Journal of Transplantation

Publications in this journal

• Article: Sirolimus enhances cyclosporine a-induced cytotoxicity in human renal glomerular mesangial cells.

  Séin O'Connell, Craig Slattery, Michael P Ryan, Tara McMorrow
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  ABSTRACT: End Stage Renal Disease (ESRD) is an ever increasing problem worldwide. However the mechanisms underlying disease progression are not fully elucidated. This work addressed nephrotoxicity induced by the immunosuppressive agents' cyclosporine A (CsA) and sirolimus (SRL). Nephrotoxicity is the major limiting factor in long term use of CsA. SRL causes less nephrotoxicity than CsA. Therefore investigations into the differential effects of these agents may identify potential mechanisms of nephrotoxicity and means to prevent ESRD induced by therapeutic drugs. Using ELISA, Western blotting, quantitative PCR and a reporter gene assay we detailed the differential effects of CsA and SRL in human renal mesangial cells. CsA treatment increased profibrotic TGF-β1 secretion in human mesangial cells whereas SRL did not, indicating a role for TGF-β in CsA toxicity. However we observed a synergistic nephrotoxic effect when CsA and SRL were co-administered. These synergistic alterations may have been due to an increase in CTGF which was not evident when the immunosuppressive drugs were used alone. The CsA/SRL combination therapy significantly enhanced Smad signalling and altered the extracellular matrix regulator matrix metalloproteinase 9 (MMP-9). Inhibition of the ERK 1/2 pathway, attenuated these CsA/SRL induced alterations indicating a potentially significant role for this pathway.
  Journal of Transplantation 01/2012; 2012:980910.
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  Available from: PubMed Central

  Article: Evaluation of the medically complex living kidney donor.

  Yasar Caliskan, Alaattin Yildiz
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  ABSTRACT: Due to organ shortage and difficulties for availability of cadaveric donors, living donor transplantation is an important choice for having allograft. Live donor surgery is elective and easier to organize prior to starting dialysis thereby permitting preemptive transplantation as compared to cadaveric transplantation. Because of superior results with living kidney transplantation, efforts including the usage of "Medically complex living donors" are made to increase the availability of organs for donation. The term "Complex living donor" is probably preferred for all suboptimal donors where decision-making is a problem due to lack of sound medical data or consensus guidelines. Donors with advanced age, obesity, asymptomatic microhematuria, proteinuria, hypertension, renal stone disease, history of malignancy and with chronic viral infections consist of this complex living donors. This medical complex living donors requires careful evaluation for future renal risk. In this review we would like to present the major issues in the evaluation process of medically complex living kidney donor.
  Journal of Transplantation 01/2012; 2012:450471.
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  Available from: PubMed Central

  Article: Inflammation and microvasculopathy in renal ischemia reperfusion injury.

  Daniel Patschan, S Patschan, G A Müller
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  ABSTRACT: Acute renal failure (ARF) severely worsens prognosis of hospitalized patients. The most frequent cause of intrarenal ARF is transient or prolonged renal hypoperfusion (ischemia). Ischemia primarily affects the function and structure of tubular epithelial cells, which, in severe cases, is characterized by epithelial cell necrosis. Nevertheless, ischemia does not exclusively lead to alterations of epithelial cells but also causes interstitial inflammation and interstitial microvasculopathy. Both inflammation and microvasculopathy are particularly important in terms of postischemic kidney repair. Postischemic microvasculopathy is characterized by endothelial cell swelling with subsequent microvascular occlusion. Thus, reperfusion is inhibited (no-reflow phenomenon). Such endothelial cell dysfunction offers new therapeutic perspectives in ischemic ARF. Newer observations point towards the role of the so-called endothelial progenitor cells (EPCs) in the treatment of ARF. Systemic administration of EPCs to mice with bilateral renal ischemia mitigates postischemic endothelial cell dysfunction and protects animals from acute renal failure.
  Journal of Transplantation 01/2012; 2012:764154.
• Article: Islet β-Cell Mass Preservation and Regeneration in Diabetes Mellitus: Four Factors with Potential Therapeutic Interest.

  Jose Manuel Mellado-Gil, Nadia Cobo-Vuilleumier, Benoit R Gauthier
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  ABSTRACT: Islet β-cell replacement and regeneration are two promising approaches for the treatment of Type 1 Diabetes Mellitus. Indeed, the success of islet transplantation in normalizing blood glucose in diabetic patients has provided the proof of principle that cell replacement can be employed as a safe and efficacious treatment. Nonetheless, shortage of organ donors has hampered expansion of this approach. Alternative sources of insulin-producing cells are mandatory to fill this gap. Although great advances have been achieved in generating surrogate β-cells from stem cells, current protocols have yet to produce functionally mature insulin-secreting cells. Recently, the concept of islet regeneration in which new β-cells are formed from either residual β-cell proliferation or transdifferentiation of other endocrine islet cells has gained much interest as an attractive therapeutic alternative to restore β-cell mass. Complementary approaches to cell replacement and regeneration could aim at enhancing β-cell survival and function. Herein, we discuss the value of Hepatocyte Growth Factor (HGF), Glucose-Dependent Insulinotropic Peptide (GIP), Paired box gene 4 (Pax4) and Liver Receptor Homolog-1 (LRH-1) as key players for β-cell replacement and regeneration therapies. These factors convey β-cell protection and enhanced function as well as facilitating proliferation and transdifferentiation of other pancreatic cell types to β-cells, under stressful conditions.
  Journal of Transplantation 01/2012; 2012:230870.
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  Available from: PubMed Central

  Article: The major histocompatibility complex in transplantation.

