Randomized, Open-Label, Phase IV, Korean Study of Kidney Transplant Patients Converting From Cyclosporine to Prolonged-Release Tacrolimus Plus Standard- or Reduced-Dose Corticosteroids.

BACKGROUND: This 24-week, multicenter, randomized, exploratory, comparative, open-label, phase-IV study assessed the safety and efficacy of prolonged-release tacrolimus (PR-T) with reduced-dose versus standard-dose corticosteroids in stable kidney transplant recipients in Korea after converting from cyclosporine-based therapy. METHODS: At baseline, patients were converted from cyclosporine-based to PR-T-based immunosuppression and randomized (1:1) to receive either corticosteroids maintained at prestudy dose (standard-dose group) or tapered from week 4 to 50% of the prestudy dose by week 12 (reduced-dose group). Patients were seen at baseline and weeks 1, 4, 12, and 24. The primary endpoint was change in estimated glomerular filtration rate (Modification-of-Diet-in-Renal-Disease-4) between baseline and week 24. Secondary endpoints included either acute rejection or patient-reported satisfaction with PR-T. Adverse events (AEs) were recorded. RESULTS: Overall, 150 patients were randomized into a reduced-dose group (n = 73) and a standard-dose group (n = 77). At week 24, mean ± standard deviation for corticosteroid dose was 2.5 ± 0.9 mg and 5.0 ± 1.3 mg, respectively. Mean change in estimated glomerular filtration rate from baseline to week 24 was +1.5 ± 9.1 mL/min/1.73 m2 (P = .1567) and +3.4 ± 10.6 mL/min/1.73 m2 (P = .0065), respectively, and not significantly different between groups. There were no acute rejection episodes. Most respondents (>70%) considered PR-T more convenient than cyclosporine. AE incidence was similar between groups. The most common AEs experienced by ≥3% of patients in either treatment group were gastrointestinal events (20.8% and 28.6% of patients receiving reduced- and standard-dose corticosteroids, respectively). Most AEs in both treatment groups were mild or moderate in severity. CONCLUSION: Renal function was maintained following conversion from cyclosporine to PR-T, irrespective of corticosteroid regimen; PR-T enables reduced corticosteroid dosage.

Clinical outcomes in Asian elderly kidney transplant recipients: a multicenter cohort study.

BACKGROUND: The kidney transplantation rate in elderly patients is increasing rapidly. However, the clinical outcomes of kidney transplantation in elderly patients have not yet been thoroughly evaluated. METHODS: This multicenter cohort study included adult kidney transplant recipients (KTRs) admitted to five major tertiary hospitals in Korea between 1997 and 2012. A total of 3,565 adult participants were enrolled. Patient survival, allograft survival, and biopsy-proven acute rejection (BPAR) of 242 elderly recipients (≥ 60 years) were assessed and compared with those of a younger population. RESULTS: Patients were divided into five groups according to age at time of transplantation. The proportion of elderly patients was 6.7 % (mean age, 63.1 ± 2.7 years; n = 242). The numbers of male patients (69.4%), those with diabetes mellitus history (36.3%), and those with pretransplantation ischemic heart disease history (17.7%) were significantly higher in the elderly group than in the younger age groups. Elderly patients were more likely to receive a cadaveric kidney, and overall mortality rates were significantly higher in the elderly patients (1-year survival 93.3%, 5-year survival 91.3%). However, death-censored allograft survival rate and BPAR were not affected by patient age (P = .104 and .501, respectively). Among the elderly, BPAR and female donors were independent risk factors for allograft loss. CONCLUSION: The overall survival rate of the elderly KTRs was significantly lower than that of younger KTRs. However, the death-censored allograft survival rate did not differ between groups. Kidney transplantation should not be stagnated especially in elderly patients with end-stage renal disease.

Socio-economic disparities in behavioural risk factors for cancer and use of cancer screening services in Korean adults aged 30 years and older: the Third Korean National Health and Nutrition Examination Survey, 2005 (KNHANES III).

