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Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring.

Fri, 03/08/2013 - 12:21
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Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring.

Transplantation. 2013 Jan 27;95(2):333-40

Authors: Kuypers DR, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, Dobbels F, Vanrenterghem Y, Kanaan N, ADMIRAD Study Team

Abstract
BACKGROUND: With effective agents available to prevent posttransplantation acute organ rejection, medication adherence becomes a key factor for successful treatment outcomes after renal transplantation. A once-daily, modified-release oral formulation of tacrolimus has been developed to simplify dosing and improve medication adherence.
METHODS: Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograft to Advagraf is a randomized multicenter controlled trial to evaluate adherence between a tacrolimus once-daily regimen and a tacrolimus twice-daily regimen using an electronic monitor to document drug intake. After enrolment, all patients continued the twice-daily regimen for 3 months and then were randomized 2:1 between the two formulations and followed for 6 months. Adherence was decomposed into patients' persistence and implementation of each regimen.
RESULTS: Two hundred nineteen patients (45% male; 3±2 years after transplantation) were analyzed (145 once daily and 74 twice daily). At 6 months after randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group remained persistent with the treatment (P=0.0824). Among patients who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the twice-daily group (P=0.0009) took the prescribed number of daily doses. When the patients took the twice-daily regimen, the average percentage of missed doses was 11.7% in the morning and 14.2% in the evening (P=0.0035).
CONCLUSIONS: Regimen implementation of tacrolimus once daily is significantly superior to the twice-daily regimen. There was a residual prevalence of suboptimal adherence that will have to be countered by means other than reformulation and regimen simplification. Electronically compiled dosing histories provide detailed data on patient adherence that can be used for efficient medication management.

PMID: 23263559 [PubMed - indexed for MEDLINE]

Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study.

Fri, 03/08/2013 - 12:21
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Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study.

Transplantation. 2013 Jan 27;95(2):397-402

Authors: van Maarseveen EM, Crommelin HA, Mudrikova T, van den Broek MP, van Zuilen AD

Abstract
BACKGROUND: Ritonavir is an extremely strong inhibitor of P450 cytochrome 3A, which is the main metabolizing enzyme of tacrolimus. Subsequently, the pharmacokinetics of tacrolimus are affected to a large extend by the coadministration of ritonavir in HIV-infected transplant recipients. Therefore, to prevent overexposure directly posttransplantation in HIV-infected patients on ritonavir-containing cART, the predictive value of a pretransplantation pharmacokinetic curve of tacrolimus was explored.
METHODS: A pretransplantation pharmacokinetic model of tacrolimus in these patients was developed, and a posttransplantation dosing advice was established for each individual patient. The pharmacokinetic population parameters were compared with HIV-negative patients, and predictive value of the pretransplantation curves was assessed in patients after the transplantation procedure.
RESULTS: No significant difference was found between the model-predicted and actual posttransplantation 24 h-tacrolimus levels (14.6 vs. 17.8 ng/mL, P=0.19). As the simulated pharmacokinetic curves lacked an absorption peak every 12 h, the mean 12 h-AUC was approximately 40 % lower compared with AUC's reported in HIV-negative recipients, when similar trough levels were targeted.
CONCLUSION: In conclusion, pretransplantation curves of tacrolimus seem a promising tool to prevent overexposure directly posttransplantation in patients on ritonavir-containing cART and raising trough levels to achieve an exposure equivalent to HIV-negative recipients is suggested.

PMID: 23250333 [PubMed - indexed for MEDLINE]

Preformed complement-activating low-level donor-specific antibody predicts early antibody-mediated rejection in renal allografts.

Fri, 03/08/2013 - 12:21
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Preformed complement-activating low-level donor-specific antibody predicts early antibody-mediated rejection in renal allografts.