  Marco Antonio Ayala García, Beatriz González Yebra, Andrea Liliana López Flores, Eduardo Guaní Guerra
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  ABSTRACT: The transplant of organs is one of the greatest therapeutic achievements of the twentieth century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the principal target of the immune response is the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells. However, we should not forget that the innate and adaptive immunities are closely interrelated and should be viewed as complementary and cooperating. When a human transplant is performed, HLA (human leukocyte antigens) molecules from a donor are recognized by the recipient's immune system triggering an alloimmune response Matching of donor and recipient for MHC antigens has been shown to have a significant positive effect on graft acceptance. This paper will present MHC, the innate and adaptive immunities, and clinical HLA testing.
  Journal of Transplantation 01/2012; 2012:842141.
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  Available from: PubMed Central

  Article: Use of cyclosporine in uterine transplantation.

  Srdjan Saso, Karl Logan, Yazan Abdallah, Louay S Louis, Sadaf Ghaem-Maghami, J Richard Smith, Giuseppe Del Priore
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  ABSTRACT: Uterine transplantation has been proposed as a possible solution to absolute uterine factor infertility untreatable by any other option. Since the first human attempt in 2000, various teams have tried to clarify which immunosuppressant would be most suitable for protecting the allogeneic uterine graft while posing a minimal risk to the fetus. Cyclosporine A (CsA) is an immunosuppressant widely used by transplant recipients. It is currently being tested as a potential immunosuppressant to be used during UTn. Its effect on the mother and fetus and its influence upon the graft during pregnancy have been of major concern. We review the role of CsA in UTn and its effect on pregnant transplant recipients and their offspring.
  Journal of Transplantation 01/2012; 2012:134936.
• Article: Stem cells as a tool to improve outcomes of islet transplantation.

  Emily Sims, Carmella Evans-Molina
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  ABSTRACT: The publication of the promising results of the Edmonton protocol in 2000 generated optimism for islet transplantation as a potential cure for Type 1 Diabetes Mellitus. Unfortunately, follow-up data revealed that less than 10% of patients achieved long-term insulin independence. More recent data from other large trials like the Collaborative Islet Transplant Registry show incremental improvement with 44% of islet transplant recipients maintaining insulin independence at three years of follow-up. Multiple underlying issues have been identified that contribute to islet graft failure, and newer research has attempted to address these problems. Stem cells have been utilized not only as a functional replacement for β cells, but also as companion or supportive cells to address a variety of different obstacles that prevent ideal graft viability and function. In this paper, we outline the manners in which stem cells have been applied to address barriers to the achievement of long-term insulin independence following islet transplantation.
  Journal of Transplantation 01/2012; 2012:736491.
• Article: Evaluation of protocol biopsy utility 12 months after renal transplantation: a multicenter observational analysis.

  Bruno Moulin, Pierre Merville, Karine Renaudin, David Buob, Sophie Ferlicot, Michel Delahousse, Jacques Dantal, Laetitia Albano, Christelle Barbet, Georges Mourad, Laure-Hélène Noel
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  ABSTRACT: The clinical merit of surveillance kidney graft biopsies remains controversial. A retrospective, multicenter analysis evaluated 12-month surveillance biopsies (SB, 154 patients) versus no SB (NSB, 138 patients (11 with diagnostic biopsy)) in patients >18 months posttransplant with estimated GFR (eGFR) ≥30 mL/min. The primary objective was to describe renal function at 18 months post-transplant in patients with or without SB at month 12. Globally, most recipients in both cohorts were at low immunological risk (<10% of patients with PRA ≥30%). The immunosuppressive regimen remained unchanged following more than half of SB that exhibited chronic lesions (18/33, 54.5%). Mean (SD) eGFR at month 18 (primary endpoint) was 56 (19) mL/min/1.73 m² with SB and 54 (15) mL/min/1.73 m² with NSB (P = 0.48). In the SB group, slight nonspecific changes were observed in 51 cases, rejection (acute or chronic) in 6 cases, CNI-related toxicity in 15 cases, recurrence of initial disease in two cases, and interstitial fibrosis/tubular atrophy (IF/TA) in 83 cases (71.6%), of which 35 cases (30.2%) were grade II/III lesions. eGFR <50 mL/min/1.73 m² at month 6 predicted IF/TA grade II or III (OR 3.85, 95% CI 1.64, 9.05, P < 0.002). SB at 12 months posttransplant did not prompt significant modification of immunosuppression, and no renal benefit was observed.
  Journal of Transplantation 01/2012; 2012:781263.
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  Available from: PubMed Central

  Article: Home and office blood pressure monitoring in renal transplant recipients.

