Evaluation of the use of tacrolimus ointment for the prevention of hypertrophic scars in experimental model.

BACKGROUND: Tacrolimus, for its activity on modulation of collagen production and fibroblast activity, may have a role in the prevention of hypertrophic scars. OBJECTIVES: Evaluate macroscopic, microscopic, metabolic, laboratory effects and side effects of the use of topical tacrolimus ointment, in different concentrations, in the prevention of hypertrophic scars. METHODS: Twenty-two rabbits were submitted to the excision of 2 fragments of 1 cm of each ear, 4 cm apart, down to cartilage. The left ear of the animals was standardized as control and Vaseline applied twice a day. The right ear received tacrolimus ointment, at concentrations of 0.1% on the upper wound and 0.03% on the lower wound, also applied twice a day. Macroscopic, microscopic, laboratory criteria and the animals' weight were evaluated after 30 days of the experiment. RESULTS: Wounds treated with tacrolimus, at concentrations of 0.1% and 0.03%, when compared to control, showed a lower average degree of thickening (p = 0.048 and p <0.001, respectively). The average of scar thickness and lymphocyte, neutrophil and eosinophil concentrations are lower in the treated wounds compared to the control (p <0.001, p=0.022, p=0.007, p=0.044, respectively). The mean concentration of lymphocytes is lower in wounds treated with a higher concentration of the drug (p=0.01). STUDY LIMITATIONS: experiment lasted only 30 days. CONCLUSIONS: Tacrolimus at the 2 concentrations evaluated reduced the severity of inflammatory changes and positively altered the macroscopic aspect of the scar in the short term. Its use was shown to be safe, with no evidence of systemic or local adverse effects.

Evaluation of the use of tacrolimus ointment for the prevention of hypertrophic scars in experimental model

Abstract BACKGROUND: Tacrolimus, for its activity on modulation of collagen production and fibroblast activity, may have a role in the prevention of hypertrophic scars. OBJECTIVES: Evaluate macroscopic, microscopic, metabolic, laboratory effects and side effects of the use of topical tacrolimus ointment, in different concentrations, in the prevention of hypertrophic scars. METHODS: Twenty-two rabbits were submitted to the excision of 2 fragments of 1 cm of each ear, 4 cm apart, down to cartilage. The left ear of the animals was standardized as control and Vaseline applied twice a day. The right ear received tacrolimus ointment, at concentrations of 0.1% on the upper wound and 0.03% on the lower wound, also applied twice a day. Macroscopic, microscopic, laboratory criteria and the animals' weight were evaluated after 30 days of the experiment. RESULTS: Wounds treated with tacrolimus, at concentrations of 0.1% and 0.03%, when compared to control, showed a lower average degree of thickening (p = 0.048 and p <0.001, respectively). The average of scar thickness and lymphocyte, neutrophil and eosinophil concentrations are lower in the treated wounds compared to the control (p <0.001, p=0.022, p=0.007, p=0.044, respectively). The mean concentration of lymphocytes is lower in wounds treated with a higher concentration of the drug (p=0.01). STUDY LIMITATIONS: experiment lasted only 30 days. CONCLUSIONS: Tacrolimus at the 2 concentrations evaluated reduced the severity of inflammatory changes and positively altered the macroscopic aspect of the scar in the short term. Its use was shown to be safe, with no evidence of systemic or local adverse effects.

Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study.

BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

Conversion From Calcineurin Inhibitors to Belatacept in HLA-sensitized Kidney Transplant Recipients With Low-level Donor-specific Antibodies.