Transplantation. 2013 Jan 27;95(2):341-6

Authors: Lawrence C, Willicombe M, Brookes PA, Santos-Nunez E, Bajaj R, Cook T, Roufosse C, Taube D, Warrens AN

Abstract
BACKGROUND.: Donor-specific anti-HLA antibodies (DSA) are a major cause of alloimmune injury. Transplant recipients with negative complement-dependent cytotoxic crossmatch (CDC-XM) and donor cell-based flow cytometric crossmatch (flow-XM) but low level DSA (i.e., by Luminex) have worse outcomes compared with nonsensitized patients. The aim of this study was to establish whether complement-activating ability in this low-level DSA, present before transplantation, as determined by this technique is important in dictating pathogenicity. METHODS.: We retrospectively studied 52 patients with preformed DSA detected by single-antigen flow cytometric fluorescent beads (SAFBs). Patients were transplanted using a steroid-sparing regimen consisting of alemtuzumab induction, 1 week of corticosteroids and tacrolimus monotherapy.Fifteen (29%) of 52 patients experienced antibody-mediated rejection (AMR), whereas 37 (71%) patients did not. There were no demographic differences between patients with AMR and those without. Pretransplant sera were retested using a modified (SAFB) assay, which detects the presence of the complement fragment C4d as a result of DSA-induced complement activation. RESULTS.: C4d+DSA were detected in 10 (19%) of 52 patients. Biopsy-proven AMR occurred in 7 (70%) of the 10 patients with C4d+DSA and in 8 (19%) of 42 patients with C4d-DSA. AMR-free survival was worse in patients with C4d+DSA (P<0.001). CONCLUSIONS.: The ability of preformed, low-level, DSA to trigger C4d fixation in vitro in patients with negative conventional crossmatch tests is predictive for AMR. C4d SAFB is potentially a powerful tool for risk stratification prior to transplantation and may allow identification of unacceptable donor antigens, or patients who may require enhanced immunosuppression.

PMID: 23197178 [PubMed - indexed for MEDLINE]

Allogeneic hematopoietic stem cell transplantation for patients with mildly reduced renal function as defined based on creatinine clearance before transplantation.

Fri, 03/08/2013 - 12:21
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Allogeneic hematopoietic stem cell transplantation for patients with mildly reduced renal function as defined based on creatinine clearance before transplantation.

Ann Hematol. 2013 Jan;92(2):255-60

Authors: Oshima K, Kanda Y, Nanya Y, Tanaka M, Nakaseko C, Yano S, Fujisawa S, Fujita H, Yokota A, Takahashi S, Kanamori H, Okamoto S, Kanto Study Group for Cell Therapy

Abstract
While renal comorbidity is generally defined by the serum creatinine level, the creatinine clearance rate (Ccr) is a more accurate indicator of renal function. Therefore, we retrospectively assessed how mildly reduced renal function as defined based on Ccr affects the outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Patients who underwent allogeneic HSCT at the eight institutes of the Kanto Study Group for Cell Therapy were included in this study. Based on the corrected Ccr, patients were classified into group 0 (n = 440,  ≥ 90 mL/min/1.73 m(2)), group 1 (n = 56, 60-89 mL/min/1.73 m(2)), or group 2 (n = 11, 30-59 mL/min/1.73 m(2)). Therefore, 67 patients were considered to have mild renal impairment, whereas only 2 had a serum creatinine level higher than 1.2 mg/dL. Twenty-eight patients required hemodialysis after HSCT, with 5.5, 5.4, and 9.1 % in groups 0, 1, and 2, respectively (p = 0.65). The incidence of non-relapse mortality (NRM) was higher in group 2, although these differences were not statistically significant probably due to the small sample size (23.7, 28.2, and 47.2 % at 3 years, p = 0.20). In conclusion, NRM may be associated with mildly reduced renal function before allogeneic HSCT, which cannot be detected by measurement of the serum creatinine level alone.

PMID: 23053182 [PubMed - indexed for MEDLINE]

Posterior reversible encephalopathy syndrome in setting of postobstructive diuresis and persistent hypocalcemia.

Fri, 03/08/2013 - 12:21
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Posterior reversible encephalopathy syndrome in setting of postobstructive diuresis and persistent hypocalcemia.

Ren Fail. 2012;34(9):1166-9

Authors: Gera DN, Patil SB, Parikh M, Modi PR, Kute VB, Trivedi HL

Abstract
Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiographic entity of heterogenous etiologies, which are grouped together because of similar findings on neuroimaging studies, associated with similar symptom complex of headache, vision loss, altered mentation, and seizures. In this report, we describe a case of PRES in setting of postobstructive diuresis in a 5-year-old male child, whose solitary functioning kidney was obstructed by a 1.6-cm radio-opaque stone, who after percutaneous nephrostomy (PCN) diversion developed persistent hypocalcemia which persisted despite maximum replacement by iv calcium gluconate drip, and the child developed repeated generalized tonic clonic convulsions and became unconscious for 4 days. Computerized tomography (CT) scan of the brain showed typical hypodensities in bilateral occipitoparietal regions suggesting PRES. Ultimately, over a period of 4 days, his hypocalcemia could be corrected and the child was neurologically normal on the 5th day. CT scan of the brain after a month was free of any hypodensities.

