Publications
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de Kort H, Willicombe M, Brookes P, et al., 2012, Microcirculation Injury Is Predictive of Graft Loss in Renal Transplant Patients with De Novo Donor-Specific Antibodies, American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 43-43, ISSN: 1600-6135
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Chan K, Taube D, Roufosse C, et al., 2011, Kidney transplantation with minimized maintenance: alemtuzumab induction with tacrolimus monotherapy--an open label, randomized trial, Transplantation, Vol: 92, Pages: 774-780
BACKGROUND: Immunosuppressive regimens for kidney transplantation which reduce the long-term burden of immunosuppression are attractive, but little data are available to judge the safety and efficacy of the different strategies used. We tested the hypothesis that the simple, cheap, regimen of alemtuzumab induction combined with tacrolimus monotherapy maintenance provided equivalent outcomes to the more commonly used combination of interleukin-2 receptor monoclonal antibody induction with tacrolimus and mycophenolate mofetil combination maintenance, both regimens using steroid withdrawal after 7 days. METHODS: One hundred twenty-three live or deceased donor renal transplant recipients were randomized 2:1 to receive alemtuzumab/tacrolimus or daclizumab/tacrolimus/mycophenolate. The primary endpoint was survival with a functioning graft at 1 year. RESULTS: Both regimens produced equivalent, excellent outcomes with the primary outcome measure of 97.6% in the alemtuzumab arm and 95.1% in the daclizumab arm at 1 year (95% confidence interval of difference 6.9% to -1.7%) and at 2 years 92.6% and 95.1%. Rejection was less frequent in the alemtuzumab arm with 1- and 2-year rejection-free survival of 91.2% and 89.9% compared with 82.3% and 82.3% in the daclizumab arm. There were no significant differences in terms of the occurrence of opportunistic infections. CONCLUSION: Alemtuzumab induction with tacrolimus maintenance monotherapy and short-course steroid use provides a simple, safe, and effective immunosuppressive regimen for renal transplantation
Tharmalingam H, Ashby DR, Busbridge M, et al., 2011, Dissociation of ferritin and hepcidin in a case of adult-onset Still's disease., International journal of hematology, Vol: 94, Pages: 408-409
Tharmalingam H, Ashby DR, Busbridge M, et al., 2011, Dissociation of ferritin and hepcidin in a case of adult-onset Still's disease, Int.J.Hematol., Vol: 94, Pages: 408-409
Willicombe M, Roufosse C, Brookes P, et al., 2011, Antibody-mediated rejection after alemtuzumab induction: incidence, risk factors, and predictors of poor outcome, Transplantation, Vol: 92, Pages: 176-182
BACKGROUND: Antibody-mediated rejection (AMR) is associated with allograft loss. Identification of factors associated with poor outcome has not been extensively studied. METHODS: We retrospectively studied 469 patients who received a negative crossmatch renal transplant with alemtuzumab induction. Forty-eight of 469 (10.2%) patients were treated for AMR. Thirty of 48 (62.5%) of the cases fulfilled the Banff criteria for definite AMR, whereas 18 of 48 (37.5%) were categorized as suspicious for AMR (tissue injury with C4d staining or donor-specific antibodies [DSAbs]). Sensitization, high human leukocyte antigen, and -DR mismatch were risk factors for the development of AMR (P = 0.0016, 0.001, and 0.012, respectively). RESULTS: Allograft survival was inferior in the AMR group (70.2%) compared with the nonrejector group (97.0%) (P<0.001). Forty-two of 48 (87.5%) of patients with acute AMR had DSAbs. Patients with CII DSAbs at the time of AMR, whether alone or in combination with CI DSAbs had the worst allograft survival (P = 0.014). Both the mean cumulative and immunodominant mean fluorescence index were higher in those patients who subsequently lost their grafts (P<0.001). Patients with diffuse C4d staining had inferior allograft survival than those with focal C4d or no staining (P = 0.02). There was no significant difference in survival by histological grade but a trend to inferior outcomes in those with vascular involvement (P = 0.06). Those patients who met the full Banff criteria had worse survival than those with suspicion for AMR only (P = 0.04). CONCLUSION: This study identifies patients at risk of graft failure from AMR. These patients may benefit from newer therapeutic strategies including the use of eculizumab or bortezomib
Bravou V, McLean AG, Loucaidou M, et al., 2011, Paraprotein 'zippers', Kidney Int., Vol: 80
Santos-Nunez E, Willicombe M, Brookes P, et al., 2011, De novo donor specific antibodies are associated with a high incidence of antibody mediated rejection, transplant glomerulopathy and graft loss, 25th Conference on European Immunogenetics and Histocompatibility, Publisher: WILEY-BLACKWELL, Pages: 453-454, ISSN: 0001-2815
Galliford J, Roufosse C, Chan K, et al., 2011, Lack of Effective Therapy for Transplant Glomerulopathy, American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 401-401, ISSN: 1600-6135
Willicombe M, Galliford J, Roufosse C, et al., 2011, Acute Cellular Rejection with a Humoral Component Is Associated with Increased Risk of Subsequent Antibody Mediated Rejection, Transplant Glomerulopathy and Allograft Loss., American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 448-448, ISSN: 1600-6135