OBJECTIVES: To estimate the current status of cancer-related health disparities in cancer risk factors and the use of cancer screening services by Korean adults. STUDY DESIGN: Cross-sectional survey study. METHODS: The disparities of behavioural cancer risk factors and use of cancer screening services according to equivalent monthly household income were evaluated, using multivariate logistic regression analysis, among 6466 subjects aged ≥30 years and who completed the health promotion knowledge, attitude and practice survey, which is part of the Third Korean National Health and Nutrition Examination Survey. RESULTS: In men, smoking (P for trend = 0.05) and physical inactivity (P for trend = 0.05) were more common in the lower-income group, while high-risk drinking (P for trend <0.01) was more common in the higher-income group. In women, physical inactivity (P for trend <0.01) was more common in the lower-income group, while smoking and high-risk drinking showed no income disparities. Income disparities were also found in the degree of participation in cancer screening programmes. Men in the highest income quintile underwent more screening for both colorectal and gastric cancer than men in the lowest income quintile and men in the second to fourth income quintiles (P for trend <0.01 for both). Women in the highest income quintile underwent more screening for cervical (P for trend <0.01) and gastric (P for trend = 0.04) cancer, while income disparities were not seen for participation in colorectal or breast cancer screening. CONCLUSIONS: In order to decrease behavioural risk factors and promote participation in cancer screening programmes, more targeted efforts are needed for cancer prevention among lower-income Koreans.

Effective removal of leptin via hemodiafiltration with on-line endogenous reinfusion therapy.

AIMS: Leptin is a middle-molecular weight uremic toxin. Hemodiafiltration with on-line endogenous reinfusion (HFR) is a novel dialytic method combining the processes of diffusion, convection and adsorption. We performed a prospective crossover study of patients with end-stage renal disease to investigate the effect of HFR therapy on the level of leptin as compared to conventional low flux hemodialysis (LHD). METHODS: Eleven stable hemodialysis patients were treated with LHD for 12 weeks and then treated with HFR (SG30 Plus; Sorin Group Italia S.r.1, Mirandola, Italy) for 12 weeks. RESULTS: After 12 weeks of HFR treatment, serum leptin levels significantly decreased (17.1 (2.66 - 39.5) at Week 12 vs. 12.3 (1.80 - 24.3) ng/ml at Week 24, p = 0.014). Although serum adiponectin levels also decreased (1.66 (1.44 - 1.86) at Week 12 vs. 1.12 (0.79 - 1.34) g/ml at Week 24, p = 0.001), the ratio of leptin to adiponectin did not increase after HFR treatment. Serum beta2-microglobulin (beta2M) levels significantly decreased (37.7 (29.8 - 42.6) at Week 12 vs. 28.3 (26.5 - 32.2) mg/dl at Week 24, p = 0.002). Dry weight, Kt/V(urea), normalized protein equivalent of nitrogen appearance, subjective global assessment, and serum albumin levels of the patients were not changed after HFR treatment. There was no difference in the serum levels of C-reactive protein or interleukin-6 between Week 12 and Week 24. CONCLUSIONS: The results of our study indicate that HFR may be a better therapy than LHD for removal of middle-molecular-weight uremic toxins such as leptin and b2M.

Association between the clara cell secretory protein (CC16) G38A polymorphism and the progression of IgA nephropathy.

AIMS: Clara cell secretory protein (CC16) is a protein with anti-inflammatory and immunomodulatory properties. Moreover, both CC16 gene knockout and antisense-transgenic mouse models developed glomerulonephritis resembling IgA nephropathy (IgAN). In the present study, we evaluated the influence of the G38A polymorphism in the CC16 gene exon 1 on the development and progression of IgAN. METHODS: Korean patients with biopsy-proven IgAN (n=267) with a minimal follow-up of 4 years (mean +/- SD 103.8 +/- 52.6 months) were recruited. Healthy normal subjects (n=315) were included as controls. The G38A polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: GG, GA and AA genotype frequencies were 36.3, 50.2 and 13.5% in IgAN patients, respectively, and 34.3, 50.2 and 15.5% in controls (chi2 = 0.596, p = 0.742). The G allele frequency was 0.614 in IgAN patients and 0.594 in controls (chi2 = 0.429, p = 0.512). Moreover, the GG genotype frequencies were 40.4% in patients showing stable disease course and 26.6% in those with progressive disease (chi2 = 4.029, p = 0.045). Patients with the GG genotype showed a better outcome by Kaplan-Meier analysis in terms of renal survival (p = 0.043). The CC16 polymorphism remained an independent risk factor for progression after multivariate analysis (Cox regression model, HR for CC16 AA genotype: 2.34, 95% CI 1.19-4.64, p = 0.014). CONCLUSION: Our results suggest that CC 16 gene G38A polymorphism is not associated with the development of IgAN, but that it is an important marker of progression in IgAN.

