Association Between Toll-like Receptors 4 and 2 Gene Polymorphisms With Chronic Allograft Nephropathy in Turkish Children

Toll-like receptor (TLR) gene polymorphism is known to impair intracellular signaling pathways following adaptive immune responses. Our aim was to investigate the distribution of TLR4 and TLR2 gene polymorphisms among pediatric renal transplantation patients in relation to chronic allograft nephropathy (CAN). In addition to 115 healthy controls, we included 69 renal recipients, 19 of whom were identified as CAN by biopsy scored according to the Banff criteria. Polymorphisms at TLR4 Asp299Gly and/or Thr399Ile were present in 11.6% of renal transplant recipients. None of these subjects was identified in cosegregation with the Thr399Ile allele, whereas three had an isolated Asp299Gly and five had an isolated Thr399Ile. Neither renal recipients nor healthy controls were homozygous for both Asp299Gly and Thr399Ile polymorphisms. However, TLR4 Thr399Ile polymorphism and Ile allele was greater among CAN (?) versus CAN (+) recipients (P > .05). The frequency of TLR2 mutant type Gln allele was significantly higher in recipients than among healthy controls (P < .0001). However, the Gln allele frequency was similar between CAN (+) and CAN (?) patients. The results of present study may be speculated to show TLR4 and TLR2 gene polymorphisms as protective factors from CAN development due to impaired immune responses.     

Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukine-10 gene polymorphisms on clinical outcome in Japanese critically ill patients

The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction.     

Efficacy and Safety of Mizoribine Combined With Tacrolimus in Living Donor Kidney Transplant Recipients: 3-Year Results by a Chinese Single Center Study

BackgroundMizoribine (MZR) was effective and safe for living Chinese donor kidney transplantation (LDKT) on tacrolimus-based treatment 1 year after transplantation. We investigated whether MZR was effective and safe for LDKT on tacrolimus-based treatment with long follow-up periods.MethodsWe compared 22 LDKT recipients who were administered MZR, tacrolimus, and corticosteroids with a control group (n = 20) treated with mycophenolate mofetil (MMF), tacrolimus, and corticosteroids. Primary efficacy endpoints were 3-year patient survival, 3-year graft survival, and acute rejection (AR) rate within 3 years after transplantation.ResultsThe 3-year patient and graft survival rates for the MZR and MMF groups were 100%. The AR rate after transplantation was 18.2% for the MZR group and 10.0% for the MMF group; the difference was not significant (P = .665). There was no significant difference in serum creatinine levels, glomerular filtration rates (eGFR), serum urate levels, blood urea nitrogen, and cystatin C levels 12, 24, and 36 months after transplantation. No significant differences in the CD3, CD4, CD8, CD4/CD8, and CD45 were observed between the 2 groups 12, 24, and 36 months after transplantation. There were no significant differences in adverse events among the MZR or the MMF group, whereas the prevalence of gastrointestinal symptoms were significantly lower in the MZR treatment group (P = .003), especially acid reflux (P = .007). Compared with the MMF group, the MZR group should lighten the burden on patients.ConclusionMZR with tacrolimus and corticosteroids provides satisfactory immunosuppression and higher safety for Chinese LDKT over a 3-year follow-up.     

Incidence of donor and recipient toll-like receptor-4 polymorphisms in kidney transplantation

Toll-like receptors (TLR) comprise an emerging family that recognize pathogen-associated molecular patterns and promote the activation of leukocytes. Recently, TLR has been demonstrated to play a role in experimental allograft rejection. However, the TLR-4 gene has a polymorphism that can be associated with a blunted immune response, especially to microbial pathogens. We sought to study the incidence of TLR 4 gene variants among renal transplant donors and recipients from living and deceased organs and then to correlate them with short-term and long-term outcomes. METHODS: Analysis of TLR4 polymorphisms at Asp299Gly and Thr399Ile codons were performed using restriction fragment length polymorphism. Demographic data was obtained from patient records. RESULTS: Among 201 patients, 141 were recipients from related donors (group 1) and 60 recipients from 45 deceased donors (group 2). Patients were followed for 108 +/- 85 months after transplantation. The incidence of polymorphism for TLR-4 Asp299Gly, Thr399Ile or both were 8.9% in recipients and 8.0% in donors. Patients who received a kidney with polymorphism, Asp299Gly, or Thr399Ile, or both, did not show a difference in rate of acute tubular necrosis compared with controls (no polymorphism). Acute rejection occurred in 17.6% of recipients with Asp299Gly/Thr399Ile polymorphisms and in 39.5% of wild-type recipients (P = .400). The incidence of bacterial infection was equal in both groups. CONCLUSION: The incidence of polymorphism in this study was similar in both groups, and donor or recipient polymorphisms were not associated with different renal graft outcomes.     

