Cyclosporine Trough Concentrations Research Articles

Assessment of risk factors for acute graft-versus-host disease post-hematopoietic stem cell transplantation: a retrospective study based on a proportional odds model using a nonlinear mixed-effects model.

Acute graft-versus-host disease (aGVHD) is a major complication following hematopoietic stem cell transplantation (HSCT). This study aimed to explore the risk factors for the incidence of aGVHD in patients post-HSCT. This was a retrospective study. A total of 407 patients were enrolled. The patients' data were recorded from the medical records. The exposure of cyclosporine was estimated based on a population pharmacokinetics model. The occurrence of aGVHD was clinically graded and staged in severity from grades I to IV. A proportional odds model that estimated the cumulative probabilities of aGVHD was used to analyze the data using a nonlinear mixed-effects model. Then, the model parameters and plausibility were evaluated by bootstrap and visual predictive checks. The typical probabilities were 18.9% and 17.9% for grade II and grades III-IV, respectively. The incidence of grade II and grade III-IV aGVHD for human leukocyte antigen (HLA) haplo sibling donor patients was higher than that for HLA-matched donor patients. The incidence of grade II and grade III-IV aGVHD decreased with increasing early cyclosporine trough concentration; however, cyclosporine exposure was not associated with the incidence of aGVHD. HLA matching and early cyclosporine trough concentration were important factors for the occurrence of aGVHD.

Reassessing the six months prognosis of patients with severe or very severe aplastic anemia without hematological responses at three months after immunosuppressive therapy

目的再评估影响免疫抑制治疗（IST）后3个月未获血液学反应的重型/极重型再生障碍性贫血（SAA/VSAA）患者6个月疗效的因素。方法回顾性分析2017−2018 年连续收治的173例初治行IST且治疗后3个月未获血液学反应的SAA/VSAA患者的临床资料，对IST后3个月时的临床特征和血液学参数进行再评估，通过单因素和多因素分析找出影响6个月疗效获得的相关指标。结果单因素分析结果显示IST后3个月无效患者的HGB（P＝0.017）、PLT（P＝0.005）、网织红细胞绝对计数（ARC）（P<0.001）、环孢素A血药浓度谷值（CsA-C0）（P＝0.042）、血清可溶性转铁蛋白受体（sTfR）（P＝0.003）、网织红细胞绝对计数改善值（ARCΔ）（P<0.001）、血清可溶性转铁蛋白受体改善值（sTfRΔ）（P<0.001）与IST后6个月疗效有关。多因素分析结果显示PLT<10×109/L（P＝0.020）和ARCΔ<6.9×109/L（P<0.001）是IST后3个月未获血液学反应患者6个月疗效的危险因素。IST后6个月未获血液学反应组3年总生存率［（80.1±3.9）％对（97.6±2.6）％，P＝0.002］和无事件生存率［（31.4±4.5）％对（86.5±5.3）％，P<0.001］均明显低于获得血液学反应组。结论对IST后3个月未获血液学反应的SAA/VSAA患者再评估以预测其6个月疗效非常重要；IST后3个月残存造血仍是影响预后的主要参数；ARCΔ可反应骨髓造血是否正在恢复及恢复的程度；IST后3个月无效患者若ARCΔ<6.9×109/L，无论PLT为何值，IST后6个月的血液学反应率均较低。

Relationship between cyclosporine area-under-the curve and acute graft versus host disease in pediatric patients undergoing hematopoietic stem cell transplant: A prospective, multicenter study

Traditionally in hematopoietic stem cell transplant (HSCT), cyclosporine doses are individualized using cyclosporine trough concentrations (C0) while area under the concentration vs time curve (AUC) is used in solid organ transplant. AUC potentially has an important relationship with the development of acute graft-versus-host-disease (aGVHD). We conducted a prospective study to describe the relationship between severe (grade III-IV) aGVHD and cyclosporine AUC in pediatric HSCT recipients. Pediatric patients who underwent allogeneic myeloablative HSCT and scheduled to receive cyclosporine for aGVHD prophylaxis participated in this multicenter study. Cyclosporine doses were adjusted based on C0 according to each center’s standard of care. Cyclosporine AUC was determined weekly until neutrophil engraftment or Day +42, whichever was later. Associations between severe aGVHD and cyclosporine AUC and other patient and treatment-related factors were evaluated. Of the 110 children enrolled, 97 were evaluable. Thirty-seven (38%) children developed aGVHD; 13 (13.4%) had severe aGVHD. On univariate analysis, there was no association between severe aGVHD and cyclosporine AUC at any time point before engraftment. Future research should focus on refinement of C0 targets for cyclosporine therapeutic drug monitoring in HSCT.

