Genetic Predisposition of Donors Affects the Allograft Outcome in Kidney Transplantation; Polymorphisms of Stromal-Derived Factor-1 and CXC Receptor 4

Genetic interaction between donor and recipient may dictate the impending responses after transplantation. In this study, we evaluated the role of the genetic predispositions of stromal-derived factor-1 (SDF1) [rs1801157 (G>A)] and CXC receptor 4 (CXCR4) [rs2228014 (C>T)] on renal allograft outcomes. A total of 335 pairs of recipients and donors were enrolled. Biopsy-proven acute rejection (BPAR) and long-term graft survival were traced. Despite similar allele frequencies between donors and recipients, minor allele of SDF1 rs1801157 (GA+AA) from donor, not from recipients, has a protective effect on the development of BPAR compared to wild type donor (GG) (P = 0.005). Adjustment for multiple covariates did not affect this result (odds ratio 0.39, 95% C.I 0.20–0.76, P = 0.006). CXCR4 rs2228014 polymorphisms from donor or recipient did not affect the incidence of acute rejection. SDF1 was differentially expressed in renal tubular epithelium with acute rejection according to genetic variations of donor rs1801157 showing higher expressions in the grafts from GG donors. Contrary to the development of BPAR, the presence of minor allele rs1801157 A, especially homozygocity, predisposed poor graft survival (P = 0.001). This association was significant after adjusting for several risk factors (hazard ratio 3.01; 95% C.I = 1.19–7.60; P = 0.020). The allelic variation of recipients, however, was not associated with graft loss. A donor-derived genetic polymorphism of SDF1 has influenced the graft outcome. Thus, the genetic predisposition of donor should be carefully considered in transplantation

Indoxyl Sulfate Might Play a Role in Sarcopenia, While Myostatin Is an Indicator of Muscle Mass in Patients with Chronic Kidney Disease: Analysis from the RECOVERY Study

Serum myostatin and indoxyl sulfate (IS) levels increase with kidney function decline and may function as uremic toxins in chronic kidney disease (CKD)-related sarcopenia. Herein, we analyzed the association between serum myostatin and IS levels and sarcopenia in patients with CKD, by performing a post hoc analysis of baseline data extracted from the RECOVERY study (clinicaltrials.gov: NCT03788252) of 150 patients with CKD. We stratified patients into two groups according to the median value of myostatin (cutoff 4.5 ng/mL) and IS levels (cutoff 0.365 mg/dL). The proportion of patients with sarcopenia was higher in those with high IS levels but lower in those with high myostatin levels. The skeletal muscle mass index (SMI) and handgrip strength (HGS) were significantly lower in patients with high IS levels but significantly higher in patients with high myostatin levels. IS levels showed a negative correlation with glomerular filtration rate (GFR), SMI, and HGS. However, myostatin levels were positively correlated with SMI and HGS, but not with GFR. Sarcopenia was independently associated with age and IS level after adjustment. Increased levels of serum total IS might play a role in sarcopenia, while increased levels of serum myostatin are associated with muscle mass in patients with CKD

Physician perceptions of blood pressure control in patients with chronic kidney disease and target blood pressure achievement rate

Background: Blood pressure (BP) control is the most-established method for the prevention of chronic kidney disease (CKD) progression. However, the ideal BP target for CKD patients is still under debate. Methods: We performed a survey of regular registered members of the Korean Society of Nephrology to determine physician perceptions of BP control in patients with CKD. In addition, we evaluated the target BP achievement rate using data from the APrODiTe-2 study. Results: Two-thirds of physicians considered the target BP for CKD to be 300 mg/day (33.7%); GFR ≥ 60 (76.4%); GFR < 30 (47.8%); no evidence of ASO (67.8%); and the presence of ASO (42.9%). Conclusion: The target BP was lower in patients with higher cerebro-cardiovascular risks. These patient groups also showed lower target BP achievement rates. We also found a relatively lower application and clinical reflection rate of home or ambulatory BP monitoring