Retrospective Evaluation of the Effect of Mycophenolate Mofetil Dosage on Survival of Kidney Grafts Based on Biopsy Results

IntroductionPlasma concentration monitoring is commonly used to adjust immunosuppressant dosage in transplant recipients, but adjustment is often based on clinical experience rather than rigorous quantitative indicators.MethodsWe examined the effect of mycophenolate mofetil (MMF) dosage on graft survival by pathologic and immunologic analysis of 88 kidney recipients who were given a postoperative immunosuppressive regimen of tacrolimus (FK506), MMF, and corticosteroids. Patients were given a conventional dosage (≥1.5 g/d; n = 40) or a reduced dosage (n = 48) of MMF owing to postoperative adverse side effects.ResultsThe reduced-dose group included patients given low doses (≤1.0 g/d; n = 27), ultra-low doses (≤0.5 g/d; n = 15), and those who discontinued MMF (n = 6). The dose reduction group had increased acute rejection, chronic rejection, and graft dysfunction, poorer pathologic scores, and increased cell infiltration of graft tissue (CD4, CD8, CD68, and CD138 positivity) and expression of interleukin-2R and HLA-DR. Finally, hazard analysis indicated that patients given low doses and ultra-low doses of MMF had poorer long-term kidney grafts survival (hazard ratios of 1.52 and 1.78, respectively).ConclusionsThese results indicate the importance of using an appropriate dosage of MMF in kidney transplant recipients.     

Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development

Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.     

Reduced CD4+ CD25++ CD45RA− Foxp3hi activated regulatory T cells and its association with acute rejection in patients with kidney transplantation

BackgroundIt was found that regulatory T cells (Tregs) importantly affect the maintenance of the kidney graft. However, Tregs are a heterogeneous population with less to more suppressive activity. The aim of this study was to determine the effects of different subsets of Tregs, as well as their ratio to effector T cells (Teff), on kidney transplantation outcomes.MethodsA total of 58 participants were enrolled in this study and divided into four groups: (i) first kidney transplant recipients (stable 1); (ii) second kidney transplant recipients (stable 2); (iii) transplant recipients with acute rejection (AR); and (iv) healthy control subjects. By using flow cytometer, the frequencies of CD4⁺ CD25⁺⁺ CD45RA⁻ Foxp3^hi activated Tregs (aTregs), CD4⁺ CD25⁺ CD45RA⁺ Foxp3^lo resting Tregs (rTregs), CD4⁺ CD25⁺ CD45RA⁻ Foxp3^lo non-suppressive T cells, CD4⁺ CD25⁺ Foxp3⁻ cells Teff, and total Tregs were analyzed in all subjects.ResultsThe frequency of aTregs (as well as the ratio of aTregs/Tregs) was significantly lower in the AR patients than the other three groups. In contrast to AR patients, stables 1 and 2 had a higher aTreg/Treg ratio than those in the control group. Although patients with AR had a significantly lower total Tregs than the other three groups, the balance of total Tregs and Teff was similar between patients with and without AR.ConclusionPatients with AR had poorer immunoregulatory properties than those with normal graft functioning, as well as those in the control group. These reduced immunoregulatory properties in patients with AR could lead to graft rejection.     

Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/sirolimus combination in kidney transplantation monitored by surveillance biopsy

BACKGROUND: Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. METHODS: In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. RESULTS: Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. CONCLUSIONS: Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.     

Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation

BACKGROUND: Although innate immunity is crucial to host defense against pathogens, the extent to which innate immune mechanisms participate in the rejection of allogenic tissues in humans is unknown. We hypothesize that activation of innate immunity through Toll-like receptors (TLRs) critically regulates the development of renal allograft rejection. We have recently demonstrated decreased acute rejection in lung transplant recipients heterozygous for either of two functional polymorphisms in TLR4 associated with endotoxin hyporesponsiveness. In the present investigation, we sought to evaluate the role of innate immune activation through TLR4, in either donor or recipient, upon the development of renal allograft rejection. METHODS: Patients and donors were screened for the TLR4 functional polymorphisms (Asp299Gly and Thr399Ile) by polymerase chain reaction (PCR) using sequence-specific primers. RESULTS: The incidence of biopsy-proven acute renal allograft rejection was significantly reduced in patients receiving donor grafts heterozygous for the Asp299Gly or Thr399Ile alleles, when compared with wild type (22% vs. 0%, respectively, p = 0.02). There was no association with recipient TLR4 allele and rejection. CONCLUSIONS: The results suggest activation of innate immunity through TLR4 in the donor kidney contributes to the development of acute rejection after renal transplantation.     

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation

The aim of this study was to evaluate long-term outcome of sirolimus (SRL) rescue in kidney-pancreas transplantation (KPTx). We reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. All patients received antibody (Ab) induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty-five patients (31%) had SRL substituted for MMF for the following indications: (1) acute rejection (AR) of kidney or pancreas despite adequate TAC levels; (2) intolerance of full-dose MMF; (3) rising creatinine; and (4) TAC-induced hyperglycemia. Target SRL and TAC levels were 10 ng/mL and 5 ng/mL, respectively. Mean follow-up was 3 +/- 2 years overall and 1.2 +/- 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival was 97%, 97%, and 95%, 90%, respectively. Of 10 patients switched to SRL for AR, 1 kidney failed from Ab-resistant AR, 1 kidney developed borderline AR, and the other 8 remain AR-free. Seven other patients developed AR despite therapeutic SRL levels; of these, 6 (86%) had mean TAC levels of <4.5 in the month preceding AR. Mean creatinine overall and for the rising creatinine group remained stable. All patients switched to SRL for TAC-induced hyperglycemia or MMF intolerance demonstrated biochemical or clinical improvement. Sirolimus-related infection or other serious adverse events (SAE) were uncommon. In conclusion, KPTx recipients can be safely switched to SRL with long-term stabilization of renal function, excellent graft and patient survival, and no increase in SAE. A minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR.     

Elevated intragraft expression of innate immunity and cell death-related markers is a risk factor for adverse graft outcome

BackgroundMolecules of the innate immune response are increasingly recognized as important mediators in allograft injury during and after kidney transplantation. We therefore aimed to establish the relationship between the expression of these genes at implantation, during an acute rejection (AR) and on graft outcome.MethodsA total of 19 genes, including Toll like receptors (TLRs), complement components and regulators, and apoptosis-related genes were analyzed at the mRNA level by qPCR in 123 biopsies with acute rejection and paired pre-transplantation tissue (n = 75).ResultsBefore transplantation, relative mRNA expression of BAX:BCL2 ratio (apoptosis marker) and several complement genes was significantly higher in tissue samples from deceased donors compared to living donors. During AR, TLRs and complement genes showed an increased expression compared to pre-transplant conditions, whereas complement regulators were decreased. A relatively high TLR4 expression level and BAX:BCL2 ratio during AR in the deceased donor group was associated with adverse graft outcome, independently of clinical risk factors.ConclusionsComplement- and apoptosis-related gene expression is elevated in deceased donor transplants before transplantation. High BAX:BCL2 ratio and TLR4 expression during AR may reflect enhanced intragraft cell death and immunogenic danger signals, and pose a risk factor for adverse graft outcome.     

Can the Toll-like receptors 4 expression in peripheral blood mononuclear cells help assess the effectiveness of immunosuppression and the chance of a future good renal transplant function?