Association of CYP3A4*1B genotype with Cyclosporin A pharmacokinetics in renal transplant recipients: A meta-analysis

ObjectiveCyclosporine (CsA) is a substrate of cytochrome P450 (CYP) 3A4 with a narrow therapeutic index and large individual difference. CYP3A4*1B is reported to be associated with CsA pharmacokinetics parameters, but the relevance is still in dispute. Therefore, a meta-analysis was employed to evaluate the influence of CYP3A4*1B on CsA pharmacokinetics at different post-transplantation times in adult renal transplant recipients. MethodsStudies on evaluating the CYP3A4*1B genotype and CsA pharmacokinetics were retrieved through a systematical search of relevant database including PubMed, Emabase, Web of science, the Cochrane Library, Clinical Trials.gov and three Chinese literature databases (up to 15 October 2017). The pharmacokinetic parameters: weight-adjusted CsA daily dose (Dose), cyclosporine trough concentration (C0) and trough concentration/weight-adjusted CsA daily dose ratio (C0/Dose ratio) were extracted, and all statistical analysis were performed by using Review Manager 5.1.0. ResultsFour studies (involving 452 adult renal transplant recipients) were included in this meta-analysis. For the C0/Dose ratio, in all included renal transplant recipients, CYP3A4*1B carriers exhibited higher C0/Dose ratio than CYP3A4*1 (WMD 7.38, 95% CI 1.26–13.51; P = 0.02). The differences between CYP3A4*1B carriers and CYP3A4*1 in Dose (WMD 0.36, 95% CI 0.85–0.12; P = 0.14), C0 (WMD 10.81, 95% CI 77.72–99.34; P = 0.81) were not statistically significant. According to post-transplantation time, subgroup analysis also showed no significant statistical significance between CYP3A4*1B carriers and CYP3A4*1 carriers in Dose or C0. However, this result should be further explored because only four studies were included. ConclusionsCYP3A4*1B is associated with CsA C0/Dose ratio in renal transplant recipients which indicates patients with CYP3A4*1B allele require lower dose of CsA to reach target blood concentration compared with the CYP3A4*1 carriers.

Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma

Recurrence of hepatocellular carcinoma (HCC) is a major complication after liver transplantation (LT). The initial immunosuppression protocol may influence HCC recurrence, but the optimal regimen is still unknown. 219 HCC consecutive patients under Milan criteria, who received an LT at 2 European centres between 2000 and 2010, were included. Median follow-up was 51 months (IQR 26-93). Demographic characteristics, HCC features, and immunosuppression protocol within the first month after LT were evaluated against HCC recurrence by using Cox regression. In the explanted liver, 110 patients (50%) had multinodular HCC, and largest nodule diameter was 3±2.1cm. Macrovascular invasion was incidentally detected in 11 patients (5%), and microvascular invasion was present in 41 patients (18.7%). HCC recurrence rates were 13.3% at 3 years and 17.6% at 5 years. HCC recurrence was not influenced by the use/non-use of steroids and antimetabolites (p=0.69 and p=0.70 respectively), and was similar with tacrolimus or cyclosporine (p=0.25). Higher exposure to calcineurin inhibitors within the first month after LT (mean tacrolimus trough concentrations >10ng/ml or cyclosporine trough concentrations >300ng/ml), but not thereafter, was associated with increased risk of HCC recurrence (27.7% vs. 14.7% at 5 years; p=0.007). The independent predictors of HCC recurrence by multivariate analysis were: high exposure to calcineurin inhibitors defined as above (RR=2.82; p=0.005), diameter of the largest nodule (RR=1.31; p<0.001), microvascular invasion (RR=2.98; p=0.003) and macrovascular invasion (RR=4.57; p=0.003). Immunosuppression protocols with early CNI minimization should be preferred in LT patients with HCC in order to minimize tumour recurrence.