Lawrence C, Willicombe M, Brookes P, et al., 2011, Preformed Anti-HLA -A, -B and -DR but Not -DQ Complement-Activating Low-Level Donor- Specific Antibodies Predict Early Antibody- Mediated Rejection in Renal Allografts., American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 471-472, ISSN: 1600-6135
Willicombe M, Brookes P, Roufosse C, et al., 2011, Detection of Donor Specific Antibodies Predicts Antibody Mediated Rejection and Transplant Glomerulopathy., American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 295-296, ISSN: 1600-6135
Galliford J, Lawrence C, Willicombe M, et al., 2011, Reversal of Refractory Acute Antibody Mediated Rejection with Eculizumab, American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 352-352, ISSN: 1600-6135
Willicombe M, Santos-Nunez E, Brookes P, et al., 2011, De Novo HLA-DQ Donor Specific Antibodies Are Associated with a Higher Risk of Rejection and Transplant Glomerulopathy, American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 203-203, ISSN: 1600-6135
Shiu KY, Mesa IR, Perucha E, et al., 2011, Alloreactive IFNγ-Producing CD4+T-Cells from Renal Transplant Recipients with Chronic Antibody-Mediated Rejection (CAMR) Are B-Cell Dependent <i>In Vitro</i>., American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 195-195, ISSN: 1600-6135
Willicombe M, Brookes P, Santos-Nunez E, et al., 2011, Outcome of patients with preformed donor-specific antibodies following alemtuzumab induction and tacrolimus monotherapy, Am.J.Transplant., Vol: 11, Pages: 470-477
It has been shown that low-level preformed donor-specific antibodies (DSAbs) detected by luminex beads in the setting of a negative CDC and flow cytometry crossmatch (CDC/FCXM) are associated with inferior allograft outcomes. The relevance of preformed DSAbs in patients receiving alemtuzumab induction and tacrolimus monotherapy has not been studied. Four hundred and eighty renal transplant recipients with a negative CDC/FCXM had their pretransplant sera retrospectively screened for DSAbs. 45/480 (9.4%) of patients were found to have preformed DSAbs. Females and patients receiving regrafts were more likely to have a DSAb (p = 0.008 and p < 0.0001, respectively). Patients with DSAbs had inferior allograft survival (p = 0.047), increased incidence of antibody-mediated rejection (p < 0.0001) and inferior allograft function at 6 months posttransplant (p = 0.017). Patients with HLA class I DSAb (alone or in combination with a Class II DSAb) with high mean fluorescence intensities (MFIs) were at highest risk. We conclude that patients with preformed DSAb are at high risk of adverse outcomes when receiving a minimal immunosuppressive regime incorporating alemtuzumab induction. Patients found to have a preformed DSAb despite a negative crossmatch might benefit from augmented immunosuppression
Arlt VM, Zuo J, Trenz K, et al., 2011, Gene expression changes induced by the human carcinogen aristolochic acid I in renal and hepatic tissue of mice, Int.J.Cancer, Vol: 128, Pages: 21-32
Aristolochic acid (AA) is the causative agent of urothelial tumors associated with AA nephropathy and is also implicated in the development of Balkan endemic nephropathy-associated urothelial tumors. These tumors contain AA-characteristic TP53 mutations. We examined gene expression changes in Hupki (human TP53 knock-in) mice after treatment with aristolochic acid I (AAI) by gavage (5 mg/kg body weight). After 3, 12 and 21 days of treatment gene expression profiles were investigated using Agilent Whole Mouse 44K Genome Oligo Array. Expression profiles were significantly altered by AAI treatment in both target (kidney) and nontarget (liver) tissue. Renal pathology and DNA adduct analysis confirmed kidney as the target tissue of AAI-induced toxicity. Gene ontology for functional analysis revealed that processes related to apoptosis, cell cycle, stress response, immune system, inflammatory response and kidney development were altered in kidney. Canonical pathway analysis indicated Nfkappab, aryl hydrocarbon receptor, Tp53 and cell cycle signaling as the most important pathways modulated in kidney. Expression of Nfkappab1 and other Nfkappab-target genes was confirmed by quantitative real-time PCR (qRT-PCR) and was consistent with the induction of Nfkappab1 protein. Myc oncogene, frequently overexpressed in urothelial tumors, was upregulated by AAI on the microarrays and confirmed by qRT-PCR and protein induction. Collectively we found that microarray gene expression analysis is a useful tool to define tissue-specific responses in AAI-induced toxicity. Several genes identified such as TP53, Rb1, Mdm2, Cdkn2a and Myc are frequently affected in human urothelial cancer, and may be valuable prognostic markers in future clinical studies
Willicombe M, Santos-Nunez E, Brookes P, et al., 2010, Preformed donor specific antibodies are associated with high incidence of antibody mediated rejection despite Alemtuzumab induction, INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Vol: 37, Pages: 419-419, ISSN: 1744-3121
Croucher A, Vera J, Akolo C, et al., 2010, Acute renal failure due to immune reconstitution inflammatory interstitial nephritis in an HIV-positive patient, AIDS, Vol: 24, Pages: 1788-1790
