritoneal dialysis,solute and water exchange between the peritoneum and peritoneal solute transport rate(PSTR)is an important indicator to evaluate peritoneal function.The most common method to estimate PSTR in clinical is 4 hour dialysate-plasma creatinine ratio(4h D/Pcr),mainly reflecting the small-molecule solute transport rate.Peritoneal solute transport capacity is the basis for adequacy of patient dialysis,but also closely related to patient survival and technical success.The initial PSTR and its longitudinal change of PD patients are of individually heterogeneity.The clinical significance and potential genetic mechanism of these differences may help to select dialysis modality,guide the treatment and improve the prognosis of PD patients,and provide clues to protect peritoneal function for maintenance PD patients.The first part of our study is to collect and analyzed clinical data from 366 incident peritoneal dialysis patients in our department from January 2007 to October 2010,including demographic information,standard peritoneal equilibrium test(PET),baseline and prognostic clinical data.Patients were divided into four groups based on baseline 4h D/Pcr: low transport rate group(group L,4h D/Pcr<0.50,N=115),low average transport rate group(group LA,0.50?4h D/Pcr<0.65,N=150),high average transport rate group(group HA,0.65?4h D/Pcr<0.80,N=90),high transport rate group(group H,4h D/Pcr?0.80,N=15).The comparison of clinical data between groups L/LA and groups H/HA revealed that patients in groups H/HA had a higher percentage of male patients,a higher level of blood urea nitrogen,creatinine and phosphate and a lower level of serum hemoglobin,albumin and GFR.The primary endpoint was defined as a composite of death and technique failure.A total of 89 patients reached the endpoint of death and 32 patients reached the endpoint of technique failure during a mean follow-up time of 43.22 months.Besides,41 patients transferred out because of renal transplant and 6 patients went to other PD center.Survival analysis showed that patients in groups H/HA had a much lower survival rate and a higher cardiovascular death rate.Yet there was no significant difference of technical survival rate between groups.Multivariate COX regression analysis showed that a high level of baseline transport rate was the independent risk factor of cardiovascular death(HR=1.73,95%CI 1.03-2.93,P=0.04).This result might be associated with the insufficient ultrafiltration,unsatisfactory volume control,unhealthy condition and inflammatory status of patients with a high transport rate.The second part of our study intended to analyze the characteristics of change of peritoneal transport function,and showed the relation of peritoneal solute transport rate alteration and prognosis of PD patients.We retrospectively analyzed 222 patients with PD therapy longer than two years.Longitudinal change of PSTR was evaluated by D-value calculated by difference of D/Pcr at 24 month and baseline.Patients with baseline L/LA transport were divided into two groups based on D-value: PSTR stable group(D-value<0.1),PSTR increasing group(D-valued?0.1).Multivariate Cox regression model was established to investigate risk factors of death and technique failure.We found longitudinal changing of PSTR tend toward the middle in the first five years of dialysis.Among 155 patients with baseline L/LA transport,there are 87 patients in PSTR stable group and 68 in PSTR increasing group.Comparing to patients in PSTR stable group,patients in PSTR increasing group had a worse prognosis after adjustment of age,gender,rGFR,MAP,hemoglobin and baseline D/Pcr value(HR=2.26,95% CI 1.13-4.54,P=0.02).Declined adequacy of peritoneal dialysis,a lower serum albumin level and faster loss of renal function might partially be attributed to the poor outcome of patients in PSTR increasing group.A total of 213 patients with available DNA samples from the 222 patients in the second part were enrolled in the third part of our study.We tried to explore the association of genetic polymorphism of members in glucose metabolism pathway and peritoneal solute transport function.We genotyped five SNPs(rs759853,rs1800624,rs1800625,rs184003 and rs2070600)in AKR1B1 and AGER and performed an association analysis between the five SNPs and baseline 4h D/Pcr furthermore.Results showed that rs1800624 A had a higher frequency in L/LA group(TT vs TA vs AA: 64.1% vs 79.6% vs 87.5%)and a lower frequency in H/HA group(TT vs TA vs AA: 35.9% vs 20.4% vs 12.5%,P=0.06).The TT genotype in L/LA group was significantly lower than TA/AA genotype(64.1% vs 80.7%,P=0.02).Compared to genotype TA/AA,patients with genotype TT had a higher 4h /Pcr level(0.60±0.12 vs 0.54±0.13,P=0.004).Multivariate Logistic regression analysis showed that genotype TT of rs1800624(OR=2.29,95%CI 1.07-4.92,P=0.03),a lower level of serum albumin and rGFR were risk factors of a high peritoneal transport status.A further study on the association between SNP and peritoneal solute transport rate was conducted.The CC and CT/TT genotypes of rs759853 were correlated with the changes of peritoneal transport rate(DPSTR)(?=0.17,P=0.013).Patients of CC genotype had a lower DPSTR values than CT/TT genotype patients(0.018±0.15 vs.0.070±0.12,P=0.01).Multivariate linear regression model showed rs759853 locus was correlated with DPSTR with a dominant model.The risk of peritoneal transport increased in patients with CT/TT genotype compared with CC genotype(?=0.142,P=0.015),while hypoalbuminemia and low baseline 4h D/Pcr value were also risk factors for increased peritoneal transport function.(18.11±7.32 vs 12.83±6.31,P = 0.01),and a high expression level of aldose reductase in erythrocyte was detected by T-allele carrier(CT/TT).In summary,patients with high baseline peritoneal transport rate had a low survival rate and higher frequency of cardiovascular and cerebrovascular mortality.The longitudinal change of peritoneal solute transport in patients with peritoneal dialysis showed a trend of "centralization",especially in patients with low solute transport status.Longitudinal increase of PSTR in PD patients was associated with poorer outcome.Longitudinal increase of PSTR in L/LA patients was an independent risk factor of all-cause death and technique failure.The rs1800624 polymorphism of AGER affected the baseline peritoneal solute transport status,and the TT genotype(compared to TA/AA genotype)tended to be a risk factor for high baseline peritoneal transport rate.The rs759853 of AKR1B1 affects the longitudinal changes of peritoneal transport function in patients with peritoneal dialysis.There was higher risk of increased PSTR in PD patients with CT/TT genotype than those with CC genotype and T-allele carrier had higher erythrocyte AR content.