Everolimus Versus Mycophenolate Mofetil in Heart Transplantation: A Randomized, Multicenter Trial

In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard-dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: -7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients

Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation. A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4(*)1G, CYP3A5(*)3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 -94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation. The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 -94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the -94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026]. These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.

Hyperhomocysteinemia After Kidney Transplantation

Objective To determine the prevalence of hyperhomocysteinemia (plasma homocysteine[Hcy] concentration ≥15 μmol/L) and evaluate its correlation with allograft function. Materials and Methods The study included 159 stable renal transplant recipients (104men and 55 women). The prevalence and severity of hyperhomocysteinemia werecompared in the transplant recipients vs 72 patients (48 men and 24 women) receivinghemodialysis therapy. Results The mean (SD; range) fasting total Hcy concentration was higher in thehemodialysis group compared with the renal transplantation group: 27.4 (18.3; 10–95)μmol/L vs 16.6 (9.5; 4.5–45.0) μmol/L ( P = .00). Hyperhomocysteinemia occurred morefrequently in patients receiving hemodialysis therapy (74% vs 49%). No significantcorrelation was observed between Hcy concentration and recipient sex, cyclosporinetrough concentration and concentration at 2 days after dosing, dyslipidemia,cytomegalovirus infection, diabetes mellitus, or aspartate or alanine aminotransferaseconcentration. Multivariate regression analysis revealed that serum creatinineconcentration ( P = .02) was the major determinant of increased total Hcy concentration inrenal transplant recipients. Conclusion A high prevalence of moderate hyperhomocysteinemia was observed in renaltransplant recipients. There was no correlation between graft function and Hcyconcentration.

Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation Helio Tedesco-Silva Jr, Claudia Rosso Felipe, Tain&aacute; Veras de Sandes Freitas, Marina Pontello Cristeli, Carolina Ara&uacute;jo Rodrigues, Jos&eacute; Osmar Medina PestanaNephrology Division, Hospital do Rim e Hipertens&atilde;o, Universidade Federal de S&atilde;o Paulo, BrazilAbstract: Everolimus is an immunosuppressive agent used for the prophylaxis of acute rejection after kidney transplantation. Everolimus inhibits the activity of the serine/threonine kinase mammalian target of rapamycin (mTOR), a key enzyme that controls cell growth and metabolism, producing cell cycle arrest from the G1 to S phase. As a consequence, everolimus has antiproliferative and antineoplastic effects. Everolimus is a drug with a narrow therapeutic index. The pharmacokinetics of everolimus indicates a need for twice-daily dosing. Intra- and interindividual variability and drug&ndash;drug interactions suggest the need for therapeutic drug monitoring to maximize the efficacy/toxicity ratio. The good correlation between exposure (area under the concentration&ndash;time curve) and trough concentration indicates that monitoring of everolimus trough concentrations is an adequate strategy after kidney transplantation. Everolimus is indicated for low- to moderate-risk de novo kidney transplant candidates. There are no conclusive studies thus far indicating that everolimus can be used in high-risk patients, such as sensitized patients, retransplants, and African Americans. In de novo kidney transplant recipients, the recommended initial dose of everolimus is 0.75 mg twice daily, adjusted to maintain blood trough concentrations of 3&ndash;8 ng/mL, in combination with progressive reduction in blood trough cyclosporine concentrations to 25&ndash;50 ng/mL. In combination with reduced trough blood tacrolimus concentrations of 4&ndash;7 ng/mL the recommended initial dose of everolimus is 1.5 mg twice daily, adjusted to maintain trough blood concentrations of 3&ndash;8 ng/mL. Everolimus can also be used as a conversion strategy, mainly to preserve renal function and to manage patients with malignancy. There is no definition of the ideal strategy for conversion, ie, abrupt or sequential, initial dose of everolimus, or target therapeutic trough blood concentrations. Intensive monitoring is recommended after conversion, especially for acute rejection and proteinuria. Because mTOR is ubiquitous and central to many intracellular processes, an array of adverse reactions may occur, including delayed tissue regeneration, proteinuria, dyslipidemia, diabetes, myelosuppression, infertility, ovarian cysts, and mouth ulcers. Because long-term benefits are the goal of any immunosuppressive strategy, further investigations aiming to understand, prevent, and manage everolimus-related adverse reactions are necessary to mitigate the risks and improve tolerability, allowing maximization of all the benefits of this drug.Keywords: everolimus, immunosuppression, mTOR inhibitors, calcineurin inhibitors, kidney transplantation

