Cyclosporine Trough Levels Research Articles

Gout and Transplantation: New Treatment Option—Same Old Drug Interaction

Calcineurin inhibitors, particularly cyclosporine, may increase the risk of gout after transplantation. Concomitant use of azathioprine (AZA) and allopurinol is usually avoided in transplant recipients because of the well-known interaction between these two drugs resulting in leukopenia (1–4). Febuxostat (Uloric) is a new, Food and Drug Administration-approved, xanthine oxidase (XO) inhibitor for chronic management of hyperuricemia in patients with gout (5). Although structurally unrelated to allopurinol, febuxostat may have a drug interaction profile similar to allopurinol because of its effect on XO. Detailed drug interaction reports of AZA and febuxostat are scarce. To our knowledge, this is one of the first case reports documenting a likely drug interaction between AZA and febuxostat. CASE REPORT A 66-year-old white woman presented to the Transplant Clinic in February 2011 with nausea, vomiting, watery diarrhea, 10 pound weight loss over 1 month, malaise, fatigue, pancytopenia, and an elevated serum creatinine level (1.6 mg/dL, baseline 1.0–1.1). Of note, 6 weeks earlier, the patient presented to her physician's office with symptoms of recurrent gout and was started on febuxostat (40 mg daily). Her medical history is significant for end-stage renal disease secondary to polycystic kidney disease, deceased donor renal transplant (1995), and gout. Her immunosuppressive regimen included AZA, modified cyclosporine, and prednisone. Before her Transplant Clinic visit, she was seen by a gastroenterologist and hematologist for similar symptoms and to investigate profound pancytopenia. Her initial workup was negative, which led to the scheduling of a bone marrow biopsy. Before her bone marrow biopsy, she was seen in the Transplant Clinic and subsequently admitted to the hospital for further evaluation and management. She appeared acutely ill, and there was concern about potential opportunistic infection or malignancy. So, empiric broad-spectrum antimicrobials were initiated. Imaging studies, tumor markers, stool studies, and cultures were negative except for a nasopharyngeal swab positive for influenza B and trace positive Epstein-Barr virus in the blood (240 copies/mL). Nadir laboratory values during admission were total white blood cell count 700/mm3, absolute neutrophil count 630/mm3, hemoglobin 8.3 g/dL, and platelet count of 34,000/mm3. Liver function tests were within normal limits except for a slight increase in total bilirubin (1.7 mg/dL) that returned to normal within 1 week. Serum creatinine and cyclosporine trough levels were 1.9 mg/dL and 125 ng/mL, respectively. AZA and febuxostat were discontinued, and the patient was maintained on modified cyclosporine and prednisone. She received filgrastim to stimulate neutrophil production, blood products to correct anemia, intravenous fluid and electrolyte correction, and marrow supportive measures. The patient's symptoms improved markedly over the next 3 days, and she was subsequently discharged. Laboratory values at discharge included a total white blood cell count of 5900/mm3, hemoglobin 11.1 g/dL, platelet count 79,000/mm3, serum creatinine 1.2 mg/dL, and cyclosporine level 92 ng/mL. Follow-up clinic visits have documented laboratory values within normal limits, and the patient has remained asymptomatic. DISCUSSION Gout can be a challenging clinical problem in solid organ transplant recipients because of potential drug interactions. The combination of AZA and allopurinol may result in AZA toxicity. Nausea, vomiting, and reversible bone marrow toxicity consisting of leukopenia, anemia, and thrombocytopenia are hallmark features of AZA toxicity (2–4,6). AZA is a prodrug of 6-mercaptopurine, which is metabolized through three different pathways (1). Metabolic alterations in this process through XO inhibition can result in increased toxicity from 6-thioguanine nucleotides. Febuxostat is a potent inhibitor of XO and concurrent use with AZA is contraindicated (7). Because febuxostat is structurally unrelated to purine or pyrimidines (like allopurinol), it does not interfere with other enzyme pathways and is selective for XO. In addition, febuxostat inhibits both reduced and oxidized forms of XO (8). This mechanistic advantage produces sustained reductions in serum uric acid levels and may lead to drug-drug interactions caused by XO inhibition. In the case study described earlier in the text, although influenza B infection or Epstein-Barr viremia could be implicated in the acute development of pancytopenia and gastrointestinal symptoms, the time course of the onset of signs and symptoms relative to the initiation of febuxostat coupled with their rapid resolution after discontinuation of febuxostat and AZA strongly suggests a drug-drug interaction. This commentary highlights the importance of identifying and preventing avoidable drug-drug interactions that may increase morbidity, mortality, and costs. Healthcare providers caring for transplant recipients should check for potential drug-drug interactions, particularly with immunosuppressants, and/or inform the transplant program before starting any new medication. We recommend avoiding the simultaneous administration of febuxostat and AZA. If concurrent use is warranted, AZA doses should be reduced and patients monitored closely to prevent toxicity. Scott Kaczmorski1 William Doares1 Stephanie Winfrey2 Samer Al-Geizawi2 Alan Farney2 Jeff Rogers2 Robert Stratta2 1Department of Pharmacy Wake Forest Baptist Medical Center Winston-Salem, NC 2Department of General Surgery Wake Forest University Baptist Medical Center Winston-Salem, NC