BACKGROUND: Belatacept could be the treatment of choice in renal-transplant recipients with renal dysfunction attributed to calcineurin inhibitor (CNI) nephrotoxicity. Few studies have described its use in patients with donor-specific antibody (DSA). METHODS: We retrospectively evaluated conversion from CNIs to belatacept in 29 human leukocyte antigen-immunized renal-transplant recipients. Data about acute rejection, DSA, and renal function were collected. These patients were compared with 42 nonimmunized patients treated with belatacept. RESULTS: Patients were converted from CNIs to belatacept a median of 444 days (interquartile range, 85-1200) after transplantation and were followed up after belatacept conversion, for a median of 308 days (interquartile range, 125-511). At conversion, 16 patients had DSA. Nineteen DSA were observed in these 16 patients, of which 11/19 were <1000 mean fluorescence intensity (MFI), 7/19 were between 1000 and 3000 MFI, and one was >3000 MFI. At last follow-up, preexisting DSA had decreased or stabilized. Seven patients still had DSA with a mean MFI of 1298 ± 930 at the last follow-up. No patient developed a de novo DSA in the DSA-positive group. In the nonimmunized group, one patient developed de novo DSA (A24-MFI 970; biopsy for cause did not show biopsy-proven acute rejection or microinflammation score). After belatacept conversion, one antibody-mediated rejection was diagnosed. The mean estimated glomerular filtration rate improved from 31.7 ± 14.2 mL/min/1.73 m to 40.7 ± 12.3 mL/min/1.73 m (P < 0.0001) at 12 months after conversion. We did not find any significant difference between groups in terms of renal function, proteinuria, or biopsy-proven acute rejection. CONCLUSIONS: We report on a safe conversion to belatacept in human leukocyte antigen-immunized patients with low DSA levels.

Influence of epidemiology, immunosuppressive regimens, clinical presentation, and treatment on kidney transplant outcomes of patients diagnosed with tuberculosis: A retrospective cohort analysis.

Tuberculosis (TB) mortality is high among kidney transplant (KT) recipients. Although local epidemiology is an important factor, diagnostic/therapeutic challenges and immunosuppressive therapy (ISS) may influence outcomes. We analyzed the cumulative incidence (CumI) of TB in KT recipients receiving a variety of ISS with long-term follow-up. Our retrospective single-center cohort study included all KT procedures performed between January 1, 1998, and August 31, 2014, with follow-up until August 31, 2014. Induction therapy was based on perceived immunological risk; maintenance ISS included prednisone and calcineurin inhibitor (CNI) plus azathioprine (AZA), and mycophenolic acid (MPA) or mechanistic target of rapamycin inhibitor (mTORi). Thirty-four patients received belatacept/MPA. KT was performed on 11 453 patients and followed for 1989 (IQR 932 to 3632) days. Among these, 152 patients were diagnosed with TB (CumI 1.32%). Median time from KT to TB was 18.8 (IQR 7.2 to 60) months, with 59% of patients diagnosed after the first year. Unadjusted analysis revealed an increasing confidence interval (CI) of TB (0.94% CNI/AZA vs 1.6% CNI/MPA [HR = 1.62, 95% CI = 1.13 to 2.34, P = .009] vs 2.85% CNI/mTORi [HR = 2.45, 95% CI = 1.49 to 4.32, P < .001] vs 14.7% belatacept/MPA [HR = 13.14, 95% CI = 5.27 to 32.79, P < .001]). Thirty-seven (24%) patients died, and 39 (25.6%) patients experienced graft loss. Cytomegalovirus infection (P = .02) and definitive ISS discontinuation (P < .001) were associated with death. Rejection (P = .018) and ISS discontinuation (P = .005) occurred with graft loss. TB occurred at any time after KT and was influenced by ISS.

Sirolimus Associated with Tacrolimus at Low Doses in Elderly Kidney Transplant Patients: A Prospective Randomized Controlled Trial.

OBJECTIVES: There is no consensus on the best immunosuppressive regimen for elderly renal transplant recipients. The objective of this study was to assess cytomegalovirus infection incidence and kidney transplant outcomes in elderly recipients treated with mammalian target of rapamycin inhibitors sirolimus/ tacrolimus at low doses compared with those receiving tacrolimus/mycophenolate sodium. MATERIALS AND METHODS: In this single-center prospective randomized study (Trial Registration No. NCT02683291), kidney transplant recipients over 60 years of age were randomly allocated into 2 groups: tacrolimus-sirolimus (21 patients) and tacrolimus-mycophenolate (23 patients). Cytomegalovirus infection rate and patient survival, biopsy-proven acute rejection, and renal function at 12 months were assessed. RESULTS: Cytomegalovirus infection rate was higher in the mycophenolate group (60.9%) than in the sirolimus group (16.7%; P = .004). The rates of biopsy-proven acute rejection, patient survival, graft survival, and estimated glomerular filtration rate over 12 months did not significantly differ between groups. CONCLUSIONS: The incidence of cytomegalovirus infection was significantly lower in the sirolimus group. The use of tacrolimus combined with sirolimus in elderly kidney transplant recipients is safe.