The clinical significances of simple renal cyst: Is it related to hypertension or renal dysfunction?

Simple renal cyst has controversy related to hypertension and renal dysfunction. We analyzed the impacts of cyst on hypertension and renal dysfunction, focusing on elimination of the confounding factors. We grouped 436 patients and 436 controls by characteristics of cyst and stratified with clinical parameters among 6603 patients who had routine health check-up in Seoul National University Bundang Hospital, Seongnam, Korea. The presence of cyst was related to hypertension but not to renal dysfunction. The number and the size of cyst were independent risk factors to the prevalence of hypertension. The presence of multiple renal cysts was related to hypertension in males, in persons over the age of 60 years, in persons with glomerular filtration rate (GFR) more than 60 ml/min/1.73 m2, or in persons without proteinuria. The effect of the large cyst and the peripheral cyst on the prevalence of hypertension was similar to that of the multiple cyst. The blood pressure of the multiple-cyst group, the large-cyst group, or the peripheral-cyst group was higher than that of the single-cyst group, the small-cyst group, or the perihilar-cyst group, respectively, regardless of antihypertensive medications. In conclusion, the presence of cysts or characteristics of cyst were not related to the decreased GFR. In conclusion, the presence of simple renal cyst was related to hypertension but not to renal dysfunction. The effect of simple cyst on hypertension was evident in males, aged persons, and persons without the evidence of renal disease. The number, size, and location were important characteristics of cyst related to hypertension.

Association of C-509T and T869C polymorphisms of transforming growth factor-beta1 gene with susceptibility to and progression of IgA nephropathy.

AIMS: Transforming growth factor (TGF)-beta1 is a cytokine with both beneficial anti-inflammatory effects and detrimental profibrotic activity in the pathophysiology and progression of glomerulonephritides. The transcriptional activity of the gene for TGF-beta1 and the plasma levels of TGF-beta1 protein are associated with C-509T polymorphism at the promoter region, and with T869C (Leu 10Pro) polymorphism at codon 10, of the TGF-beta1 gene. METHODS: Using PCR-RFLP and the amplification refractory mutation system PCR, we investigated the C-509T and T869C polymorphisms, respectively, to elucidate whether allele frequency differences exist between IgA nephropathy (IgAN) patients who were followed up for at least 3 years (n = 108) and a normal population (n = 55). We also determined the correlations between the TGF-beta1 polymorphisms and the progression of IgAN. RESULTS: In C-509T polymorphism, there were significant differences in genotype frequency between IgAN patients and normal controls (CC: CT: TT, 20:29:33 vs. 11:31:13, chi2 = 6.299, p = 0.043). In Kaplan-Meier survival analysis, the patients with TT genotype showed a poorer renal survival than those with CC + CT genotypes (p = 0.042). In T869C polymorphism, there were also significant differences in genotype frequency between IgAN patients and normal controls (TT : TC : CC, 4 : 79 : 25 vs. 0 : 52 : 2, chi2 = 12.552, p = 0.002). The initial serum creatinine (Scr) level was higher in the patients with CC genotype than in those with TT + TC genotypes. In Kaplan-Meier survival analysis, the patients with CC genotype showed a poorer renal survival than those with TT + TC genotypes, but not to a statistically significant extent (p = 0.076). In the combined survival analyses, the high TGF-beta1 producer group showed a poor renal survival rate (p = 0.014). CONCLUSION: Compared to normal population, the frequencies of genotypes producing high TGF-beta1 protein were higher in IgAN patients. Moreover, patients with genotypes producing high TGF-beta1 plasma levels showed a poor renal survival rate.