Quantifying the impact of nonadherence patterns on exposure to oral immunosuppressants

Background and objectives:Nonadherence to oral immunosuppressive drugs in renal transplant patients remains a major challenge. The objective of this study was to develop an adherence-exposure model that 1) quantifies the impact of nonadherence patterns on cyclosporine levels and 2) identifies nonadherence patterns that are associated with unfavorable transplantation outcomes.Design, setting, participants, and measurements:This model quantified variability in drug exposure, expressed as the coefficient of variation (CV%), for time-averaged and trough cyclosporine levels (Cavg and Cmin, respectively), and percentage of days spent below the therapeutic Cmin target. Simulated patterns of nonadherence closely matched those observed in clinical practice for four nonadherence clusters and an “Others” category.Results:Patients in simulated nonadherence clusters 1–3 spent a mean (standard deviation) 5.8% (4.9), 9.0% (5.0), and 6.5% (3.4) of days below the Cmin target, compared with 76.8% (6.5) for cluster 4 and 38.3% (6.4) for the “Others” category. Mean (standard deviation) CV% values for Cmin were 24.1 (7.9), 35.4 (11.7), and 34.1 (10.6) for clusters 1–3, compared with 136.4 (23.6) for cluster 4 and 64.8 (10.3) for the “Others” category. Findings for Cavg were similar.Conclusion:Based on nonadherence patterns and known relationships between CV% for Cmin and Cavg, and transplantation outcomes, patients in cluster 4 and the “Others” category are expected to be at high risk of allograft rejection. The proposed drug adherence-exposure model is useful to identify high-risk patients who can be targeted for interventions aimed at enhancing drug adherence to optimize clinical long-term outcomes.

Randomized Trial on GvHD Prophylaxis with or without Anti-T-Cell Globulin ATG-Fresenius (ATG-F) In Allogeneic Hematopoietic Cell Transplantation From Matched Unrelated Donors: Final Results and Analysis of Prognostic Factors

AbstractAbstract 1249Previously, we could demonstrate that addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control group) significantly reduces severe acute and chronic GvHD, without negatively affecting non-relapse mortality (NRM), relapse rate (RR), disease-free survival (DFS) or overall survival (OS) (Finke et al., Lancet Oncol, 2009). Here we present final data of extended follow-up with a median of 3 (25%-quartile 2.5, 75%-quartile 3.9) years on 201 patients with median age of 40 (range 18–60) years, transplanted between 2003 and 2007, with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94). At Day +100, the primary efficacy endpoint - severe acute GvHD (aGvHD grade III-IV) or death was reached in 21.4% of patients in the ATG-F group versus 34.7% in the control group (p=0.098). Incidence of grade III-IV aGvHD was 11.7% in the ATG-F group and 25.5% in the control group (p=0.039). With extended follow-up the incidence of extensive chronic GvHD (cGvHD) after three years was 12.2% in the ATG-F group versus 45.0% in the control group (p<0.0001). DFS after three years was 48.0% in the ATG-F and 38.4% in the control group (p=0.71). Incidence of relapse after three years was 32.6% in the ATG-F and 28.2% in the control group (p=0.47). Incidence of NRM after three years was 19.4% in the ATG-F and 33.5% in the control group (p=0.18). OS after three years was 55.2% in the ATG-F and 43.3% in the control group (p=0.39).The effects of the prognostic factors patient age, donor age, patient/donor sex mismatch, patient/donor CMV status, HLA-C difference, type and status of disease, conditioning regimen, source of stem cells, cyclosporine trough levels during the first 30 days, on occurrence of aGvHD III-IV, extensive cGvHD, DFS, relapse, NRM, and OS were analyzed. Factors showing an effect with p<0.05 in univariate analyses were analyzed in multivariate analyses (both adjusted for treatment). Donor age above 40 years negatively affected the risk for aGvHD III-IV (hazard ratio (HR)=2.6, p=0.009), extensive cGvHD (HR=2.1, p=0.021) and OS (HR=1.7, p=0.016); patient age above 40 years negatively influenced NRM (HR=1.8. p=0.041), whereas advanced disease was a risk factor for aGvHD III-IV (HR=2.1, p=0.018), DFS (HR 1.7, p=0.004), relapse (HR=1.7, p=0.038), and OS (HR=1.9, p=0.002). Conclusion: ATG-F significantly reduces severe acute and chronic GvHD. Younger donors are to be preferred in unrelated donor transplantation. Older and advanced disease patients need special precautions to improve outcome. Disclosures:Finke:Fresenius Biothech GmbH: Research Funding. Bethge:Fresenius Biothech GmbH: Lecture remuneration.