BackgroundA small percentage of peripheral blood mononuclear cells (PBMCs) circulating during the kidney transplantation (KT) period remain in the blood long after transplantation. A part of the PBMCs penetrates the graft.AimTo examine if the choice of immunosuppression may change TLR4ex and how TLR4ex affects the transplant function in the future.MaterialThe study population-143 transplanted patients (pts) (55 females, 88 males), mean age on recruitment day 50.33 ± 12.8 years old, mean BMI 25.04 ± 4.18. 41 pts. experienced delayed graft function (DGF+). 55 pts. were treated with cyclosporine A (CsA) and 88 with tacrolimus (Tac). All were treated with mofetil mycophenolate (MMF). The PBMCs acquisition and starting point of the follow-up (TLR-day) was at least one month after KT.MethodWe investigated averaged mRNA expression of Toll-like receptors 4 (TLR4ex) in non-stimulated peripheral blood mononuclear cells with the use of real-time polymerase chain reaction. The KT pts. (All, Tac, CsA, DGF+) were divided by the respective median of their TLR4ex (lower: L-TLR4ex, higher: H-TLR4ex). Main clinical parameters and transplant biopsy files (if available) were assessed on TLR-day and post follow-up.ResultsWe found that TLR4ex was reduced for a long time in patients who experienced delayed graft function. L-TLR4ex had a higher proportion of DGF+ patients, and patients treated with CsA but lower of those treated with Tac than in H-TLR4ex. The amplitude of changes in renal function parameters (ΔEGFR%/ΔsCr/ΔsCr%) was clearly less favorable for L-TLR4ex. Tacrolimus expressed a stabilizing effect. Both the positive vasculitis score and chronic graft nephropathy were more frequent in the L-TLR4ex group. On TLR-day an association of renal function and Tac concentration with TLR4ex was clear only in the tacrolimus population. The TLR4ex was lower in patients with a future deterioration of the graft function.ConclusionIn kidney transplant recipients the occurrence of DGF results in a long-term reduction of the averaged TLR4ex in PBMC. Tacrolimus exerts a clear, stabilizing, positive and dose-dependent effect on TLR4ex. An improvement in renal transplant function may be expected in KT patients with high TLR4ex. Evaluation of the averaged TLR4ex can be used to assess the efficacy of immunosuppression in the treatment with tacrolimus and to estimate the likelihood of deterioration in renal function.     

Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus

BACKGROUND: Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. METHODS: A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. RESULTS: The mean patient age was 49+/-9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65-13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. CONCLUSION: Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism.     

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation

Sirolimus (SRL) rescue in kidney-pancreas transplantation has not been well described. We reviewed 112 KPTxs performed at our institution between December 3, 1995 and June 27, 2002. All patients received antibody induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. In 35 patients, SRL was substituted for MMF for the following reasons: acute rejection (AR) of kidney or pancreas despite adequate TAC levels, MMF intolerance, increasing creatinine levels, and TAC-induced hyperglycemia. Three-year kidney and pancreas graft survivals were 97% and 90%, respectively. Of 10 patients who were switched to SRL because of AR, one kidney failed because of antibody-resistant AR, and one kidney developed borderline AR; the other eight patients remain AR-free. AR developed in seven other patients despite therapeutic SRL levels; six had TAC levels less than 4.5 ng/mL. The mean creatinine levels overall and for the group with increasing creatinine remained stable. All patients who were switched to SRL for TAC-induced hyperglycemia or MMF intolerance improved. Kidney-pancreas transplant recipients can be safely switched to SRL with excellent graft and patient survival.     