Expression of FasL and perforin/granzyme B mRNA in chronic hepatitis B virus infection.

Cytotoxic T lymphocytes are essential components of immune responses during chronic hepatitis B (CHB). It has been known that Fas ligand (FasL) and perforin/granzyme B-based mechanisms account for all T cell-mediated cytotoxicity. In the present work, we examined the correlation between injury of the hepatocytes and mRNA expression of FasL and perforin/granzyme B in liver tissue to investigate the roles of both the FasL and the perforin/granzyme B pathways in CHB. Reverse transcription-polymerase chain reaction was used to identify intrahepatic expression of FasL and perforin/granzyme B in liver biopsy specimens from 24 patients with hepatitis B virus (HBV) infection. In addition, the transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) method was used to determine the degree of apoptosis. The degree of mRNA expression and apoptosis were compared with the histologic activity index (HAI) and serology, including alanine aminotransferase (ALT). Intrahepatic mRNA expression rates of FasL, perforin and granzyme B were seen in 79.2, 62.5 and 33.3% of patients, respectively, and correlated with ALT levels (P < 0.05). Intrahepatic expression of FasL and perforin mRNA were significantly correlated with HAI (P < 0.05). Also, apoptosis documented by the TUNEL assay was correlated with HAI and intrahepatic mRNA expression of FasL and perforin (P < 0.05). Our results show that the T-cell mediated perforin death pathway as well as the Fas system play important roles in liver cell injury in HBV infection and that apoptosis mediated by the Fas/FasL system is closely correlated with HAI in chronic HBV infection.

Association of the CD14 gene -159C polymorphism with progression of IgA nephropathy.

The risk factors associated with the progression of IgA nephropathy (IgAN), the most common form of glomerulonephritis, are unclear. It has been suggested that CD14 signalling in response to various microbes affects the natural history of chronic inflammatory conditions. It has been hypothesised that variants in the promoter region of the CD14 gene might alter the expression of CD14, and this in turn could influence the progressive nature of IgAN. PCR-RFLP was used to determine the polymorphism at the -159 site (T to C). The distribution of the CD14/-159 polymorphism was no different in patients with IgAN (n=216) compared to 171 healthy controls. After follow up for 86 months, it was found that an excess of the C genotype occurred in patients with progressive disease (p=0.03) and the risk of disease progression increased as the number of C alleles increased (p for trend = 0.002). The hazard ratio for progression in the patients with the CC genotype was 3.2 (p=0.025) compared with the patients possessing the TT genotype. After LPS stimulation, sCD14 was released more abundantly from the PBMCs of the TT subjects than from that of the CC subjects (p=0.006), even though mCD14 expression level was no different. In addition, the TT subjects released less IL-6 than the CC subjects after stimulation (p=0.0003). These results suggest that the CD14/-159 polymorphism is an important marker for the progression of IgAN and may modulate the level of the inflammatory responses.

Differential expression of various cytokine and chemokine genes between proliferative and non-proliferative glomerulonephritides.

BACKGROUND: Intraglomerular cellular proliferation is one of the major determinants for dividing various glomerulonephritis (GN) into two groups, such as proliferative versus non-proliferative. Cytokines and chemokines are involved in the pathogenetic pathways and would affect the functional and histologic sequelae. We hypothesized that the morphological difference might be based on the differential intrarenal expression of various cytokines and chemokines. We quantified the intrarenal gene expression of various cytokines and chemokines, and correlated it with clinical parameters. METHODS: Total RNA was extracted from 54 proliferative GN (PGN) core biopsy specimens and 42 non-proliferative GN (NPGN) specimens. Using the internal competitors, RT-PCR was instituted to quantify mRNAs. RESULTS: The magnitude of the gene expressions of IL-2, IFN-gamma, and IFN-gamma/IL-10 ratio were significantly higher in PGN than in NPGN. RANTES and IL-8 had more abundant gene messages in PGN. It was shown that Th1 cytokine was upregulated if GN was mediated by immune complexes regardless of cellular proliferation. But chemokines had the elevated levels of expression in PGN among immune complex-mediated GN. Up-regulation of the IFN-gamma/IL-10 ratio and TNF-alpha was associated with poor renal function at the time of biopsy. Renal tissues from the patients with a non-nephrotic range of proteinuria showed abundant messages for proinflammatory cytokines and chemokines. CONCLUSION: Th1, proinflammatory cytokines, and chemokines were more abundant in proliferative GN, and correlated with unfavorable clinical parameters. We propose that the clinical manifestations and diverse histologic features of human GN are associated with differential expressions of specific cytokines and chemokines.