Validation of the Korean coefficient for the modification of diet in renal disease study equation

Background/Aims: Race and ethnicity are important determinants when estimating glomerular filtration rate (GFR). The Korean coefficients for the isotope dilution mass spectrometry (IDMS) Modification of Diet in Renal Disease (MDRD) Study equations were developed in 2010. However, the coefficients have not been validated. The aim of this study was to validate the performance of the Korean coefficients for the IDMS MDRD Study equations. Methods: Equation development and validation were performed in separate groups (development group, n = 147 from 2008 to 2009; validation group, n = 125 from 2010 to 2012). We compared the performance of the original IDMS MDRD equations and modified equations with Korean coefficients. Performance was assessed by comparing correlation coefficients, bias, and accuracy between estimated GFR and measured GFR, with systemic inulin clearance using a single injection method. Results: The Korean coefficients for the IDMS MDRD equations developed previously showed good performance in the validation group. The new Korean coefficients for the four- and six-variable IDMS MDRD equations using both the development and validation cohorts were 1.02046 and 0.97300, respectively. No significant difference was detected for the new Korean coefficients, in terms of estimating GFR, between the original and modified IDMS MDRD Study equations. Conclusions: The modified equations with Korean coefficients for the IDMS MDRD Study equations were not superior to the original equations for estimating GFR. Therefore, we recommend using the original IDMS MDRD Study equation without ethnic adjustment in the Korean population.Y

Clinical usefulness of serum cystatin C and the pertinent estimation of glomerular filtration rate based on cystatin C