Introduction of Mycophenolate Mofetil in Maintenance Liver Transplant Recipients: What Can We Expect? Results of a 10-Year Experience

Background Mycophenolate mofetil (MMF) is a cornerstone immunosuppressive drug after liver transplantation (OLT). The aim of this study was to evaluate the long term results of the addition of MMF in maintenance OLT recipients. Methods From 1996 to 2006, MMF was introduced because of (1) histologic features of rejection or (2) calcineurin inhibitor (CNI) toxicity in order to reduce CNI dosage. Results The study population included 208 patients (median, age 54 ± 9 years), with a median delay between OLT and MMF introduction of 54 ± 43 months. The median dosage of MMF was 1180 mg/d at the end of follow-up. After a median follow-up of 50 ± 26 months, 26.4% of the patients taking MMF did present ≥1 side effect and MMF discontinuation rate was 13.8% (transient in 3.8%). The main side effects were digestive disorders (45%), pruritus ± rash ± mucitis (12.7%), and myelosuppression (16.4%). MMF was withdrawn because of digestive disorders (17.2%), pruritus ± rash ± mucitis (17.2%), and myelosuppression (24.1%). The mean glomerular filtration rate as calculated by the Cockcroft-Gault formula value significantly increased after the introduction of MMF (58.1 vs 71.4 mL/min; paired t-test; P < .01). Improvement of renal function was significantly associated with initial association with tacrolimus (vs cyclosporine), initial trough level of cyclosporine (not tacrolimus), delay between OLT and MMF introduction, and age of renal impairment. Conclusion Our results suggest that the introduction of MMF in OLT maintenance recipients is efficient and well-tolerated (one quarter of the patients presented significant side effects, leading to treatment discontinuation in 10% of the patients).

Response to oral cyclosporine therapy and high sensitivity‐CRP level in chronic idiopathic urticaria

Chronic idiopathic urticaria (CIU) is often resistant to common treatment of uriticaria. To find out clinical and laboratory findings affecting the response of oral cyclosporine therapy in CIU. The response of oral cyclosporine therapy in 15 patients with CIU (male:female = 5:10, age 16-60 years old, mean 40.0 years old) was studied. Cyclosporine trough level was measured with an enzyme-multiplied immunoassay, and high sensitivity-CRP was measured with a nephelometric assay. The relation between high sensitivity-CRP level and clinical and laboratory findings in CIU was also studied. All the 15 CIU patients responded to oral cyclosporine therapy. High sensitivity-CRP levels before the start of therapy were elevated in nine of 15 CIU patients. The distributions of treatment duration and basophile leukocytes counts in elevated high sensitivity-CRP patients (8.7 +/- 1.3 months, 0.20 +/- 0.05%) were significantly shorter and elevated than those in patients showing no elevation (22.7 +/- 1.7 months, 0.40 +/- 0.05%) (P < 0.05, P < 0.05), respectively. No other clinical and laboratory findings between patients with elevated and not elevated high sensitivity-CRP showed any significant differences. Chronic idiopathic urticaria patients with elevated high sensitivity-CRP showed good response to oral cyclosporine therapy.

A Case of Successful Treatment of Cutaneous Aspergillosis with Voriconazole at the Low Cyclosporine Trough Level in a Renal Transplant

Aspergillosis is a serious infectious complication with high mortality in transplant recipients. Voriconazole is a broad spectrum triazole antifungal agent, but it has a drug-drug interaction with immunosuppressants. Herein we report a case of the use of a small dose of cyclosporine (CsA) with coadministration of voriconazole. A 23 year old woman received a kidney transplant from a deceased donor. The initial immunosuppressant was tacrolimus, mycophenolate mofetil, steroids, and basiliximab. Thirty-two days after kidney transplantation, because of hemolytic uremic syndrome, she received Rabbit anti-human thymocyte immunoglobulin and plasmapheresis. Cyclosporine was used instead of tacrolimus. Three months after transplantation, she was admitted to the hospital because of an erythematous nodule on her trunk and a dry cough. Skin biopsy revealed an Aspergillus species and tissue culture showed that it was A. fumigatus. We treated her with itraconazole and subsequently with amphotericin B. Afterwards, her condition got worse. So we changed amphotericin B to voriconazole and a minimum dose of CsA (25 mg bid) at the peril of graft failure. Eventually, she recovered and maintained good graft function. The trough level of CsA ranged from 3.2 to 27.9 ng/mL.