Th1/Th2 predominance and proinflammatory cytokines determine the clinicopathological severity of IgA nephropathy.

BACKGROUND: IgA nephropathy is one of the most common forms of primary glomerulonephritis in adults. Its pathogenesis is complex. The nature of infiltrating and proliferating cells and of cellular mediators could contribute to the progression of IgA nephropathy towards end-stage renal failure. METHODS: To evaluate this hypothesis, we attempted to quantify the magnitude of intrarenal gene expression of various cytokines (IL-1 beta, TNF-alpha, IL-6, IL-15, IL-2, IFN-gamma, IL-10) and chemokines (IL-8, RANTES, MCP-1) in 48 renal core biopsy specimens, diagnosed as IgA nephropathy by immunofluorescence microscopy. Semi-quantitative reverse-transcriptase polymerase chain reaction using internal competitors was used for the quantification of gene transcripts. RESULTS: The expression of intrarenal gene transcripts of various cytokines and chemokines was closely interrelated, but not associated with the pathological grading system. The IFN-gamma/IL-10 ratio was higher in patients with renal dysfunction than in those with normal renal function (P=0.0483). Gene transcript levels of proinflammatory cytokines were related to the amount of proteinuria. In patients with severe glomerular sclerosis, the ratio of IFN-gamma/IL-10 gene transcripts was high (P=0.04). IL-10 gene transcript level was related to the severity of tubulointerstitial damage. The levels of gene expression of IL-10 (P=0.009), IFN-gamma (P=0.03), and TNF-alpha (P=0.005) were related to the degree of mesangial matrix expansion and the extent of intrarenal arteriolar changes correlated with the expression of the IL-8 gene transcript (r=0.43, P=0.004). CONCLUSIONS: We propose that Th1/Th2 predominance and the level of proinflammatory cytokines could determine the pathogenetic processes and the severity of the clinical manifestations of IgA nephropathy.

Cadaveric renal allograft at the time of implantation has the similar immunological features with the rejecting allograft.

BACKGROUND: Compared to living donations, cadaveric transplants have a poorer outcome, and the immunologic status of renal tissues at the time of transplantation might influence the final outcome of the renal allograft. PATIENTS AND METHODS: We used quantitative RT-PCR to evaluate the differential expression of cytokine genes from 37 implantation tissues [18 cadaveric tissues (CI), 19 specimens from living donors (LI)]. We compared them with 17 acutely rejecting allograft (AR). RESULTS: Acute rejection within 6 months after transplantation occurred 8 times in patients with cadaveric allograft, but the living-donor recipients experienced 4 episodes (P<0.05). Proinflammatory cytokines were co-expressed more frequently in CI than in LI. The levels of IFN-gamma, TNF-alpha and IL-10 mRNA were also higher in CI. We compared the profiles of several cytokine expressions of CI with those of AR. The messages for IL-6 were more abundant in the CI, IFN-gamma was more expressed in AR, and the other cytokine expression levels were similar in both types. However, when comparing LI and AR, all the cytokine messages except IL-6 were up-regulated in AR than in LI. In CI, the levels of cytokine gene expressions were similar despite various cold ischemic time except IL-10 that were elevated for those cases where the operation was done within 4 hr of nephrectomy. CONCLUSIONS: The numbers and levels of gene transcription of inflammatory cytokines were higher in the tissues from a cadaver, and were not different from those of AR. This immunologic hostility at the time of implantation would contribute to the poorer outcome of cadaveric allograft.