Belatacepte para profilaxia de rejeição de órgãos em pacientes que recebem transplante de rim / Belatacepte for prophylaxis of organ rejection in patients receiving kidney transplantation

TECNOLOGIA: Nulojix® (belatacepte). INDICAÇÃO NA BULA: profilaxia de rejeição de órgãos em pacientes adultos que recebem um transplante de rim. Uso em combinação com indução de basiliximabe, micofenolato de mofetila e corticosteroides. PERGUNTA: belatacepte é eficaz e seguro para profilaxia de rejeição de órgãos em pacientes que recebem transplante de rim? EVIDÊNCIAS: foram incluídos um ensaio clínico randomizado com duração de 84 meses e uma revisão sistemática com metanálise, que avaliaram o belatacepte para profilaxia de rejeição de órgãos em pacientes adultos com transplante de rim, frente aos inibidores de calcineurina, ciclosporina (no ensaio clínico e na revisão sistemática) e/ou tacrolimo (na revisão sistemática). De acordo com o ensaio clínico, uma redução de 43% no risco de óbito ou perda de enxerto foi observada para os regimes de belatacepte mais intensivo e menos intensivo em comparação com o regime de ciclosporina. Em ambos os estudos, belatacepte apresentou melhor função do enxerto. Até três anos após o transplante, belatacepte e os receptores tratados com inibidores de calcineurina estavam com risco similar de óbito frente aos inibidores da calcineurina, conforme revisão sistemática, e até sete anos após o transplante, as razões de risco de óbito na comparação entre belatacepte (mais intensivo e menos intensivo) e ciclosporina não apresentaram diferenças estatisticamente significante, de acordo com o ensaio clínico. No final de sete anos, as taxas de óbito dos pacientes em uso de belatacepte mais intensivo, belatacepte menos intensivo e ciclosporina foram 9,2%, 8,2% e 14,4% e as estimativas para as taxas de perda de enxerto entre os pacientes foram 4,7%, 5,4% e 9,8%, respectivamente. As razões de risco de perda de enxerto na comparação entre belatacepte (mais intensivo e menos intensivo) não apresentaram diferenças estatisticamente significantes frente à ciclosporina. Já as taxas cumulativas de rejeição aguda comprovada por biópsia foram de 24,4%, 18,3% e 11,4% com belatacepte mais intensivo, belatacepte menos intensivo e ciclosporina, respectivamente, no ensaio clínico. De acordo com a revisão sistemática, os pacientes tratados com belatacepte apresentaram menor pressão arterial, melhor perfil lipídico (não HDL e triglicérides) e redução na incidência de diabetes em comparação com os pacientes tratados com inibidores da calcineurina. De acordo com o ensaio clínico, as frequências cumulativas de eventos adversos graves para os regimes de belatacepte mais intensivos e menos intensivos e para a ciclosporina foram de 70,8%, 68,6% e 76,0%, respectivamente. As infecções graves foram os eventos adversos mais comuns em cada grupo de tratamento. O ensaio clínico selecionado foi financiado pela indústria que produz o Nulojix®. CONCLUSÕES: belatacepte é indicado para profilaxia de rejeição de órgãos em pacientes adultos que recebem transplante de rim. Não há evidências de diferença na eficácia entre o belatacepte e os inibidores da calcineurina na prevenção de rejeição aguda, perda de enxerto e óbito em pacientes que receberam transplante renal. No entanto, o tratamento com belatacepte está associado com melhor função do rim transplantado. As infecções graves foram os eventos adversos mais comuns apresentados durante o tratamento dos pacientes com transplante renal, tanto para os que usaram belatacepte quanto para os que usaram ciclosporina. Há recomendações para que o uso do belatacepte seja direcionado para a terapia de manutenção.(AU)

Conversion to Mycophenolate Mofetil Monotherapy in Liver Recipients: Calcineurin Inhibitor Levels are Key