Aim: Although cystatin C has been developed as an alternative marker for estimating glomerular filtration rate (GFR), its clinical use is as yet limited. The significance of cystatin C for differentiating chronic kidney disease (CKD) stages and established cystatin C-based equations estimating GFR were evaluated. Methods: The fresh frozen serum samples from CKD (n = 119) and healthy volunteers (n = 22) were evaluated. Serum creatinine (sCr) was measured by the kinetic Jaffe method, and recalibrated to the isotope dilution mass spectrometry (IDMS). Cystatin C was measured using a particle-enhanced nephelometric assay. Results: CKD stages were more sensitively differentiated by cystatin C compared to sCr, especially in moderate and severe kidney dysfunction. Sex and body mass index did not affect cystatin C level. Pearson`s correlation coefficients of reciprocal of cystatin C, measured and recalibrated sCr compared to systemic inulin clearance (Cl(in)) were 0.757, 0.734 and 0.709, respectively. We derived novel pertinent equations based on cystatin C (model 1: 1.404 x cystatin C-0.895 x age0.006 x weight1.074 x height-1.562 x (0.865; if female); model 2: 43.287 x cystatin C-0.906 x age0.101 x (0.762; if female)]. Models 1 and 2 showed superior performance in representing systemic Cl(in) than the IDMS Modification of Diet in Renal Disease (MDRD) study equations did (adjusted r2 = 0.76 and 0.72 for models 1 and 2, and 0.64 and 0.65 for 4 and 6 variable IDMS MDRD equations, respectively). Conclusion: Cystatin C reflects kidney dysfunction sensitively, and thus cystatin C-based estimation of GFR could provide a reliable support for clinical practice.This work was supported by a grant from the Korean Society of Nephrology, Republic of Korea (H-0701-006-193).Bell M, 2009, NEPHROL DIAL TRANSPL, V24, P3096, DOI 10.1093/ndt/gfp196Astor BC, 2009, J AM SOC NEPHROL, V20, P2214, DOI 10.1681/ASN.2008090980Chudleigh RA, 2009, DIABETOLOGIA, V52, P1274, DOI 10.1007/s00125-009-1379-7Madero M, 2009, J AM SOC NEPHROL, V20, P1086, DOI 10.1681/ASN.2008030318Perkins BA, 2009, CURR OPIN NEPHROL HY, V18, P233, DOI 10.1097/MNH.0b013e3283293db1Madero M, 2009, CURR OPIN NEPHROL HY, V18, P258, DOI 10.1097/MNH.0b013e328326f3ddSong S, 2009, NEPHROL DIAL TRANSPL, V24, P1157, DOI 10.1093/ndt/gfn626Bui AL, 2009, AM J KIDNEY DIS, V53, P389, DOI 10.1053/j.ajkd.2008.06.025Maillard N, 2008, TRANSPLANTATION, V85, P1855, DOI 10.1097/TP.0b013e3181744225Servais A, 2008, AM J MED, V121, P426, DOI 10.1016/j.amjmed.2008.01.040Premaratne E, 2008, DIABETES CARE, V31, P971, DOI 10.2337/dc07-1588Stevens LA, 2008, AM J KIDNEY DIS, V51, P395, DOI 10.1053/j.ajkd.2007.11.018Zahran A, 2007, NEPHROL DIAL TRANSPL, V22, P2659, DOI 10.1093/ndt/gfm243Roos JF, 2007, CLIN BIOCHEM, V40, P383, DOI 10.1016/j.clinbiochem.2006.10.026Levey AS, 2006, ANN INTERN MED, V145, P247MacIsaac RJ, 2006, DIABETOLOGIA, V49, P1686, DOI 10.1007/s00125-006-0275-7Stevens LA, 2006, NEW ENGL J MED, V354, P2473Poge U, 2006, NEPHROL DIAL TRANSPL, V21, P660, DOI 10.1093/ndt/gfi305Myers GL, 2006, CLIN CHEM, V52, P5, DOI 10.1373/clinchem.2005.052514Rule AD, 2006, KIDNEY INT, V69, P399, DOI 10.1038/sj.ki.5000073HAN KH, 2006, KOREAN J NEPHROL, V25, P737Grubb A, 2005, CLIN CHEM, V51, P1420, DOI 10.1373/clinchem.2005.051557van Rossum LK, 2005, PEDIATR NEPHROL, V20, P777, DOI 10.1007/s00467-004-1782-8Filler G, 2005, CLIN BIOCHEM, V38, P1, DOI 10.1016/j.clinbiochem.2004.09.025Larsson A, 2004, SCAND J CLIN LAB INV, V64, P25, DOI 10.1080/00365510410003723Hoek FJ, 2003, NEPHROL DIAL TRANSPL, V18, P2024, DOI 10.1093/ndt/gfg349Pastore A, 2001, J CHROMATOGR B, V751, P187Le Bricon T, 2000, CLIN CHEM, V46, P1206Hayashi T, 1999, NEPHRON, V82, P90Levey AS, 1999, ANN INTERN MED, V130, P461Orlando R, 1998, BRIT J CLIN PHARMACO, V46, P605FLORIJN KW, 1994, KIDNEY INT, V46, P252DUBOIS D, 1989, NUTRITION, V5, P303BLAND JM, 1986, LANCET, V1, P307

Genetic interactions between the donor and the recipient for susceptibility to acute rejection in kidney transplantation: polymorphisms of CCR5