PMID: 22978361 [PubMed - indexed for MEDLINE]

Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years.

Thu, 03/07/2013 - 12:10

Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years.

Int J Cancer. 2013 Mar 5;

Authors: Christensson A, Savage C, Sjoberg DD, Cronin AM, O'Brien MF, Lowrance W, Nilsson PM, Vickers AJ, Russo P, Lilja H

Abstract
Patients with chronic renal failure show a greater incidence of malignancies. We evaluated whether moderately impaired renal function at baseline influenced risk of all cancers during long-term follow in young persons. Our cohort included 33,346 subjects, aged 26-61 years at baseline, in a representative, population-based study enrolling subjects from 1974 to 1992. Median follow-up time was 28 years. Plasma creatinine was analysed as a single measure at baseline. Incident cases of cancer were identified from the Swedish Cancer Registry. We studied 24,552 subjects from the cohort. To account for the unique sampling design, participants were divided by sex and age at baseline into 1,132 older men (age 60), 14,254 younger men (age 40-52), 7,498 older women (age 47-57) and 1,688 younger women (age 35-43). Glomerular filtration rate (GFR) was estimated using the CKD-EPI formula. Patients were classified as having either normal to mildly impaired kidney function (eGFR≥60 mL/min/1.73m2 ), or moderate kidney dysfunction (eGFR<60 mL/min/1.73m2 ). We calculated the risk of all cancers using competing risks regression. Overall, 6,595 participants were diagnosed with cancer, and 854 subjects (3.5%) had moderately impaired renal dysfunction at baseline. There was a significant association between moderately decreased GFR and subsequent risk of kidney cancer in younger men (hazard ratio, 3.38; 95% CI, 1.48 to 7.71; P=0.004). However, we found no association with overall long-term cancer risk. Our confirmation of an association between moderately impaired renal function and risk of kidney cancer in younger men requires further exploration of high-risk groups and biological mechanisms. © 2013 Wiley Periodicals, Inc.

PMID: 23463659 [PubMed - as supplied by publisher]

Reno-portal anastomosis as an approach to pediatric kidney transplantation in the setting of inferior vena cava thrombosis.

Thu, 03/07/2013 - 12:10

Reno-portal anastomosis as an approach to pediatric kidney transplantation in the setting of inferior vena cava thrombosis.

Pediatr Transplant. 2013 Mar 6;

Authors: Cauley RP, Potanos K, Fullington N, Lillehei C, Vakili K, Kim HB

Abstract
In pediatric renal transplantation in the setting of IVC thrombosis, the retrohepatic IVC or gonadal veins are often used for outflow. However, if use of systemic venous outflow is unsuccessful, options become limited. We report the use of the portal vein for venous outflow in kidney retransplantation in the setting of IVC thrombosis. The patient is a 19-month-old male who developed end-stage renal failure at seven months of age secondary to hypotension after spontaneous rupture of an accessory renal vein. The IVC was occluded during emergent laparotomy, and the patient developed extensive IVC thrombosis. The first two transplant attempts used the retrohepatic IVC for venous outflow. Despite good initial flow, in both instances the renal vein thrombosed on post-operative day 1. In an unsuccessful salvage attempt of the second transplant, a reno-portal anastomosis was performed. With few options for vascular access, a third transplant was attempted. The reno-portal stump from the second transplant was used for outflow. The patient recovered well from his third transplant (creatinine 0.6 mg/dL 35 months post-surgery), demonstrating that the portal vein can be used for outflow in cases of extensive IVC thrombosis.

PMID: 23461835 [PubMed - as supplied by publisher]

Renal Transplantation in Nepal: Beginning of a new era!

Thu, 03/07/2013 - 12:10

Renal Transplantation in Nepal: Beginning of a new era!