Abstract: The use of calcineurin inhibitors (CNI) after liver transplantation is associated with post-transplant nephrotoxicity. Conversion to mycophenolate mofetil (MMF) monotherapy improves renal function, but is related to graft rejection in some recipients. Our aim was to identify variables associated with rejection after conversion to MMF monotherapy. Conversion was attempted in 40 liver transplant recipients. Clinical variables were determined and peripheral mononuclear blood cells were immunophenotyped during a 12-month follow- up. Conversion was classified as successful (SC) if rejection did not occur during the follow-up. MMF conversion was successful with 28 patients (70%) and was associated with higher glomerular filtration rates at the end of study. It also correlated with increased time elapsed since transplantation, low baseline CNI levels (Tacrolimus ≤ 6.5 ng/mL or Cyclosporine ≤ 635 ng/mL) and lower frequency of tacrolimus use. The only clinical variable independently related to SC in multivariate analysis was low baseline CNI levels (p = 0.02, OR: 6.93, 95%, CI: 1.3-29.7). Mean baseline fluorescent intensity of FOXP3+ T cells was significantly higher among recipients with SC. In conclusion, this study suggests that baseline CNI levels can be used to identify recipients with higher probability of SC to MMF monotherapy. Clinicaltrials.gov identification: NCT01321112.

Conversion to mycophenolate mofetil monotherapy in liver recipients: Calcineurin inhibitor levels are key.

 The use of calcineurin inhibitors (CNI) after liver transplantation is associated with post-transplant nephrotoxicity. Conversion to mycophenolate mofetil (MMF) monotherapy improves renal function, but is related to graft rejection in some recipients. Our aim was to identify variables associated with rejection after conversion to MMF monotherapy. Conversion was attempted in 40 liver transplant recipients. Clinical variables were determined and peripheral mononuclear blood cells were immunophenotyped during a 12-month follow-up. Conversion was classified as successful (SC) if rejection did not occur during the follow-up. MMF conversion was successful with 28 patients (70%) and was associated with higher glomerular filtration rates at the end of study. It also correlated with increased time elapsed since transplantation, low baseline CNI levels (Tacrolimus ≤ 6.5 ng/mL or Cyclosporine ≤ 635 ng/mL) and lower frequency of tacrolimus use. The only clinical variable independently related to SC in multivariate analysis was low baseline CNI levels (p = 0.02, OR: 6.93, 95%, CI: 1.3-29.7). Mean baseline fluorescent intensity of FOXP3+ T cells was significantly higher among recipients with SC. In conclusion, this study suggests that baseline CNI levels can be used to identify recipients with higher probability of SC to MMF monotherapy. Clinicaltrials.gov identification: NCT01321112.

Longitudinal Pharmacokinetics of Tacrolimus in Elderly Compared With Younger Recipients in the First 6 Months After Renal Transplantation.

BACKGROUND: Elderly (Eld) (≥60 years) recipients are receiving renal transplants more frequently. The pharmacokinetics (PK) studies of immunosuppressive drugs in healthy volunteers, rarely, include old patients. METHODS: We studied 208 12-hour tacrolimus (TAC) PK (0, 20, 40, 60, 90, 120, 180, 240, 360, 480, 600, 720 min) in 44 Eld (65 ± 3 years) and compared the results with 31 younger controls (Ctrl) (35 ± 6 years) recipients, taking oral TAC/mycophenolate sodium (MPS)/prednisone, at 4 different timepoints: PK1 (8 ± 2 days; n = 72), PK2 (31 ± 4 days; n = 61), PK3 (63 ± 6 days; n = 44), and PK4 (185 ± 10 days; n = 31). Tacrolimus PK was measured by ultraperformance liquid chromatography coupled to a mass spectrometer repetition and noncompartmental PKs were analyzed using Phoenix WinNonlin. RESULTS: Mean TAC dose was lower in the Eld group than in Ctrl ones throughout timepoints either by total daily dose or adjusted (Adj) per body weight. Mean TAC trough level (Cmin), used to adjust daily dose, was not different between the 2 groups in all timepoints. AdjCmax and AdjTAC-area under the curve at dosing interval were both higher in the Eld compared to the Ctrl group in PKs1, 3, and 4. Estimated total body clearance normalized by dose and weight was lower in the Eld group compared with the Ctrl in all PKs and statistically lower at PKs 1 and 3. Similar to younger recipients TAC trough level has also a high correlation (R = 0.76) with area under the curve at dosing interval. CONCLUSIONS: These data indicate that Eld recipients have a lower TAC clearance and therefore need a lower TAC dose than younger recipients.

Longitudinal Pharmacokinetics of Everolimus When Combined With Low-level of Tacrolimus in Elderly Renal Transplant Recipients.