Rationale for Monitoring Cyclosporine Concentration at 2 Hours After Administration in Infants Posttransplantation

Therapeutic drug monitoring is critical to avoid overimmunosuppression or underimmunosuppression in young pediatric transplant recipients. The objective of this study was to examine cyclosporine (CsA) trough (C0) and 2-hour post-dose (C2) concentrations in the early period after liver transplantation (OLT) to determine whether CsA C2 monitoring is justified. Seventeen infants younger than 2 years treated with CsA (Neoral) were monitored at C0. The biopsy-proved acute rejection rate was 65% at 3 months post-OLT. No correlation was observed between values at C0 and C2. Poor absorption of CsA was observed in most infants during the first 2 weeks post-OLT, as well as interindividual variability in CsA clearance. Exposure to CsA could not be estimated using either C0 or C2 determinations in the early post-OLT period. As a marker of poor absorption, C2 is useful but does not indicate delayed or rapid clearance of drug without simultaneous measurement of concentration at C0. We suggest the use of both C0 and C2 monitoring, or AUC monitoring on an individual basis during at least the first 2 weeks post-OLT.

Enfuvirtide: A safe and effective antiretroviral agent for human immunodeficiency virus-infected patients shortly after liver transplantation

The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV)-coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir-exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm3. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence.

Ralstonia pickettiiSepticemia in a Dog with Immune‐Mediated Thrombocytopenia

<i>Ralstonia pickettii</i>Septicemia in a Dog with Immune‐Mediated Thrombocytopenia

CYP3A7, CYP3A5, CYP3A4, and ABCB1 Genetic Polymorphisms, Cyclosporine Concentration, and Dose Requirement in Transplant Recipients

Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype; n = 8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P < 0.05) and required significantly higher daily doses per weight (P < 0.01) than the nonexpressors (*3/*3 genotype; n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437C>T influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P < 0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.

Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.

Inactivity of Hidradenitis Suppurativa After Renal Transplantation

phylactic effect. Other drugs had never been tried and major surgery had not been performed. When the patient learned about his irreversible renal failure he wished to receive a renal transplant. At first we were concerned due to the risk of infectious complications and the lack of reports in the literature. As a preliminary step the patient was prescribed cyclosporine in order to test the effect of immunosuppressive treatment ontheskindisease,hopingforacurative response but monitoring for an infectious exacerbation. In spite of a cyclosporine trough concentration of about 100 g/L for nine months, no change was noted. A year ago, the patient received a living donor kidney which has functioned adequately (serum creatinineconcentrationof130–160mol/L) onanimmunosuppressiveregimenconsisting of tacrolimus, mycophenolate mofetilandprednisolone.Alreadyinthe first postoperative weeks it was noticed that new skin lesions did not develop. Now, when the patient is receiving tacrolimus 6 mg b.i.d. (trough concentration 8–12 ng/L) and mycophenolate mofetil 750 mg b.i.d., there are still no signs of disease activity. In this case, immunosuppressive treatment was accompanied by a total regression of the activity of hidradenitis suppurativa, leaving only old scars. Low-dose cyclosporine monotherapy had no effect whereas an immunosuppressive regimen including tacrolimus andmycophenolatemofetiltotallyabolished the disease activity during an observation period of one year. There are no reports of tacrolimus treatment in hidradenitis suppurativa but mycophenolate mofetil has been reported to be effective in pyoderma gangrenosum (3), a skindiseasethatsharessomefeatureswith hidradenitissuppurativa.Thepresentcase supports the notion that it is of great importance to master the inflammatory component of hidradenitis suppurativa. Moreover, it serves as an encouragement for transplanting organs to these patients.