Background. Acute rejection (AR) contributes to the development of chronic allograft nephropathy that is the major cause of graft failure. We analyzed the 59029G>A polymorphism and an internal 32 bp deletion (CCR5 32) of CCR chemokine receptor 5 (CCR5) and tried to prove the hypothesis that genetic interactions between the donor and the recipient influence the development of AR. Methods. We detected genetic polymorphisms by the TaqMan (R) method and by sizing PCR amplicons (n = 486). The primary outcomes were early acute rejection (EAR) and repeated early acute rejection (RR). We defined EAR as the occurrence of a biopsy-proven AR within 3 months after transplantation. Results. The development of EAR was dependent on the number of A alleles in recipients and showed a dose-response relationship (P = 0.002). When we combined the number of A alleles in both donor and recipient, episodes of EAR and RR were more prevalent as the allelic number increased (A allelic number 0 & 1, 2 versus 3 & 4, P = 0.048; 0 & 1 versus 3 & 4, P = 0.006). Statistical significance was preserved after multivariate analysis of sex, HLA mismatch and type of donor with the recipient`s age as the continuous term. Also, graft survival was different according to the presence of the A allele, i.e. recipients carrying A allele (+) grafts showed poor graft survival (P = 0.008 by a log-rank test). Again, the number of A alleles affected graft survival as the recipients who carried more A alleles had poor graft survival (A allele number 0 & 1 versus 2 versus 3 & 4, P = 0.011; 0 & 1 versus 3 & 4, P = 0.08; 0 & 1 versus 2, P = 0.002; by a log-rank test). All of the participants were wild-type homozygotes for CCR5 delta 32. Conclusions. The A allele of CCR5 59029G > A was a risk factor for EAR and RR. As the number of A alleles increased, episodes of EAR were more frequently observed.This study was supported by a grant from the Korea Health 21 R & D project, Ministry of Health and Welfare, Republic of Korea (03-PJ10-PG13-GD01-0002).Thio CL, 2008, J IMMUNOL, V181, P7944Wang F, 2008, SCHIZOPHR RES, V101, P341, DOI 10.1016/j.schres.2008.01.015Berce V, 2008, J ASTHMA, V45, P780, DOI 10.1080/02770900802386024Takacova M, 2008, ACTA VIROL, V52, P261Yigit B, 2007, CELL BIOCHEM FUNCT, V25, P423, DOI 10.1027/cbf.1322Ahn SH, 2006, J MED VIROL, V78, P1564, DOI 10.1002/jmv.20739Prahalad S, 2006, GENES IMMUN, V7, P468, DOI 10.1038/sj.gene.6364317Nankivell BJ, 2006, TRANSPLANTATION, V81, P643, DOI 10.1097/01.tp.0000190423.82154.01Marin LA, 2006, TISSUE ANTIGENS, V67, P117, DOI 10.1111/j.1399-0039.2005.00538.xSimeoni E, 2005, TRANSPLANTATION, V80, P1309, DOI 10.1097/01.tp.0000178378.53616.caLacha J, 2005, TRANSPLANT P, V37, P764, DOI 10.1016/j.transproceed.2004.12.224ABUL KA, 2005, CELLULAR MOL IMMUNOL, P375Hoffmann S, 2004, KIDNEY INT, V66, P1686Fernandez-Mestre MT, 2004, HUM IMMUNOL, V65, P725, DOI 10.1016/j.humimm.2004.05.002Ruster M, 2004, CLIN NEPHROL, V61, P30CLARK VJ, 2004, HUM GENOMICS, V1, P255Nakajima K, 2003, DIABETES CARE, V26, P892Schroppel B, 2002, J CLIN IMMUNOL, V22, P381El-Sawy T, 2002, CURR OPIN IMMUNOL, V14, P562Keen LJ, 2002, TRANSPL IMMUNOL, V10, P143Inston NG, 2002, NEPHROL DIAL TRANSPL, V17, P1374Abdi R, 2002, J AM SOC NEPHROL, V13Fischereder M, 2001, LANCET, V357, P1758Hancock WW, 2001, J EXP MED, V193, P975Hancock WW, 2000, CURR OPIN IMMUNOL, V12, P511Grone HJ, 1999, FASEB J, V13, P1371Schlondorff D, 1997, KIDNEY INT, V51, P610Naruse K, 1996, GENOMICS, V34, P236

Validation of the Korean coefficient for the modification of diet in renal disease study equation