Clinical Outcomes of Everolimus With Reduced-Dose Tacrolimus vs Mycophenolate Mofetil With Standard-Dose Tacrolimus in De Novo ABO-Incompatible Kidney Transplant Recipients: 1-Year Follow-up

BackgroundOne of the major barriers for long-term renal graft survival is considered to be calcineurin inhibitor nephrotoxicity, contributing to chronic graft dysfunction. Thus, recent immunosuppressive strategies are focused on regimens that can reduce or avoid exposure to calcineurin inhibitors. Herein, we carried out a small-scale pilot study to assess whether everolimus (EVR) with reduced-dose tacrolimus (Tac) is an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant compared with mycophenolate mofetil (MMF) with standard-dose Tac.MethodsThis retrospective single-center cohort study included patients who underwent ABO-incompatible kidney transplant at our institution between January 2016 and December 2019. Those whose immunosuppressive regimen was changed by reasons other than rejection during the 1-year follow-up period were excluded.ResultsA total of 24 patients were enrolled in this study: 10 patients who received an EVR with reduced-dose Tac regimen and 14 patients who received an MMF with standard-dose Tac regimen. Tac trough levels in the EVR group were significantly lower than those in the MMF group (P < .001). No patients died or lost their grafts during the follow-up period. There were no significant differences in renal function, proteinuria, and prevalence of hyperlipidemia between the 2 groups at 1 year after transplant. There were no significant differences in the incidence of rejection (acute cellular rejection, steroid-resistant acute cellular rejection, acute antibody-mediated rejection) and infection (cytomegalovirus viremia, cytomegalovirus disease, BK viremia, BK virus nephropathy) between the 2 groups.ConclusionsComparable with MMF with standard-dose Tac, EVR with reduced-dose Tac might be an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant.     

Single-shot antithymocyte globuline and daclizumab induction in simultaneous pancreas and kidney transplant recipient: three-year results

Since 1996, preoperative single-shot dose antithymocyte globuline (ATG) with prednisolone (PRD), mycophenolate mofetile (MMF), and tacrolimus (TAC) is the favorite induction therapy in our center. In a series of 25 first simultaneous pancreas and kidney transplant (SPK) recipients, 5 doses of daclizumab were administered in addition to standard induction. Here we present our 3-year experience. Immunosuppression was started prior to reperfusion consisting of daclizumab (1 mg/kg body weight [bw]), ATG (4-6 mg/kg bw) and 250 mg PRD. After surgery, PRD was reduced gradually, TAC trough levels were between 8-15 ng/mL, MMF was given twice daily (2-3 g/d) as well as 4 further doses dacilzumab every 14 days. After 3 years, patient, pancreas, and kidney graft survival rates are 100%, 84%, and 92%, respectively. Four pancreas grafts were lost (chronic allograft dysfunction, n = 2; recurrent abdominal infection, n = 1; acute rejection [AR] without treatment, n = 1). Both patients suffering from severe infection and untreated AR lost their kidney graft too. During the first 3 months after SPK, 3 AR episodes were observed in 2 patients (8%). After a 3-year period, 8 AR episodes occurred in 7 recipients (28%). AR was treated using PRD (n = 5) or ATG (n = 1). In 1 case, immunosuppression was switched from TAC to sirolimus successfully. Overall, 8 AR episodes occurred in 7 patients (28%) during the first 3 years after SPK. One severe infection led to graft lost 13 months after SPK. In this series, the combination of ATG and daclizumab prevented AR episodes, successfully providing considerable 3-year survival rates.     

Rapidity of fibrosis progression in liver transplant recipients with recurrent hepatitis C is influenced by toll‐like receptor 3 polymorphism

Liver transplantation activates the innate immune system through toll‐like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single‐nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two‐center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real‐time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (−1237T/C and −1486C/T). The CC genotype of TLR3 Leu412Phe in liver recipients was associated with severe recurrence (odds ratio (OR) = 2.01, 95% confidence interval (95% CI) = 1.02‐3.93, p = 0.04). We also analyzed this polymorphism in 72 of their donors but no association was found with severity of HCV recurrence (p = 0.89). Multivariate analysis showed donor age older than 40 yr (OR=2.93; 95% CI = 1.49–5.8, p = 0.002) and the TLR3 Leu412Phe CC genotype (OR=2.02, 95%CI=1.01–4.05, p = 0.046) were independently associated with severe HCV recurrence. Our results show that the TLR3 Leu412Phe CC genotype is independently associated with severity of hepatitis C recurrence after LT.     