BACKGROUND: Although the proportion of elderly patients among renal transplant recipients has increased, pharmacokinetic (PK) studies of immunosuppressants rarely include older patients. METHODS: We studied 12-hour everolimus (EVL) PK in 16 elderly renal transplant recipients (all whites; 10 men; mean age, 64 ± 2 years (61-71 years), in 4 separate timepoints (at 7, 30, 60, and 150 days) after EVL introduction, corresponding to a mean postrenal transplantation day: PK1 (43 ± 4 days), PK2 (65 ± 7 days), PK3 (106 ± 17 days), and PK4 (206 ± 40 days). Patients received EVL (target trough level (Ctrough, 3-8 ng/mL), prednisone, and tacrolimus (TCL) (target Ctrough, 2-5 ng/mL). RESULTS: Mean TCL-Ctrough was 7.2 ± 3.8, 4.9 ± 2.2, 4.9 ± 2.2, and 4.5 ± 1.2 ng/mL at PK1, PK2, PK3, and PK4, respectively. There were no differences among timepoints for mean EVL daily dose (data shown as PK3) (3.5 ± 1.3 mg/d), Ctrough (4.7 ± 2.5 ng/mL), AUC0-12h (106 ± 51 ng/h per mL), Caverage (8.8 ± 4.2 ng/mL), Cmax (19.2 ± 9.7 ng/mL), apparent Half-life (11.7 ± 4.2 hours), estimated total body clearance (0.39 ± 0.27 L/h), or fluctuation (166 ± 65%). Also, none of those PK parameters differed statistically when adjusted for body weight. EVL-Ctrough showed a very high correlation (r = 0.849) with AUC0-12h. CONCLUSIONS: Our data indicate that elderly renal transplant recipients starting EVL 1 month after transplantation along with a steady-state TCL level, present stable EVL-PK parameters without significant changes in dose or exposure during the first 6 months after renal transplantation.

Long-Term Follow-Up of De Novo Use of mTOR and Calcineurin Inhibitors After Kidney Transplantation.

BACKGROUND: Long-term efficacy and safety of de novo use of the mammalian target of rapamycin inhibitors (mTORi) have been evaluated primarily using registry data. METHODS: This was a pooled retrospective analysis of data obtained from 10 prospective randomized trials in de novo kidney transplant recipients (n = 581) receiving calcineurin inhibitors (CNIs) combined with sirolimus (n = 329), everolimus (n = 128), or antimetabolites (n = 124). RESULTS: There were no differences in patient (84.5 versus 80.9 versus 89.7%, P = 0.996), graft (65.4 versus 59.5 versus 73.1%, P = 0.868), and biopsy-confirmed acute rejection-free (78.1 versus 77.3 versus 79.0%, P = 0.976) survivals, respectively. The incidence of cytomegalovirus infection was lower (6 versus 3 versus 11%, P = 0.024) but treatment discontinuation was higher among patients receiving mTORi (66.0 versus 47.7 versus 31.5%, P < 0.001), respectively. At 5 years, median estimated glomerular filtration rate (49.6 versus 43.9 versus 53.2 mL/min, P = 0.006) was lower and the proportion of patients with proteinuria (53 versus 40 versus 23%, P < 0.001) was higher among patients receiving mTORi, respectively. CONCLUSIONS: The efficacy of de novo use of mTORi is comparable with that of antimetabolites in kidney transplant recipients receiving calcineurin inhibitor. Apart from the lower cytomegalovirus infection rate, the safety profile is unfavorable, showing higher treatment discontinuation rates and higher incidence of proteinuria.

Epidemiology and clinical evolution of non-melanoma skin cancer in renal transplant recipients: a single-center experience in São Paulo, Brazil.