Induction Immunosuppression with Anti-CD25 Monoclonal Antibody (Basiliximab) Allows Delayed Initiation and Uptitration of Calcineurin Inhibitor Post Cardiac Transplant

Background:The role of anti-CDmonoclonal antibodies in induction immunosuppression for cardiac transplantation remains unclear. This study sought to determine if basiliximab allows delayed commencement, slower uptitration and reduced nephrotoxicity or allograft rejection with cyclosporin. Methods: We performed retrospective analysis of cardiac transplant patients on cyclosporin, mycophenolate mofetil, and corticosteroids and compared the results depending on whether they received basiliximab post transplant. Data was collected for 21 days post transplant. Exclusion criteria: <18 yrs old, alternative immunosuppression, multi-organ transplant. Results: 39 patients studied (basiliximab: 22; nonbasiliximab: 17). More patients in the non-basiliximab group were ex-smokers (71% vs. 32%, p= 0.025) and type 2 diabetics (35% vs. 4.5%, p= 0.03) but had similar demographics for stroke, hypertension, mechanical support and indication for transplant. No patients received OKT3 or antithymocyte globulin. Time to cyclosporin initiation (mean± 1SD) was 0.12± 0.35 days for non-basiliximab versus 1.50± 2.54 days for basiliximab (p= 0.003). Therapeutic cyclosporin levels (250–300mg/L) were reached later in the basiliximab arm (11.1± 3.7 days) versus (17.1± 7.4 days) (p= 0.003). There was a trend to decreased Grade 3 rejection on day 14 in the basiliximab arm (p= 0.09). There were no significant differences in average creatinine clearance between the groups within the initial 21 days (p= 0.71). Conclusion: Post cardiac transplant, basiliximab allowed delayed initiation and time to therapeutic trough levels of cyclosporin with a trend to decreased severe rejection on day 14. Nephrotoxicity was not reduced. A larger study group is needed to evaluate basiliximab’s effect on rejection rate and renal function.

Relationship Between Serum Homocysteine and Other Parameters in Renal Transplant Patients

Hyperhomocysteinemia frequently occurs after renal transplantation. We therefore assessed whether serum homocysteine (Hcy) concentrations were correlated with clinical, paraclinical, and arterial Doppler parameters among renal transplant patients. A cross-sectional study was performed on 47 patients (30 males, 17 females) who received unrelated living donor renal transplants. The mean serum Hcy concentration was 21.7 +/- 8.4 micromol/L (range = 5.8-48 micromol/L); 37 patients (79%) showed hyperhomocysteinemia (Hcy >or= 15 micromol/L). Serum Hcy was strongly related to body mass index (BMI; r = .43, P = .002), cyclosporine trough level (r = .44, P = .005), and serum creatinine concentration (r = .32, P = .028), but not to age, transplant duration, or sex. Multivariate analysis showed that only BMI (P = .003) and cyclosporine trough level (P = .0037) were independent predictors of serum Hcy concentrations. Hyperhomocysteinemia was more prevalent among patients taking mycophenolate mofetil (MMF) than azathioprine (86% vs 50%; P = 0.017). The hyperhomocysteinemia and normohomocysteinemia groups did not differ significantly in mean carotid intima-media thickness (IMT; 0.78 +/- 0.348 vs 0.77 +/- 0.419 mm, P = .97) or mean intrarenal resistive index (RI) (0.7 +/- 0.06 vs 0.7 +/- 0.06, P = .85). The two groups also did not differ in sex prevalence, diabetes, C-reactive protein >or= 5 mg/L, or mean low-density lipoprotein, high-density lipoprotein, and mean arterial pressure (MAP) values. Serum Hcy correlated with higher cyclosporine trough levels and obesity. Hyperhomocysteinemia was more common among patients taking MMF than azathioprine, but had no effect on intrarenal RI or carotid IMT.