BACKGROUND/AIMS: Race and ethnicity are important determinants when estimatingglomerular filtration rate (GFR). The Korean coefficients for the isotope dilution mass spectrometry (IDMS) Modification of Diet in Renal Disease (MDRD) Study equations were developed in 2010. However, the coefficients have not been validated. The aim of this study was to validate the performance of the Korean coefficients for the IDMS MDRD Study equations. METHODS: Equation development and validation were performed in separate groups (development group, n = 147 from 2008 to 2009; validation group, n = 125 from 2010 to 2012). We compared the performance of the original IDMS MDRD equations and modified equations with Korean coefficients. Performance was assessed by comparing correlation coefficients, bias, and accuracy between estimated GFR and measured GFR, with systemic inulin clearance using a single injection method. RESULTS: The Korean coefficients for the IDMS MDRD equations developed previously showed good performance in the validation group. The new Korean coefficients for the four- and six-variable IDMS MDRD equations using both the development and validation cohorts were 1.02046 and 0.97300, respectively. No significant difference was detected for the new Korean coefficients, in terms of estimating GFR, between the original and modified IDMS MDRD Study equations. CONCLUSIONS: The modified equations with Korean coefficients for the IDMS MDRD Study equations were not superior to the original equations for estimating GFR. Therefore, we recommend using the original IDMS MDRD Study equation without ethnic adjustment in the Korean population

Bone marrow-derived endothelial progenitor cells confer renal protection in a murine chronic renal failure model

Sangidorj O, Yang SH, Jang HR, Lee JP, Cha R, Kim SM, Lim CS, Kim YS. Bone marrow-derived endothelial progenitor cells confer renal protection in a murine chronic renal failure model. Am J Physiol Renal Physiol 299: F325-F335, 2010. First published May 19, 2010; doi:10.1152/ajprenal.00019.2010.-Endothelial cell damage and impaired angiogenesis substantially contribute to the progression of chronic renal failure (CRF). The effect of endothelial progenitor cell (EPC) treatment on the progression of CRF is yet to be determined. We performed 5/6 nephrectomy to induce CRF in C57BL/6 mice. EPCs were isolated from bone marrow, grown in conditioned medium, and characterized with surface marker analysis. The serial changes in kidney function and histological features were scrutinized in CRF mice and EPC-treated CRF (EPC-CRF) mice. Adoptively transferred EPCs were present at the glomeruli and the tubulointerstitial area until week 8 after transfer. In CRF mice, renal function deteriorated steadily over time, whereas the EPC-CRF group showed less deterioration of renal function as well as reduced proteinuria along with a relatively preserved kidney structure. Renal expression of proinflammatory cytokines and adhesion molecules was already decreased in the EPC-CRF group at the early stage of disease, at which point the renal function and histology of CRF and EPC-CRF mice were not different. Angiogenic molecules including VEGF, KDR, and thrombospondin-1, which were decreased in the CRF group, were restored by EPC treatment. In conclusion, EPCs trafficked into the injured kidney protected the kidney from the inflammatory condition and consequently resulted in functional and structural renal preservation. Our study suggests EPCs as a potential candidate for a novel therapeutic approach in CRF.Choi S, 2009, STEM CELLS DEV, V18, P521, DOI 10.1089/scd.2008.0097Chu K, 2008, STROKE, V39, P1441, DOI 10.1161/STROKEAHA.107.499236Yip HK, 2008, STROKE, V39, P69, DOI 10.1161/STROKEAHA.107.489401Tongers J, 2007, J AM SOC NEPHROL, V18, P2843, DOI 10.1681/ASN.2007050597Li JH, 2007, STEM CELLS, V25, P697, DOI 10.1634/stemcells.2006-0133SCHATTEMAN GC, 2007, AM J PHYSIOL-HEART C, V292, P1Zhang A, 2006, PHYS MED BIOL, V51, P6047, DOI 10.1088/0031-9155/51/23/007Ninichuk V, 2006, KIDNEY INT, V70, P121, DOI 10.1038/sj.ki.5001521Rodriguez-Ayala E, 2006, BLOOD PURIFICAT, V24, P196, DOI 10.1159/000090519George J, 2005, ARTERIOSCL THROM VAS, V25, P2636, DOI 10.1161/01.ATV.0000188554.49745.9eChan CT, 2005, AM J PHYSIOL-RENAL, V289, pF679, DOI 10.1152/ajprenal.00127.2005Walenta K, 2005, BIOCHEM BIOPH RES CO, V333, P476, DOI 10.1016/j.bbrc.2005.05.153Uchimura H, 2005, J AM SOC NEPHROL, V16, P997MEGUID EL, 2005, LANCET, V365, P331Cheng HG, 2005, NEPHRON EXP NEPHROL, V101, P75, DOI 10.1159/000086645NISHIMURA H, 2005, EXS, P147Urbich C, 2004, CIRC RES, V95, P343, DOI 10.1161/01.RES.0000137877.89448.78de Groot K, 2004, KIDNEY INT, V66, P641Choi JH, 2004, ARTERIOSCL THROM VAS, V24, P1246, DOI 10.1161/01.ATV.0000133488.56221.4aVerma S, 2004, CIRCULATION, V109, P2058, DOI 10.1161/01.CIR.0000127577.63323.24Gadola L, 2004, KIDNEY INT, V65, P1224Landray MJ, 2004, AM J KIDNEY DIS, V43, P244, DOI 10.1053/j.ajkd.2003.10.037ASAHARA T, 2004, AM J PHYSIOL-CELL PH, V287, P572Rookmaaker MB, 2003, AM J PATHOL, V163, P553Ma LJ, 2003, KIDNEY INT, V64, P350Levey AS, 2002, NEW ENGL J MED, V347, P1505Pelosi E, 2002, BLOOD, V100, P3203, DOI 10.1182/blood-2002-05-1511Asahara T, 2002, J HEMATOTH STEM CELL, V11, P171Masuda Y, 2001, AM J PATHOL, V159, P599Shintani S, 2001, CIRCULATION, V103, P2776Gill M, 2001, CIRC RES, V88, P167Szekanecz Z, 2000, ARTHRITIS RES, V2, P368Megyesi J, 1999, P NATL ACAD SCI USA, V96, P10830Asahara T, 1999, CIRC RES, V85, P221Asahara T, 1997, SCIENCE, V275, P964