Nephrology (Carlton). 2013 Mar 5;

Authors: Shah DS, Shrestha S, Kafle MP

Abstract
AIM: To assess the first year outcomes in terms of patient survival rate, graft survival rate and secondary outcomes after starting the first live related renal transplant in Tribhuvan University Teaching Hospital, Nepal. METHODS: A retrospective analysis was done of the first 70 renal transplants, who have completed a minimum of 1 year of follow up. All recipients were on Tacrolimus, Mycophenolate Mofetil, and corticosteroids. RESULTS: Patient and graft survival rate at the end of one year was 94.3% (95% CI 86.2 - 97.8).Mean serum creatinine and e GFR at 1 year was 115 ± 25 μmol/L (range 63-192) and 66 ± 15 ml/min/1.73 m2 (range 37- 102) respectively. 22 episodes of biopsy proven acute rejection occurred in 18 recipients (25.7%). 3 patients (4.2%) had acute tubular necrosis; however, only one (1.4%) had delayed graft function. One patient, with focal segmental glomerulosclerosis had recurrence of native kidney disease. 32 episodes of urinary tract infection were observed in 22 recipients (31.4%), and Escherichia coli was the most commonly isolated organism, 17 (53.1%) out of 32 episodes. New onset diabetes mellitus after transplant occurred in 16 recipients (22.8%). CONCLUSION: One year patient survival, graft survival and secondary outcomes of our kidney transplant recipients, with our limited facilities, were within acceptable limits.

PMID: 23461620 [PubMed - as supplied by publisher]

Effects of Immunosuppression on Circulating AAV Capsid-Specific T cells in Humans.

Thu, 03/07/2013 - 12:10

Effects of Immunosuppression on Circulating AAV Capsid-Specific T cells in Humans.

Hum Gene Ther. 2013 Mar 6;

Authors: Parzych EM, Liu H, Yin X, Liu Q, Wu TL, Podsakoff G, High KA, Levine MH, Ertl HC

Abstract
In humans AAV-mediated gene transfer is followed by expansion of AAV capsid-specific T cells, evidence of cell damage and loss of transgene product expression, implicating immunogical rejection of vector transduced cells, which may be prevented by immunosuppressive drugs. We undertook this study to assess the effect of immunosuppression (IS) used for organ transplantation on immune responses to AAV capsid antigens. Recipients of liver or kidney transplants were tested prior to and four weeks following induction of IS in comparison to matched samples from healthy human adults and an additional cohort with co-morbid conditions similar to those of the transplant patients. Our data show that transplant patients and comorbid controls have markedly higher frequencies of circulating AAV capsid-specific T cells compared to healthy adults. On average, IS resulted in a reduction of AAV-specific CD4+ T cells, while numbers of circulating CD8+ effector and central memory T cells tended to increase. Independent of the type of transplant or the IS regimens, the trend of AAV capsid-specific T cell responses following drug treatment varied; in some patients responses were unaffected while others showed decreases or even pronounced increases casting doubt on the usefulness of prophylactic IS for AAV vector recipients.

PMID: 23461589 [PubMed - as supplied by publisher]

Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: A tertiary case series.

Thu, 03/07/2013 - 12:10

Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: A tertiary case series.

Pediatr Transplant. 2013 Mar 6;

Authors: Forbes TA, Bradbury MG, Goodship TH, McKiernan PJ, Milford DV

Abstract
We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondary to complement factor H mutation: one isolated renal transplant; one previously reported isolated liver transplant; and one combined liver and kidney transplant. All three patients were treated prior to the licensing of eculizumab for this condition, and all have had favourable outcomes with maintenance of graft function for years following transplantation. We discuss the evolution of transplantation therapy for aHUS over the last two decades. Transplantation decision-making in aHUS has evolved over this time with expanding knowledge of pathophysiology and genetics, alongside refined plasma exchange and anticoagulation protocols and improved centre experience. Our cases demonstrate how individual patient factors within this heterogeneous condition also underlie transplantation decisions and outcomes. Whilst our cases demonstrate that transplantation in aHUS can be a successful long-term treatment providing good quality of life, worldwide experience has proven that most curative treatment for aHUS strategies represents significant risks. Whether new pharmacotherapies such as eculizumab will alter this risk is yet to be determined.

PMID: 23461281 [PubMed - as supplied by publisher]

Mesenchymal stem cells attenuate peritoneal injury through secretion of TSG-6.

Thu, 03/07/2013 - 12:10
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Mesenchymal stem cells attenuate peritoneal injury through secretion of TSG-6.