Does Everolimus Associated With a Low Dose of Cyclosporine in Long-Term Cardiac Transplant Recipients Improve Renal Function? Initial Experience

Background Cyclosporine (CsA) renal toxicity is a well-known side effect. Various immunosuppressive strategies have been developed to minimize renal insufficiency. The use of everolimus associated with low levels of CsA can be an alternative strategy. Methods From October 2007 to April 2008, everolimus was started with a lower dose of cyclosporine (trough levels from 109.3 ± 27.5 to 93.7 ± 30.1 ng/mL after 45 days) in 21 cardiac transplant recipients (18 male and 3 female patients, mean age 56.4 ± 10.7 years). Pre-everolimus therapy creatinine levels, creatinine clearances, and glomerular filtration rates were 1.9 ± 0.9 mg/dL, 54.2 ± 18.1 mL/mins and 44.3 ± 16.5 mL/min/m 2, respectively. Results We observed a significant reduction in creatinine levels (from 1.9 ± 0.9 to 1.4 ± 0.3 mg/dL, P = .022) as well as a significant improvement in creatinine clearances (from 54.2 ± 18.1 to 69.0 ± 19.0 mL/min, P = .020) and glomerular filtration rates (from 44.3 ± 16.5 to 57.1 ± 16.3 mL/min/m 2, P = .010) after 7 days of everolimus therapy. Upon univariate analysis patient age, pretransplantation creatinine clearance, creatinine clearance after everolimus introduction, glomerular filtration rate at 45 days, and time from transplantation were associated with renal improvement. Upon multivariate analysis, only creatinine clearance at 7 days was related to the renal improvement. Conclusions These preliminary data suggested that everolimus with a low dose of CsA may be safe and effective to reduce CsA-related renal insufficiency among selected, heart transplant patients.

Successful Outcome after Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Renal Dysfunction

Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is a transplantation approach that enables patients with comorbid conditions to undergo allogeneic HSCT. We investigated the outcome of patients with reduced renal function as a single comorbidity before HSCT. Thirteen patients with a glomerular filtration rate (GFR) of <60 mL/min/1.73 m2 were matched on sex, age, and type of transplant to 26 controls with normal renal function. All patients received a nonmyeloablative HSCT with fludarabine and/or total body irradiation conditioning (TBI). Graft-versus-host disease (GVHD) prophylaxis consisted of mycophenolate mofetil and cyclosporine. Data on renal function, cyclosporine dose, cyclosporine trough levels, hypertension, and GVHD were collected. Of the 13 patients with impaired renal function, 7 patients (54%) improved or stabilized to a GFR>or=60 mL/min/1.73 m2 at last follow-up. Four patients (31%) developed chronic kidney disease stage 3 (GFR <60 mL/min/1.73 m2) compared to 3 patients (12%) in the control group (P=.039). There was no difference in survival between cases and controls. Furthermore, there were no differences in complications after HSCT, and cyclosporine dose and trough levels were similar between cases and controls. Nonmyeloablative HSCT can be safely offered to patients with mildly reduced renal function. Cyclosporine can be administered at the same dose as patients without renal dysfunction, as long as cyclosporine trough levels and creatinine are monitored and dose adjustments are made if necessary.

The correlation between response to oral cyclosporin therapy and systemic inflammation, metabolic abnormality in patients with psoriasis

Psoriasis is a disease presenting cutaneous, immunological and vascular abnormalities. Oral cyclosporin therapy has been shown to be effective for the disease. Clinical and laboratory findings affecting the response of oral cyclosporin therapy in patients with psoriasis were studied. Forty-seven patients with psoriasis (male:female = 27:20, age 56.7 + 12.6 years) were studied. The response to oral cyclosporin therapy was categorized as excellent, good, fair and poor according to decrease of PASI score and decrease of cyclosporin dose. Clinical and laboratory findings including cyclosporin trough level and high sensitivity-CRP were statistically analyzed. Nine patients showed excellent response, 17 good response, 19 fair response and 2 poor response. High sensitivity-CRP (0.11 +/- 0.02 mg/dl) in fair response patients to oral cyclosporin therapy was significantly lower than those in excellent response patients (0.42 +/- 0.21 mg/dl) (P < or = 0.05). Body mass index (23.4 +/- 0.6 kg/m(2)), HDL-cholesterol (57.1 +/- 3.6 mg/dl) and fasting plasma glucose (105 +/- 5 mg/dl) in fair response patients to oral cyclosporin therapy was significantly lower, higher and lower than those in excellent response patients (25.7 +/- 0.9 kg/m(2); 43.0 +/- 2.8, 140 +/- 20 mg/dl) (P < 0.05, P < 0.05, P < 0.05), respectively. No other clinical and laboratory findings showed statistical significance among excellent, good and fair response patients. These results showed the correlation between response of oral cyclosporin therapy and systemic inflammation, metabolic abnormality in patients with psoriasis.