BACKGROUND: Non-melanoma skin cancer (NMSC) is very common among renal transplant recipients (RTRs) as a result of the immunosuppressed status of these patients and other factors. Few studies have examined the clinical characteristics and evolution of NMSC in RTRs in tropical countries. OBJECTIVES: The aim of this study was to characterize the epidemiology and clinical evolution of NMSC in RTRs. METHODS: We conducted a retrospective study including 68 RTRs with NMSC diagnosed from July 2004 to December 2009 with a minimum follow-up of three years. We analyzed demographic and transplant- and NMSC-related data. RESULTS: The mean age of patients at the first diagnosis of NMSC was 51 years (range: 29-71 years). Most first diagnoses occurred within nine years post-transplant. The majority of patients (n = 48) had Fitzpatrick skin phototype II, although NMSC was also observed in those with skin phototypes III and IV. Forty-six (67.6%) RTRs had received a kidney from a living donor. Fifty-five (80.9%) RTRs had received cytotoxic immunosuppressives, 51 (75.0%) had received calcineurin inhibitors, and two (2.9%) had received mTOR inhibitors. Most of the RTRs developed about eight NMSC lesions, but up to 25 NMSC lesions were diagnosed in one patient. Most lesions (67.6%) were located on sun-exposed areas. Squamous cell carcinoma (SCC) represented the predominant tumor type, accounting for 70.6% of all tumors, whereas basal cell carcinoma accounted for 29.4% of all tumors. Invasive SCC predominated over in situ SCC. Finally, 48.5% of patients had a previous history of viral warts. CONCLUSIONS: Long-term use of immunosuppressive therapy increases the risk for tumor occurrence. Multiple NMSC tumors can develop in patients in tropical countries, even in patients with a high skin phototype. Therefore, RTRs should understand the high risk for the development of malignant tumors and should be properly informed about the prevention and treatment of NMSC.

Subclinical Lesions and Donor-Specific Antibodies in Kidney Transplant Recipients Receiving Tacrolimus-Based Immunosuppressive Regimen Followed by Early Conversion to Sirolimus.

BACKGROUND: There is no evidence on the incidence of subclinical inflammation and scaring lesions in patients receiving tacrolimus (TAC) minimization and elimination immunosuppressive regimens. METHODS: This study analyzed preimplantation, 3 and 24 months protocol biopsies and anti-HLA donor-specific antibodies (DSA) in 140 low immunological risk kidney transplant recipients receiving reduced TAC exposure, prednisone, and mycophenolate, randomized at 3 months to be converted or not to sirolimus (SRL). RESULTS: Mean TAC concentrations were 6.0 ± 2.4 ng/mL and 5.8 ± 2.2 ng/mL at 3 and 24 months. The incidence of subclinical inflammation lesions at 3 months was 9.3%. The incidence of (interstitial fibrosis) IF/(tubular atrophy) TA at month 24 was 57.6%, higher in SRL compared to TAC group (68.8 vs 44.4%; P = 0.022). Patients converted to SRL showed higher incidence of acute rejection (7.3% vs 0%), proteinuria (59.6% vs 25%; P = 0.001), and DSA (17.8% vs 7.3%; P = 0.201), respectively. Biopsy-proven acute rejection (odds ratio [OR] 2.32, 95% confidence interval [95% CI], 0.979-5.518, P = 0.056), subclinical inflammation lesions at 3 months (OR, 11.75; 95% CI, 1.286-107.474; P = 0.029) and conversion to SRL (OR, 2.72; 95% CI, 1.155-6.383; P = 0.022) were associated with IF/TA at month 24. Black ethnicity (OR, 0.22; 95% CI, 0.058-0.873; P = 0.031), donor age (OR, 2.74; 95% CI, 1.329-5.649; P = 0.006), and conversion to SRL (OR, 2.34; 95% CI, 1.043-5.267; P = 0.039) were associated with inferior renal function at 24 months. CONCLUSIONS: In kidney transplant recipients receiving reduced TAC exposure, subclinical inflammation lesions at 3 months were associated with IF/TA at 24 months. Conversion from TAC to SRL was associated with inferior renal function, higher incidence of IF/TA, and trends to higher incidence of DSA at 24 months.

Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-ß signalling pathway in kidney transplant.