Long-term outcomes of kidney allografts obtained by transplant tourism: Observations from a single center in Korea

Aim: Organ shortages lead end stage renal disease patients to seek overseas kidney transplantations (OTs), but the long-term outcomes of OTs have not been evaluated extensively. Methods: Patients who received OT and were followed at Seoul National University Hospital (SNUH) from 2000 to 2009 (n = 87) were compared with patients who received kidneys from local donors (LTs) and were followed at SNUH (n = 577). Furthermore, we matched OT patients and LT patients via a propensity score using operation date, age, renal replacement therapy duration, and donor sources (n = 87 vs 87). Results: The recipient age was older in the OT group (48 vs 41 years), and donor age was younger in the OT group (29 vs 39 years). The estimated glomerular filtration rates (eGFR) of functioning grafts between the groups were not different throughout the follow-up period. Biopsy-proven acute rejection, infectious disease, and hospitalization were more frequent in the OT group (27/87 vs 141/577, log-rank P &lt; 0.001; 39/87 vs 28/577, log-rank P &lt; 0.001; 66/87 vs 99/577, log-rank P &lt; 0.001). The graft survival rate was lower in the OT group (82/87 vs 542/577, log-rank P = 0.003). Patient survival rate, however, was similar between the groups. After propensity score matching, the donor age was still younger in the OT group (29 vs 38 years). The risks of biopsy-proven acute rejection, infectious disease, and hospitalization were still higher in the OT group (27/87 vs 36/87, log-rank P = 0.04; 39/87 vs 3/87, log-rank P &lt; 0.001; 66/87 vs 19/87, log-rank P &lt; 0.001). Conclusion: Overseas kidney transplantation connotes risk factors that may negatively affect the long-term graft outcome.N