Combined Pancreatic Islet-Lung Transplantation With Islet Percutaneous Portal Embolization in Cystic Fibrosis

Combined Pancreatic Islet-Lung Transplantation With Islet Percutaneous Portal Embolization in Cystic Fibrosis

Effect of Multiple Oral Dosing of Fluconazole on the Pharmacokinetics of Cyclosporine in Healthy Beagles

Fluconazole (Fcz) is successfully used in human organ transplant patients as an antifungal therapy. However, Fcz can increase the cyclosporine (CsA) trough level and lead to CsA nephrotoxicity. In canine renal transplantation, CsA has been used as a major immunosuppressant, and it is important to control its trough level. However, the interaction of Fcz with CsA has not yet been reported in dogs. In this study, the effect of Fcz treatment on the pharmacokinetics of CsA in four healthy beagles was investigated using a four-period crossover design. The treatments included CsA alone (A), CsA + multiple-dose Fcz 50 mg (B), CsA + multiple-dose Fcz 25 mg (C) and CsA + single-dose Fcz 50 mg (D). Blood CsA concentrations were measured at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after CsA administration. The AUC(0-12) and C(max) values for treatment B were significantly higher than those for the other treatments. In particular, the AUC(0-12) of treatment B was about two times higher than that of treatment A. Fcz administration did not significantly prolong the half-life or mean residence time of CsA. The results of our study show that administration of multiple therapeutic doses of Fcz can significantly increase the CsA blood concentration, which might partially depend upon the Fcz blood concentration. When Fcz is used in CsA-based canine renal transplantation, it may be necessary to adjust the CsA trough level by decreasing the dose.

Early renal injury after myeloablative cord blood transplantation in adults

We report a retrospective analysis of acute renal failure (ARF) in a group of 54 adult patients with hematological malignancies treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. ARF was defined as the doubling serum creatinine occurring within the first 100 days after CBT. A statistically significant decrement of renal function from baseline was observed in days between 11 and 20. ARF occurred in 27.8% of patients. Although no difference was seen in maximum cyclosporine trough levels, the maximum of vancomycin (VCM) trough levels were significantly higher in patients with ARF (p = 0.01). Our result suggests that it is important to monitor VCM dosing more strictly with pharmacokinetic assessment, especially in days 11 – 20, when the most frequently observed declining renal function.

Dry‐eye syndrome after allogeneic stem‐cell transplantation in children

To report the prevalence of dry-eye syndrome (DES) in children and young adults treated with allogeneic stem-cell transplantation (SCT) during childhood; to relate DES to conditioning regimes, including total body irradiation (TBI) and chemotherapy, and to immunosuppressive drugs and graft-versus-host disease (GVHD). This cross-sectional study included 60 children/young adults transplanted because of leukaemia, various haematological disorders and inborn errors of metabolism between 1986 and 2004, with a follow-up time of 7.0 years (median, range 2-18). Clinical assessments, performed at a median age of 15.6 years (range 5.5-23.5), included an inquiry form on dry-eye symptoms, corneal status including fluorescein staining, 'break-up time' (BUT) and Schirmer test. A total of 37 of 60 patients had DES defined as presence of corneal epithelial lesions with a pathological BUT and/or Schirmer test. Twenty-nine had had staining <1-10% of the corneal surface while eight patients had staining > or =10-25% of the corneal surface. All 37 patients with objective signs of DES, graded and not graded, had significant associations to subjective symptoms of dry eyes including dry eyes, red eyes, ocular irritation, secretion and sensitivity to light. Frequent occasions (above median; n = 7) of high cyclosporine A trough levels above 250 ng/ml were associated significantly with DES (P = 0.002). However, there was no association between DES and conditioning with single-dose (s-TBI) or fractionated TBI (f-TBI), busulfan or other chemotherapy. There were no associations between prolonged corticosteroid treatment or chronic GVHD and DES in the present study. DES was more common in patients with malignant diseases (P = 0.02). Malignant disease increased the risk of DES in girls but not in boys. Increased age at SCT increased the risk for DES in boys but not in girls (P = 0.02). Although severe keratitis occurred in three patients, nobody suffered corneal perforation. DES with epithelial punctata keratopathy was common in children/young adults treated with SCT and more common if the patients were exposed to repeated high trough levels of cyclosporine A; however, DES was not associated with irradiation, corticosteroids or GVHD in the present study. Patients with objective DES also had subjective symptoms of dry eyes, which facilitate diagnosis. Girls with malignant diseases and boys who underwent SCT at later ages seem to demand higher attention and more frequent check-ups regarding DES. Patients with diagnosed severe DES needed frequent and continuous ophthalmological care to maintain treatment motivation.