PLoS One. 2012;7(8):e43768

Authors: Wang N, Li Q, Zhang L, Lin H, Hu J, Li D, Shi S, Cui S, Zhou J, Ji J, Wan J, Cai G, Chen X

Abstract
BACKGROUND: Mesothelial cell injury plays an important role in peritoneal fibrosis. Present clinical therapies aimed at alleviating peritoneal fibrosis have been largely inadequate. Mesenchymal stem cells (MSCs) are efficient for repairing injuries and reducing fibrosis. This study was designed to investigate the effects of MSCs on injured mesothelial cells and peritoneal fibrosis.
METHODOLOGY/PRINCIPAL FINDINGS: Rat bone marrow-derived MSCs (5 × 10(6)) were injected into Sprague-Dawley (SD) rats via tail vein 24 h after peritoneal scraping. Distinct reductions in adhesion formation; infiltration of neutrophils, macrophage cells; number of fibroblasts; and level of transforming growth factor (TGF)-β1 were found in MSCs-treated rats. The proliferation and repair of peritoneal mesothelial cells in MSCs-treated rats were stimulated. Mechanically injured mesothelial cells co-cultured with MSCs in transwells showed distinct increases in migration and proliferation. In vivo imaging showed that MSCs injected intravenously mainly accumulated in the lungs which persisted for at least seven days. No apparent MSCs were observed in the injured peritoneum even when MSCs were injected intraperitoneally. The injection of serum-starved MSCs-conditioned medium (CM) intravenously reduced adhesions similar to MSCs. Antibody based protein array of MSCs-CM showed that the releasing of TNFα-stimulating gene (TSG)-6 increased most dramatically. Promotion of mesothelial cell repair and reduction of peritoneal adhesion were produced by the administration of recombinant mouse (rm) TSG-6, and were weakened by TSG-6-RNA interfering.
CONCLUSIONS/SIGNIFICANCE: Collectively, these results indicate that MSCs may attenuate peritoneal injury by repairing mesothelial cells, reducing inflammation and fibrosis. Rather than the engraftment, the secretion of TSG-6 by MSCs makes a major contribution to the therapeutic benefits of MSCs.

PMID: 22912904 [PubMed - indexed for MEDLINE]

Human amniotic fluid stem cell injection therapy for urethral sphincter regeneration in an animal model.

Thu, 03/07/2013 - 12:10
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Human amniotic fluid stem cell injection therapy for urethral sphincter regeneration in an animal model.

BMC Med. 2012;10:94

Authors: Kim BS, Chun SY, Lee JK, Lim HJ, Bae JS, Chung HY, Atala A, Soker S, Yoo JJ, Kwon TG

Abstract
BACKGROUND: Stem cell injection therapies have been proposed to overcome the limited efficacy and adverse reactions of bulking agents. However, most have significant limitations, including painful procurement, requirement for anesthesia, donor site infection and a frequently low cell yield. Recently, human amniotic fluid stem cells (hAFSCs) have been proposed as an ideal cell therapy source. In this study, we investigated whether periurethral injection of hAFSCs can restore urethral sphincter competency in a mouse model.
METHODS: Amniotic fluids were collected and harvested cells were analyzed for stem cell characteristics and in vitro myogenic differentiation potency. Mice underwent bilateral pudendal nerve transection to generate a stress urinary incontinence (SUI) model and received either periurethral injection of hAFSCs, periurethral injection of Plasma-Lyte (control group), or underwent a sham (normal control group).For in vivo cell tracking, cells were labeled with silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate (MNPs@SiO2 (RITC)) and were injected into the urethral sphincter region (n = 9). Signals were detected by optical imaging. Leak point pressure and closing pressure were recorded serially after injection.Tumorigenicity of hAFSCs was evaluated by implanting hAFSCs into the subcapsular space of the kidney, followed two weeks later by retrieval and histologic analysis.
RESULTS: Flow activated cell sorting showed that hAFSCs expressed mesenchymal stem cell (MSC) markers, but no hematopoietic stem cell markers. Induction of myogenic differentiation in the hAFSCs resulted in expression of PAX7 and MYOD at Day 3, and DYSTROPHIN at Day 7. The nanoparticle-labeled hAFSCs could be tracked in vivo with optical imaging for up to 10 days after injection. Four weeks after injection, the mean LPP and CP were significantly increased in the hAFSC-injected group compared with the control group. Nerve regeneration and neuromuscular junction formation of injected hAFSCs in vivo was confirmed with expression of neuronal markers and acetylcholine receptor. Injection of hAFSCs caused no in vivo host CD8 lymphocyte aggregation or tumor formation.
CONCLUSIONS: hAFSCs displayed MSC characteristics and could differentiate into cells of myogenic lineage. Periurethral injection of hAFSCs into an SUI animal model restored the urethral sphincter to apparently normal histology and function, in absence of immunogenicity and tumorigenicity.