  Rebecca Sberro-Soussan, Marion Rabant, Renaud Snanoudj, Julien Zuber, Lynda Bererhi, Marie-France Mamzer, Christophe Legendre, Eric Thervet
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  ABSTRACT: Background. Arterial hypertension in renal transplant recipients (RTR) is associated with increased morbid mortality. In the general population, home blood pressure monitoring (HBPM) was found to be superior to office blood pressure (OBP) in identifying true hypertensive patients. The aim of this study was to investigate HBPM for the assessment of blood pressure profile in RTR. Methodology and Principal Findings. We included prospectively 87 stable RTR. Sitting OBP was measured during the outpatient clinic. HBPM was performed by measuring BP every morning and night for 4 days. The accepted limits for the OBP and HBPM, were respectively, 140/90 mmHg and 135/85 mmHg. Patients were classified as "normotensive," "uncontrolled," "white-coat hypertensive" and "masked hypertensive", (OBP below the limit and HBPM above). During the study, 81 patients (55 males, age 48.5 ± 14 years) were available for analysis. The mean OBP and HBP were 138/83 ± 14/10 mmHg and 133/79 ± 14/8 mmHg; 29% of patients were uncontrolled, 28% normotensive, 21% white coat, and 21% masked hypertensive. Age, glycemia, and number of antihypertensive drugs were associated with hypertension. Conclusion and Significance. In RTR, HBPM is well accepted and better define BP profile since there is 42% discrepancy between OBPM and HBPM. Whether this discrepancy is associated with worst outcome in the long term remains to be demonstrated.
  Journal of Transplantation 01/2012; 2012:702316.
• Article: Exenatide pretreatment improved graft function in nonhuman primate islet recipients compared to treatment after transplant only.

  Jill L Buss, Amer Rajab, Elizabeth D Essig, Valerie K Bergdall, Jie Wang, Kwame Osei
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  ABSTRACT: The GLP-1 receptor agonist, exenatide, has previously been shown to improve insulin secretion, protect beta cells from apoptosis, and promote beta cell regeneration. We propose that pretreatment with exenatide will promote islet graft survival and improve graft function. Pancreatectomized cynomolgus monkeys underwent islet allotransplantation and were treated with exenatide beginning on day 0 or day -2. A third group of animals was treated with an immunosuppressive regimen while a fourth group remained untreated. Fasting blood glucose (FBG) was used to evaluate graft function along with intravenous glucose tolerance tests (IVGTTs) performed at study endpoint (day 10 for untreated and posttransplant exenatide or day 90 for pretreatment exenatide and immunosuppression). The average FBG for pre-treated animals day 5 following transplant was 52.7 ± 14.8 mg/dl, compared to 154.3 ± 105.5 mg/dl for animals treated only following transplant, 59.4 mg/dl ±12.1 for animals treated with immunosuppression, and 265.5 ± 172.3 mg/dl for untreated animals. IVGTTs performed at study endpoint showed normal glucose and insulin curves in the pre-treated exenatide and immunosuppression groups only, with beta cell function actually improving after transplant in the pre-treated group. We conclude, therefore, that exenatide pre-treatment can successfully maintain islet graft survival in nonhuman primates.
  Journal of Transplantation 01/2012; 2012:382518.
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  Available from: PubMed Central

  Article: Antibody-mediated rejection: pathogenesis, prevention, treatment, and outcomes.

  Olivia R Blume, Sarah E Yost, Bruce Kaplan
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  ABSTRACT: Antibody-mediated rejection (AMR) is a major cause of late kidney transplant failure. It is important to have an understanding of human-leukocyte antigen (HLA) typing including well-designed studies to determine anti-MHC-class-I-related chain A (MICA) and antibody rejection pathogenesis. This can allow for more specific diagnosis and treatment which may improve long-term graft function. HLA-specific antibody detection prior to transplantation allows one to help determine the risk for AMR while detection of DSA along with a biopsy confirms it. It is now appreciated that biopsy for AMR does not have to include diffuse C4d, but does require a closer look at peritubular capillary microvasculature. Although plasmapheresis (PP) is effective in removing alloantibodies (DSAs) from the circulation, rebound synthesis of alloantibodies can occur. Splenectomy is used in desensitization protocols for ABO incompatible transplants as well as being found to treat AMR refractory to conventional treatment. Also used are agents targeted for plasma cells, B cells, and the complement cascade which are bortezomib rituximab and eculizumab, respectively.
  Journal of Transplantation 01/2012; 2012:201754.