Effect of tangerine juice on cyclosporine levels in renal transplant children

The aim of our study was to investigate the effect of tangerine juice on the pharmacokinetics of cyclosporine A (CsA), in children who had received a renal transplant. This placebo-controlled study was done on ten kidney transplant recipients with stable cyclosporine trough levels who received either tangerine (Unshio Satsuma) juice or water. Patients were given their morning doses of CsA and then 250 ml water or the juice, and 12 h, investigations of the pharmacokinetics (PK) were performed. The main outcome measures were peak concentration and time to peak and area under the concentration-time curve. Administration of CsA with tangerine juice compared with water did not increase significantly the area under the whole-blood concentration versus time curve from 0-12 h (AUC(0-12)) of CsA, (tangerine juice 2,797 +/- 1,361 (P = 0.5); water 3,053 +/- 1,532). Co-administration of tangerine juice with CsA compared with water had no significant effects on the AUC(0-12), peak concentration (C(max)) or time to C(max) (t(max)) of the CsA in pediatric renal transplantation.

Adapting Cyclosporine to Calcineurin Activity Rather Than to Cyclosporine Blood Levels: Toward a Functional Management of Graft-Versus-Host Disease Prophylaxis.

We have previously shown [1] that a calcineurin activity (CA) < 28 pmol RII/mg proteins/min was significantly associated with the absence of acute GVHD after allogeneic stem cell transplant (SCT). The CA is poorly correlated with cyclosporine (CsA) trough level which is not a good marker of CsA efficacy. Therefore, the in vitro assessment of CA could help in adapting the cyclosporine doses for GVHD prophylaxis, better than blood CsA levels. Objective: The aim of this prospective study was to evaluate the feasibility of adapting the CsA doses to the values of in vitro CA either until GVHD occurs, or until day 100, whichever occurs first.Methods: CA assessment methods in PBMC of transplant patients and monoclonal CsA level measurement methods were previously reported [1]. CA and CsA levels were measured once a week from d0–d15, twice a week from d16–d35, then once a week up to d100. The CsA doses were adapted in order to maintain a CA < 28 from transplant by 20% progressive changes of the CsA daily dose. Adaptation was stopped in case of clinical CsA blood levels ≥ 600 ng/ml, creatinine clearance < 40 ml/mn, serum bilirubin > 40 m/L, or severe clinical toxicity.Patients: 39 adult patients with malignant hemotologic diseases (acute leukemia: 28; chronic leukemia: 4; others: 4) or aplastic anemia (3), and undergoing myeloablative SCT were included (HLA-id donor: 20; unrelated donor: 19). GVHD prophylaxis consisted in short course Methotrexate and CsA (initial dose: 3 mg/kg IV).Results: Out of 39 patients, 2 were adapted until d100 and did not develop GVHD; 27 were adapted without CsA toxicity until they developed GVHD (grade I: n=2; grade II: n=18; grade III–IV: n=7). In 10 (26%) patients, adaptation was stopped before d100, due to neurologic (n=1), renal (n=2) or liver (n=2) toxicity, severe nausea (n=1), investigator decision (n=1) or protocol violation (no CsA increase despite high CA and no CsA toxicity: n=3).Conclusion: Our study shows that CsA dose adaptation is feasible on the basis of CA regular assessment within the safety limits defined in our protocole. This adaptation is, however, limited by CsA toxicity, due to the need to significantly increase the CsA dose to get a CA < 28 pmol in 26% of the patients. A prospective controlled study is needed to compare the routine use of CA to the use of CsA blood levels for managing CsA doses in GVHD prophylaxis.

Primate uterus allograft transplantation

To present uterus allograft transplantation in a primate model. Animal model. 7 adult female rhesus monkeys (Macaca mulatta, Wt: 6.5–10.9 kg, age: 8–15 yrs) all parous, were used in an IACUC approved protocol for uterus transplant; 4 for uterus retrieval and 3 as recipients. Matching of donors and recipient was performed by blood-typing and MHC. Surgeries included general anesthesia (isoflurane) with intubation. 1 week preoperatively an internal jugular vein catheter was surgically inserted (remote sampling setup with jacket and cable attached to a single line). Prior to transplant surgery a femoral/carotid artery catheter was inserted. Both catheters allowed long and short term monitoring and injection of drugs. Pre-retrieval medications included low dose heparin, cyclosporine and vaginal antibiotics. Midline incision permitted retrieval from renal vessels to inguinal ligaments. Bolus heparin (1 mg/kg) adjusted by ACT (activated clotting time) was given prior to aorta cross-clamp. Retrieved organs were preserved in University of Wisconsin solution (UW) for a maximum of 4–8 hrs on ice, re-perfused with Ringer Lactate and anastomosed to the external iliac arteries/veins or the aorta/vena cava. Gravity flushing (1–2 liters UW) produced clear vena cava return. Gonadal vessel ligation improved perfusion efficiency. All 4 specimens could be retrieved (operative time initially 6, then <4 hours) i.e. low resistance, high volume flow with clear vena cava return for later transplantation. First retrieval animal suffered intra-op cardiac arrest; remaining 3 were euthanized. All 3 organs were anastomosed, reperfused and attached to the vagina. EBL was acceptable. One recipient received an autologous blood transfusion (100 ml). One recipient suffered an intra-op cardiac arrest during incision closing possibly secondary to a PE or reperfusion electrolyte changes. Another recipient survived to the following post-op day but received an erroneous high heparin dose and hemorrhaged. Last recipient is in stable condition with normal menses and normal pelvic sono/Doppler blood flow (>21 days). Target cyclosporin trough levels (150 ng/ml) achieved with 6.5 mg/kg/day after adjusting doses (range: 5–8 mg/kg) and daily determination of cyclosporine levels and bone marrow activity via blood sampling. Uterus allograft transplantation is possible in primates. Other large animal pregnancies have been achieved. They may now be possible in non-human primates.