Willicombe M, Galliford J, Corbett R, et al., 2010, Donor Specific Antibody Titres Predict Antibody Mediated Rejection and Response to Treatment., 10th American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 234-234, ISSN: 1600-6135
Galliford J, Chan K, Lawrence C, et al., 2010, Antibody Mediated Rejection after ABO Incompatible Living Donor Renal Transplantation Is Mainly Associated with HLA Donor Specific Antibodies., 10th American Transplant Congress, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 164-164, ISSN: 1600-6135
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Roufosse C, Smith APT, Chan K, et al., 2010, Comparison of Histological Features in 1-Year Surveillance Biopsies in a Randomized Controlled Trial of Daclizumab/Tacrolimus/MMF Versus Alemtuzumab/Tacrolimus Monotherapy., 10th American Transplant Congress, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 49-49, ISSN: 1600-6135
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Chan K, Lawrence C, Charif R, et al., 2010, Steroid Sparing Regimes Are Not Associated with a High Incidence of Recurrent Disease after Renal Transplantation., 10th American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 513-513, ISSN: 1600-6135
Willicombe M, Roufosse C, Palmer A, et al., 2010, C4d Positivity Does Not Predict Acute Rejection in Patients with Anti-HLA Donor Specific Antibodies., 10th American Transplant Congress, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 235-235, ISSN: 1600-6135
Roufosse CA, 2010, The contribution of bone marrow stem cells to renal parenchymal regeneration.
Shea-Simonds P, Cairns TD, Roufosse C, et al., 2009, Lupus podocytopathy, Rheumatology.(Oxford), Vol: 48, Pages: 1616-1618
Roufosse CA, Cook HT, 2009, Pathological predictors of prognosis in immunoglobulin A nephropathy: a review, Curr.Opin.Nephrol.Hypertens., Vol: 18, Pages: 212-219
PURPOSE OF REVIEW: To provide a review and discussion of histological prognostic indicators in immunoglobulin A (IgA) nephropathy (IgAN). RECENT FINDINGS: A variety of histological parameters and classifications have been used to attempt to predict prognosis in patients with IgAN. Grading systems used thus far do not consistently provide a useful adjunct to clinical prognostic parameters. This may be due to the variety of grading systems used, to inconsistent patient recruitment processes, and to the use of actuarial renal survival as an end point. This has led to the development of a new IgAN classification proposal by the International IgA Nephropathy Network in conjunction with the Renal Pathological Society. Additional potential markers of disease progression currently under investigation include glomerular parameters such as number and size, markers of podocyte function and of complement activation, inflammatory infiltrates and mediators of tubulointerstitial fibrosis. SUMMARY: There is a need for an internationally accepted, reproducible and clinically meaningful pathological classification of IgAN. Such a classification is currently being developed. By using only reproducible, single parameters and validating them on a large group of cases from all over the world, it is hoped that a useful clinically predictive tool will be developed
Chan K, Galliford J, Charif R, et al., 2009, Tacrolimus Weaning Is Not Necessary after Alemtuzumab Induction in Live Related Renal Transplantation., 9th Joint Meeting of the American-Society-of-Transplant-Surgeon/American-Society-of-Transplantation, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 675-675, ISSN: 1600-6135
Galliford J, Chan K, Charif R, et al., 2009, ABO Incompatible Live Donor Transplantation with Alemtuzumab Induction, Tacrolimus Monotherapy and a Steroid Sparing Protocol., 9th Joint Meeting of the American-Society-of-Transplant-Surgeon/American-Society-of-Transplantation, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 557-557, ISSN: 1600-6135
Galliford J, Chan K, Willicombe M, et al., 2009, Renal Allograft Rejection after Alemtuzumab Induction and Tacrolimus Monotherapy., 9th Joint Meeting of the American-Society-of-Transplant-Surgeon/American-Society-of-Transplantation, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 620-621, ISSN: 1600-6135
Roufosse C, Cook HT, 2008, Stem cells and renal regeneration, Nephron Exp.Nephrol., Vol: 109, Pages: e39-e45
The role of embryonal or adult stem cells, in particular bone marrow (BM)-derived stem cells, in regenerating the kidney after injury has been the subject of intensive investigation. BM-derived stem cells have been shown to give rise to small numbers of most renal cell types, including tubular cells, mesangial cells, podocytes, vascular cells and interstitial cells. However, the role this infrequent display of BM cell plasticity plays in organ regeneration is less certain. Injections of BM-derived cells do improve renal function in many animal models of renal disease. Current opinion attributes this renoprotective effect mainly to paracrine factors supporting regeneration by local renal cells and to immunomodulatory effects, rather than to transdifferentiation of BM cells into renal cells. Several groups have identified native renal stem cell populations, although their role in renal regeneration has not yet been well defined
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