PMID: 22906045 [PubMed - indexed for MEDLINE]

The organ transplantation act and recent trends in Korea.

Wed, 03/06/2013 - 11:29

The organ transplantation act and recent trends in Korea.

Asia Pac J Public Health. 2013 Mar;25(2):209-13

Authors: Joo HN

Abstract
The Organ Transplantation Act, including transplantation of organs from brain-dead donors, entered into force in Korea on February 9, 2000. This article introduces the Organ Transplantation Act, focusing on scope of the Act, determination of brain death, removal of organs from brain-dead or deceased donors, removal from living donors, organ allocation, and prohibition of trade in human organs. Especially, some primary ethical dilemmas surrounding organ allocation arise from the shortage of available organs. The primary ethical problems surrounding organ allocation are as follows. A key purpose of the organ donation incentive system is to increase the number of organ transplants from brain-dead donors. In particular, the priority for kidney patient was allowed in consideration of doctor's strong desire to increase the brain-dead donors. Also, the organ allocation criteria based on the organ donation incentive system appear unfair, especially for the kidney patient, because the criteria do not fit the principles of distributive justice. In the future, the organ donation incentive system itself may need to be reexamined.

PMID: 23460587 [PubMed - in process]

Genetic variants of FOXP3 influence graft survival in kidney transplant patients.

Wed, 03/06/2013 - 11:29

Genetic variants of FOXP3 influence graft survival in kidney transplant patients.

Hum Immunol. 2013 Feb 28;

Authors: Engela AU, Boer K, Roodnat JI, Peeters AM, Eilers PH, Kal-van Gestel JA, Rivadeneira F, Weimar W, Baan CC

Abstract
FOXP3+ regulatory T cells (Treg) play a role in controlling alloreactivity. It has been shown that short (GT)n dinucleotide repeats (⩽ (GT)15; S) in the promoter region of the FOXP3 gene enhance the promoter activity when compared to long (GT)n repeats (⩾ (GT)16; L). The present study retrospectively investigated the influence of this (GT)n FOXP3 gene polymorphism on renal allograft survival. A total of 599 consecutive first-time kidney transplant patients (median follow-up time 7.7 years) were subdivided according to their FOXP3 genotype into the S-genotype group (SG) and the L-genotype group (LG). The SG was superior to the LG in both general graft survival censored for death (logrank test, p = 0.013) and graft survival following acute rejection (p = 0.021). Multivariate analysis defined the (GT)n FOXP3 dinucleotide repeat polymorphism as an independent factor and confirmed an advantage for the SG in renal allograft survival (HR = 0.67, 95% CI 0.48 - 0.94, p = 0.02). This gene association study identified a beneficial effect of FOXP3 genetic variants on graft survival in kidney transplant patients.

PMID: 23459079 [PubMed - as supplied by publisher]

Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis.

Wed, 03/06/2013 - 11:29

Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis.

Pharmacogenet Genomics. 2013 Mar 1;

Authors: Zuo XC, Ng CM, Barrett JS, Luo AJ, Zhang BK, Deng CH, Xi LY, Cheng K, Ming YZ, Yang GP, Pei Q, Zhu LJ, Yuan H, Liao HQ, Ding JJ, Wu D, Zhou YN, Jing NN, Huang ZJ

Abstract
OBJECTIVE: Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients. MATERIALS AND METHODS: Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1). CONCLUSION: This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.

PMID: 23459029 [PubMed - as supplied by publisher]

Effects of intravenous administration of pentoxifylline in pancreatic ischaemia-reperfusion injury.

Wed, 03/06/2013 - 11:29

Effects of intravenous administration of pentoxifylline in pancreatic ischaemia-reperfusion injury.