Decline in 51Cr-labelled EDTA measured glomerular filtration rate following lung transplantation

The nephrotoxity of calcineurin inhibitors in lung-transplanted patients is well described, but previous studies have estimated rather than directly measured glomerular filtration rate (GFR). This study describes the decline of measured GFR in a large cohort of lung-transplanted patients from a national centre, and the correlation between measured and calculated GFR. All lung-transplanted patients 1992-2004 (n = 390) were included in a longitudinal analysis. Seven patients were excluded due to retransplantation. Pre- and post-transplant parameters included (51)Cr-labelled EDTA clearance (mGFR) and the Cockcroft-Gault calculated clearance (cGFR). Trough cyclosporine levels (C0) and demographic and transplant information were also included in the analysis. A total of 66959 C0 and serum creatinine and 1945 mGFR measurements pertaining to 383 patients were included in the analysis. Pre-transplant mGFR was significantly lower with respect to recipient age over 60 years; and patients with a referral diagnosis of pulmonary hypertension had a lower mGFR and higher baseline serum creatinine levels than patients with emphysematous disease (P < 0.05). There were linear correlations between log(10) mean interval serum creatinine and log(2) mGFR at all time points pre- and post-transplantation (P < 0.0001, Spearman correlation coefficient = -0.81) and between log(2) cGFR and log(2) mGFR (P < 0.0001, Spearman correlation coefficient = 0.81), however, the agreement between mGFR and cGFR was poor (-2.7 +/- 38.6 ml/min). A simplified repeated measure ANOVA model describing post-transplant GFR over time demonstrated a 54% decline in mGFR within the first 6 months post-transplant. Pre-transplant mGFR was an important determinant of 6 month post-transplantation mGFR. Increasing mean C0, body mass index and early acute renal failure were independent risk factors for a more rapid decline in post-transplant mGFR. mGFR decreases dramatically during the first 6 months after lung-transplantation. Avoidance of high dose calcineurin inhibition may postpone the onset of post-transplant end-stage renal failure.

Duplex Sonographic Measurements in Allografted Kidneys: A Cross-Sectional Study

Objectives The measurement of color Doppler sonography indices, such as resistive index (RI) and pulsatility index (PI), can help in the evaluation of an transplanted kidney. The aim of this study was to determine the correlation between Doppler sonography indices and demographic paraclinical findings in transplanted kidneys. Methods A cross-sectional study was performed on 47 (27 male and 20 female) unrelated living renal transplanted patients. Results The mean age, body mass index (BMI), time since transplantation, pulse pressure index (PPI), intrarenal RI and PI were 38 ± 13 years, 25 ± 4.5, 48 ± 31 months, 0.34 ± 0.06, 0.69 ± 0.06, and 1.3 ± 0.3, respectively. There were significant negative correlations between time since transplantation and intrarenal RI and PI ( r = −.38, P < .01; r = −.4, P < .01, respectively). There was a significant correlation between patient age, creatinine clearance, and intrarenal RI ( r = .30, P = .039; r = .3, P = .043, respectively). There were no significant correlations between intrarenal RI, PI, and BMI, cyclosporine trough level, PPI, recipient and donor sexes, and rejection episodes. Diabetic patients displayed higher RI (0.76 ± 0.02 vs 0.68 ± 0.06, P = .048) and patients with serum high-density lipoprotein (HDL) level < 40 mg/dL had higher PI than patients with HDL ≥ 40 mg/dL (1.6 ± 0.4 vs 1.2 ± 0.3, P = .006). Conclusions Intrarenal RIs did not decrease over a few years after transplantation. They can be a useful, feasible predictor of graft function. However, future multicenter trials should be performed to prove the predictive power of RI determination as a marker of renal function.