Clinical Significance of Mycophenolate Mofetil Withdrawal in Kidney Transplant Recipients

IntroductionThe most effective immunosuppressant protocol in kidney transplantation (KT) is the combination of a calcineurin inhibitor, steroid, and mycophenolate mofetil (MMF) until now. However, MMF withdrawal (MW) is performed for many reasons, and the clinical course of the KT recipients after MW is not clearly known. The purpose of this study was to investigate the clinical outcomes of KT after MW.Materials and MethodsWe retrospectively analyzed the medical records of 626 KT recipients between 2000 and 2016. We evaluated the incidence of biopsy-proven acute rejection (BPAR), graft and patient survival rates, and risk factors related with graft failure.ResultsThe proportion of MW was 33.2% (208 of 626 patients). The median time between KT and MW was 6.4 months (range, 3.2–32.1 months). The common causes of MW were infection (70.7%), hematologic abnormalities (9.1%), and gastrointestinal trouble (7.7%). The incidence of BPAR was significantly higher in the MW group compared with the MMF continuation group (27.4% vs 8.9%, respectively, P < .001). Death-censored graft survival and patient survival rates were significantly lower in the MW group compared with the MMF continuation group (P < .001; P < .001, respectively). In the multivariate analysis, BPAR after MW was an independent risk factor for graft failure (hazard ratio 6.058, 95% confidence interval, 3.172–11.569, P < .001).ConclusionsThe incidence of rejection, graft failure, and patient mortality in KT were high after MW. Therefore, MW should be considered carefully.     

The changes in the expression levels of β-catenin gene in pre- and post- Kidney Transplants

PurposeWnt signaling is an important pathway in kidney development and disease. We aimed to establish the levels of β-catenin expression in CD4⁺ T cells before and after renal transplantation and to associate it with the form of transplant type, rejection, and graft dysfunction.MethodsCD4⁺ T cells were isolated from patients before and after kidney transplantation and their purity was confirmed by flow cytometer. RNA isolation and cDNA synthesis were carried out from these cells. The expression changes of the β-catenin were investigated by real-time polymerase chain reaction (RT-PCR). Changes in the β-catenin protein levels were determined by the western blot analysis.ResultsThe increasing expression levels of β-catenin were detected in 60.8% of the patients 6 months after transplantation when compared to patients before transplantation result. 12 of these 14 patients had no graft rejection. It was observed that 11 of 14 patients with increased β-catenin expression had not graft dysfunction after the transplantation.ConclusionAccording to our results, the increased levels of β-catenin expression after transplantation may have a protective function for kidney survival. To understand this protective mechanism, further analysis of this signaling pathway is necessary.     

Avoidance of Chronic Steroid Therapy in African American Kidney Transplant Recipients Monitored by Surveillance Biopsy: 1-Year Results

African American (AA) kidney recipients receive chronic steroid therapy to improve outcomes, despite their high susceptibility to side effects, particularly diabetes and hypertension. This study evaluated the safety and efficacy of avoidance of chronic steroid therapy in AA compared to non-AA kidney recipients. Two hundred and six kidney recipients were studied; 103 AA recipients versus 103 non-AA recipients. Induction was basiliximab and maintenance was a calcineurin inhibitor plus mycophenolate mofetil or sirolimus. Surveillance biopsies were preformed at 1, 6 and 12 months to assess subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Biopsy-proven acute rejection (AR) and SCAR were treated by methylprednisolone. The primary end point was AR. Secondary end points were graft function, 1-year patient and graft survival. AR was observed in 16% of AA and 13% of non-AA recipients. SCAR at 1 month was significantly higher in the AA group (p=0.04). One-year actual patient and graft survival in the AA group was 96% and 88% and in the non-AA group 97% and 89%, respectively. Avoidance of chronic steroid therapy directed by surveillance biopsies provides equivalent AR, CAN and 1-year patient and graft survival in AA versus non-AA recipients and a 5% incidence of new onset diabetes mellitus. All recipients remain free of chronic steroid therapy. Longer-term follow-up is ongoing.