The relationship between plasma leptin and nutritional status in chronic hemodialysis patients.

Leptin serves an important role in suppressing appetite in mice and is known to be elevated in chronic renal failure (CRF) patients. But clinical significance of leptin as an appetite-reducing uremic toxin, remains to be determined. So we studied the relationship between plasma leptin and nutritional status in 46 chronic hemodialysis (HD) patients. Pre HD leptin was measured and divided by body mass index (BMI) to give adjusted leptin levels. KT/Vurea (K, dialyzer urea clearance; T, duration of HD; V, volume of distribution of urea), C-reactive protein (CRP), plasma insulin and nutritional parameters such as serum albumin, normalized protein catabolic rate (nPCR), subjective global assessment (SGA), BMI and mid-arm muscle circumference (MAMC) were also measured. Mean plasma leptin levels were 8.13+/-2.91 ng/mL (male 3.15+/-0.70; female 14.07+/-6.14, p<0.05). Adjusted leptin levels were positively correlated with nPCR (male r=0.47, p<0.05; female r=0.46, p<0.05), SGA (male r=0.43, p<0.05; female r=0.51, p<0.05) and MAMC (male r=0.60, p<0.005; female r=0.61, p<0.05). They did not correlate with KT/Vurea, serum albumin, hematocrit, bicarbonate, insulin and CRP. Presence of DM and erythropoietin therapy had no effect on leptin levels. These results suggest that leptin is a marker of good nutritional status rather than a cause of protein energy malnutrition in chronic HD patients.

Interleukin-15 signals T84 colonic epithelial cells in the absence of the interleukin-2 receptor beta-chain.

Interleukin-15 (IL-15) shares many biological functions with interleukin-2 (IL-2) due to common receptor components. IL-15 binds to the IL-2 receptor (IL-2R) beta-chain and the common gamma-chain receptor in addition to one other IL-15 binding receptor protein (IL-15R alpha). Both IL-2R beta- and gamma-chains are required to promote cell growth in hematopoietic cells. The colonic cryptlike epithelial cell line T84 contains the common gamma-chain but lacks the IL-2R beta-chain. We report IL-15R alpha-chain mRNA in T84 cells with the use of reverse transcriptase-polymerase chain reaction. T84 and normal colonic epithelial cells bind a FLAG-IL-15 fusion protein in immunoperoxidase and flow cytometric experiments. In addition, IL-15, but not IL-2, accelerates and enhances the development of transepithelial resistance across T84 monolayers in a dose-dependent fashion. We conclude that normal and T84 colonic epithelial cells express IL-15R alpha and are able to bind IL-15. IL-15 can deliver a nonproliferative functional signal in the absence of IL-2R beta-chain in T84 cells.

Distribution of IL-15 receptor alpha-chains on human peripheral blood mononuclear cells and effect of immunosuppressive drugs on receptor expression.

IL-15, a newly described cytokine exerting IL-2-like in vitro activities, binds to and induces proliferation of cells co-expressing IL-15R alpha, IL-2R beta, and IL-2R gamma chains. To study the expression of human IL-15R alpha chains, we have utilized tagged human IL-15 protein and FACS analysis. In contrast to resting cells, mitogen-activated macrophages, NK cells, and CD4+ and CD8+ T cells express IL-15R alpha chains. Neither IL-2R alpha nor IL-2R beta chains are required for IL-15 binding. Dexamethasone, but not cyclosporine or rapamycin, blocks mitogen-induced IL-15R alpha expression. Dexamethasone-pretreated cells respond to IL-15 poorly, while the response to IL-2 is not affected. Thus, despite structural and functional similarities between IL-2R alpha and IL-15R alpha chains, the activation-triggered mechanisms of induction are different. Since IL-15R alpha chain is necessary and sufficient for IL-15 binding, regulation of IL-15R alpha expression may represent a new target for T cell-directed pharmacologic intervention.