HPB (Oxford). 2012 Dec 17;

Authors: Le Campion ER, Jukemura J, Coelho AM, Patzina R, Carneiro D'Albuquerque LA

Abstract
BACKGROUND: Therapeutic strategies to reduce the occurrence of pancreatic ischaemia-reperfusion (I-R) injury might improve outcomes in human pancreas and kidney transplantation. In addition to its haemorrheologic effects, pentoxifylline has an anti-inflammatory effect by inhibiting NF-κB activation. This group has previously demonstrated that pentoxifylline induces an anti-inflammatory response in acute pancreatitis and liver I-R models. This led to the hypothesis that pentoxifylline might reduce pancreatic and renal lesions and the systemic inflammatory response in pancreatic I-R injury. The aim of this experimental study was to evaluate the effect of pentoxifylline administration in a rat model of pancreatic I-R injury. METHODS: Pancreatic I-R was performed in Wistar rats over 1 h by clamping the splenic vessels. The animals submitted to I-R were divided into two groups: Group 1 (n = 20, control) rats received saline solution administered i.v. at 45 min after ischaemia, and Group 2 (n = 20) rats received pentoxifylline (25 mg/kg) administered i.v. at 45 min after ischaemia. Blood samples were collected to enable the determination of amylase, creatinine, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-10. Pancreatic malondialdehyde (MDA) content, pancreas histology and pulmonary myeloperoxidase (MPO) were also assessed. RESULTS: Significant reductions in serum TNF-α, IL-6 and IL-10 were observed in Group 2 compared with Group 1 (P < 0.05). No differences in pancreatic MDA content or serum amylase levels were observed between the two groups. The histologic score was significantly lower in pentoxifylline-treated animals, denoting less severe pancreatic histologic damage. CONCLUSIONS: Pentoxifylline administration reduced the systemic inflammatory response, the pancreatic histological lesion and renal dysfunction in pancreatic I-R injury and may be a useful tool in pancreas and kidney transplantation.

PMID: 23458290 [PubMed - as supplied by publisher]

A fatal case of prostatic abscess in a post-renal transplant recipient caused by Cladophialophora carrionii.

Wed, 03/06/2013 - 11:29
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A fatal case of prostatic abscess in a post-renal transplant recipient caused by Cladophialophora carrionii.

Saudi J Kidney Dis Transpl. 2013 Jan;24(1):76-9

Authors: Kindo AJ, Ramalakshmi S, Giri S, Abraham G

Abstract
Fungal infection secondary to renal transplantation poses a significant threat to the life of the recipient with a high rate of morbidity and mortality. A high index of suspicion is necessary for early diagnosis of fungal infections in such patients. We herein report a fatal case of prostatic abscess in a post-renal transplant recipient.

PMID: 23354196 [PubMed - indexed for MEDLINE]

Single-center experience on renal transplantation in primary focal and segmental glomerulosclerosis using hematopoietic stem cell transplantation in thymus, bone marrow, portal and peripheral circulation.

Wed, 03/06/2013 - 11:29
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Single-center experience on renal transplantation in primary focal and segmental glomerulosclerosis using hematopoietic stem cell transplantation in thymus, bone marrow, portal and peripheral circulation.

Saudi J Kidney Dis Transpl. 2013 Jan;24(1):15-21

Authors: Vanikar AV, Trivedi HL, Shah PR, Kanodia KV, Patel RD, Modi PR, Dave SD, Singhai AM, Shah VR, Trivedi VB, Shankar V

Abstract
Recurrence of primary focal segmental glomerulosclerosis (FSGS) is an important cause of graft loss after renal transplantation (RTx). We report our experience in 34 patients with primary FSGS who underwent RTx between April 1999 and June 2009, using hematopoietic stem cell transplantation (HSCT). They belonged to four groups: group 1 (n = 12) received high-dose HSCT in periphery, thymus, bone-marrow, and portal circulation with low-dose non-myeloablative conditioning; group 2 (n = 7) was modified with HSCT without marrow/thymic infusion; and group 3 (n = 3) received HSCT and proteasome inhibitor Bortezomib replacing conditioning. Group 4 (n = 12), were controls who opted for RTx under standard triple-drug immunosuppression. Patient/donor demographics were comparable in all. No recurrence was noted in group 1 with mean follow-up of 8.1 years, whereas 28.6% of group 2, 33.3% of group 3, and 36.4% of group 4 had recurrence over mean follow-up of 2.6, 1.1, and 6.5 years, respectively. Mean serum creatinine was 1.62, 1.69, 1.41, and 1.73 mg%, respectively. Rejections were noted in 41.7%, 28.6%, 0%, and 45.5% grafts, respectively. Groups 1 and 4 had 25% patient loss each, group 2 had 28.6% loss, and no loss was observed in group 3. Graft loss was noted in 33.3% in group 1, 14.3% in group 2, nil in group 3, and 16.7% in the last group. Recurrent FSGS was prevented in RTx with HSCT in thymic, marrow infusion under low-dose non-myeloablative conditioning compared to controls and Bortezomib group, thus suggesting potential role of central tolerance in FSGS.