AIM: The focus in renal transplantation is to increase long-term allograft survival. One of the limiting factors is calcineurin inhibitor (CNI)-induced fibrosis. This study attempted to examine the histological aspect of interstitial fibrosis and the modulation of the transforming growth factor-ß (TGF-ß) canonical signalling pathway following early withdrawal of CNI from sirolimus-based immunosuppressive therapy. METHODS: Forty-five kidney transplant recipients with low-medium immunologic risk were randomized and underwent protocol biopsies obtained at the time of transplantation and at 3 and 12 months thereafter. The recipients were taking tacrolimus, sirolimus and prednisone. After the 3rd month, patients were randomized into two groups: sirolimus (SRL) (removed CNI and increased sirolimus) and tacrolimus (TAC) (maintained CNI). Renal biopsies were analyzed according to Banff's 2007 criteria. The sum of Banff's ct and ci constituted the chronicity index. Fibrosis was evaluated by the histomorphometrical analysis of the total collagen and myofibroblast deposition. Immunohistochemical characterization and quantification of TGF-ß, TGF-ß receptor 1 (TGF-ß-R1), receptor 2 (TGF-ß-R2) and phospho-Smad2/3 (p-Smad2/3) were performed. RESULTS: Maintenance of CNI was associated with the increase of the surface density of collagen and α-smooth muscle actin (α-SMA), (P = 0.001). Furthermore, increased TGF-ß (P = 0.02), TGF-ß-R1 (P = 0.02), p-Smad2/3 (P = 0.03) and stabilized TGF-ß-R2. On the other hand, the removal of CNI with increase in the dose of sirolimus limited the enhancement of the chronicity index at 12 m (SRL, 2.18 vs TAC, 3.12, P = 0.0007), diminished the deposition of fibrosis and promoted the stabilization of TGF-ß, TGF-ß-R2, p-Smad2/3 and myofibroblasts as well as the reduction of TGF-ß-R1 (P = 0.01). CONCLUSION: The early withdrawal of CNI limited the fibrosis progression through the stabilization of chronicity index and of the canonical TGF-ß signalling pathway.

Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin.

BACKGROUND: Cyclosporin is a calcineurin inhibitor widely used in renal transplant patients to prevent organ rejection. Several position papers have been published but no reports on the practical experience in pediatric patients undergoing conversion between cyclosporin innovator and generic products are available. OBJECTIVE: To evaluate the pharmacokinetics and safety as part of therapeutic monitoring of cyclosporin in renal transplant pediatric patients who switch from the innovator to the generic formulation in Argentina. SETTING: Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina. METHODS: Stable pediatric renal transplant patients (6 months post-transplant) switched from the innovator to the generic formulation of cyclosporin microemulsion capsule. Cyclosporin pharmacokinetic parameters were obtained while taking the innovator and after starting with the generic formulation. Blood samples were drawn before and 1, 2, and 3 h after drug administration and subsequently quantified. Pharmacokinetic parameters were obtained by means of a Bayesian approach. MAIN OUTCOMES MEASURE: Cyclosporin pharmacokinetic parameters (area under the curve, AUC; Blood concentration after 2 h, C2), adverse events and graft rejection. RESULTS: A total of 12 patients were included. Median (range) age and time post-transplant were 10.7 years (6.5-17.7) and 8.3 years (3.4-14.0), respectively. Two patients or their parents did not consent to the switch. Median (range) dose normalized cyclosporin AUC and C2 were 1.15 (mg*h/L)/mg/kg (0.72-3.0) and 265.5 (ng/ml)/mg/kg (120.8-725.7), respectively, on the innovator therapy and 1.05 (mg*h/L)/mg/kg (0.54-2.22) and 317.1 (ng/ml)/mg/kg (116.7-564.7) for the generic drug after the switch. The median (range) percentage of change in the AUC and C2 when switching between formulations were 16.7 % (0.7-56.7) and 13.1 % (3.7-68.6), respectively. No significant changes in serum creatinine levels were registered when comparing before and after substitution of products. Adverse events (number of events) recorded 5 months before and after the switch included hirsutism (2), hypertension (2), and gingival hyperplasia (1). CONCLUSION: Conversion of cyclosporin from innovator brand to generic in pediatric renal transplant patients needs to be closely monitored.

Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients.

AIMS: Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on TAC metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and TAC disposition in a cohort of Brazilian transplant recipients. METHODS: Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan® PCR technique. Diplotypes were analyzed for correlation with the TAC dose-normalized ratio (Co : dose). RESULTS: We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1 TTT/TTT diplotype showed a higher Co : dose ratio compared with wild type subjects [median (interquartile range) 130.2 (97.5-175.4) vs. 71.3 (45.6-109.0), P < 0.0001 and 151.8 (112.1-205.6) vs. 109.6 (58.1-132.9), P = 0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1 TTT/TTT individuals showed a higher Co : dose ratio compared with non-TTT/TTT individuals [167.8 (130.4-218.0) vs. 119.4 (100.2-166.3), P = 0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors. CONCLUSIONS: CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC PK, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect TAC disposition, showing independent and additive effects on the TAC dose-normalized concentration.