PMID: 23354186 [PubMed - indexed for MEDLINE]

Focal and segmental glomerulosclerosis in renal allograft recipients: a clinico-pathologic study of 37 cases.

Wed, 03/06/2013 - 11:29
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Focal and segmental glomerulosclerosis in renal allograft recipients: a clinico-pathologic study of 37 cases.

Saudi J Kidney Dis Transpl. 2013 Jan;24(1):8-14

Authors: Gupta R, Sharma A, Mahanta PJ, Agarwal SK, Dinda AK

Abstract
Focal and segmental glomerulosclerosis (FSGS) in renal allografts may occur as a recurrence of primary FSGS, as a de novo phenomenon or as a complication of calcineurin inhibitor toxicity. There are very few studies in the literature describing the clinico-pathologic characteristics of FSGS in renal allografts. To the best of our knowledge, no such study exists from the Indian subcontinent. Thirty-seven cases showing FSGS, of 426 transplant biopsies performed over a 4-year period (2006-2009), were included in this study. The pre- and post-transplant clinical data were noted. FSGS was classified as per the Columbia scheme. Appropriate statistical tests were applied. The age of the study patients ranged from 13 to 54 years, with a male preponderance. Thirty-five patients (94.6%) were diagnosed as FSGS more than 12 months after transplantation. All the patients presented with renal dysfunction (median serum creatinine 2.8 mg/dL) and detectable proteinuria at the time of diagnosis. Histologically, FSGS-NOS (70.3%) was observed as the most common subtype, followed by collapsing and perihilar varieties (13.5% each). Most of the biopsies (83.7%) showed grade-2 to -3 interstitial fibrosis and tubular atrophy. Follow-up data were available in 27 patients (73%), of whom 12 (44.4%) had graft loss with dialysis-dependent state at last follow-up. FSGS is one of the important causes of graft dysfunction, especially late in the post-transplantation period in cases of de novo FSGS. The long-term outcome of renal allografts developing this glomerular pathology is quite dismal, with a significant proportion of patients suffering graft loss.

PMID: 23354185 [PubMed - indexed for MEDLINE]

Post-transplantation lymphoproliferative disorders in renal vs. simultaneous renal-pancreas allograft recipients: a survey and analysis of data from the literature.

Wed, 03/06/2013 - 11:29
Related Articles

Post-transplantation lymphoproliferative disorders in renal vs. simultaneous renal-pancreas allograft recipients: a survey and analysis of data from the literature.

Saudi J Kidney Dis Transpl. 2013 Jan;24(1):1-7

Authors: Khedmat H, Taheri S

Abstract
The epidemiology and other aspects of post-transplantation lymphoproliferative disorders (PTLD) are different in different transplant populations. In this study, we sought to determine the clinical, histopathological and various other features of PTLD in recipients of pancreas-renal allografts and to compare their data with renal-only transplant patients, based on the current available literature. We conducted a comprehensive search for the available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders after renal and simultaneous pancreas-renal (SPR) transplantations. A total of 229 recipients of renal and pancreas-renal allografts were included in the analysis. Localizations for SPR recipients were significantly higher than renal recipients in the pancreas (P <0.0001), skin (P = 0.035), liver (P = 0.043) and bone marrow (P = 0.022). Involvement of lymph nodes was more prevalent in renal recipients (P = 0.046). The occurrence of metastasis was more common among SPR recipients (P = 0.005). Hodgkin's and Hodgkin's-like PTLD were also more prevalent among SPR transplant patients (P <0.0001). Time to development of PTLD was significantly shorter among recipients of SPR (P <0.0001). In this study of international data, we found that PTLD in SPR transplant recipients have various characteristics in their site of involvement, disease presentation time and histopathological features. However, no difference in outcome was detected in these groups of PTLD patients. Future studies with larger study populations are needed for confirming and extending our study results.

PMID: 23354184 [PubMed - indexed for MEDLINE]

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