Disposition of Two Oral Formulations of Cyclosporine in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants

To compare the disposition of cyclosporine after the administration of two oral formulations to children undergoing hematopoietic stem cell transplantation, and to evaluate the relationship between whole blood cyclosporine concentrations during the dosing interval and the area under the whole blood concentration-time curve. Prospective, descriptive, crossover study.Setting. Hematopoietic stem cell transplantation unit in a tertiary-quaternary university-affiliated pediatric hospital. Twenty-four pediatric patients aged 0.5-16.9 years undergoing allogeneic hematopoietic stem cell transplantation. The modified oral formulation of cyclosporine was given on the first day (divided as two doses), and a single identical dose of the original oral formulation was given on the morning of the second day. Blood samples were obtained at 0, 0.5, 1.25, 2, 4, 6, 9, and 12 hours after the morning dose from the lumen of the central venous catheter not previously used for intravenous cyclosporine administration. Cyclosporine concentration-time data were analyzed by using noncompartmental methods. Mean +/- SD maximum concentrations were significantly higher after administration of the modified form than after administration of the original form (594.9 +/- 349.7 vs 483.0 +/- 363.0 microg/L, p=0.003), as was the area under the concentration-time curve from 0-12 hours (AUC0-12; 3432 +/- 1563 vs 3144 +/- 1780 microg/L x hr, p=0.022). For both formulations, cyclosporine concentrations at 4 hours after administration were most strongly correlated with the AUC0-12. Unlike that of the original formulation, the trough cyclosporine concentration of the modified form had the weakest relationship with AUC (Spearman rho coefficient 0.584, p=0.003). Cyclosporine absorption is lower in children undergoing hematopoietic stem cell transplantation than in children receiving solid organ transplants. Dosage adjustment for the modified formulation based on trough concentration may not be appropriate because its relationship with the AUC was weak. The link between pharmacokinetic parameters and clinical outcomes, such as graft-versus-host disease, must be further studied.

Does Bioequivalence Between Modified Cyclosporine Formulations Translate into Equal Outcomes?

Neoral was replaced with a generic cyclosporine formulation on our hospital formulary. We compared outcomes for de novo kidney transplant recipients who either received Gengraf (n=88) or Neoral (n=100) in a single-center, retrospective review. As compared to patients who received Neoral, patients who received Gengraf were significantly more likely to have an acute rejection episode (39% vs. 25%, P=0.04), more likely to have a second rejection episode (13% vs. 4%; P=0.03), or to have received an antibody preparation to treat acute rejection (19% vs. 8%; P=0.02). Patients treated with Gengraf had a higher degree of intrapatient variability for cyclosporine trough concentrations as determined by %CV (P<0.05). The incidence of acute rejection at 6 months posttransplant was significantly higher in patients who received Gengraf compared to Neoral. A larger, prospective analysis is warranted to compare these formulations of cyclosporine in de novo kidney transplant recipients.

Leukocyte phenotype and function predicts infection risk in renal transplant recipients

The degree to which transplant recipients are immunosuppressed influences their risks of rejection, infection and cancer. Current measures of immune suppression are crude (clinical events) or indirect (drug exposure). We assessed a direct measure of immune status, leukocyte phenotype and function (LPF, a composite measure of five aspects of peripheral blood leukocyte phenotype and function), as a predictor of infection. A double-blind, prospective, cohort study was conducted, to determine the burden of infection in stable renal transplant recipients with moderate-severe (Group I, n = 34) or minimal (Group II, n = 36) impairment of LPF, a composite score of: (i) CD4 count; (ii) lymphocyte proliferation in response to phytohaemagglutinin A (PHA); (iii) serum Ig concentrations; (iv) neutrophil phagocytic function; and (v) reactive oxygen species generation. Subjects completed a 6 month diary and each recorded infection was scored 1-4: 1, minor undefined infection (e.g. URTI); 2, minor, microbiologically defined infection (e.g. UTI); 3, major defined infection (requiring hospitalization); 4, opportunistic infection (e.g. Herpes zoster). Final infection score was the sum of all infective episodes. Subjects were then followed-up for 5 years for outcome measures. Groups were well matched for age, sex, diabetes, serum creatinine, rejection and trough cyclosporin concentrations. Group I (moderate to severe impairment of LPF) recorded a higher infection score, 2.4+/-2.8 vs 1.2+/-1.2 for Group II, P = 0.02, due to a higher incidence of moderate to severe infection. This relationship was confirmed by multivariate analysis (OR 1.83, CI 1.08, 3.11, P = 0.03 per unit increase in infection score). During the 5 year follow-up period they had significantly more episodes of admission to hospital, and twice as many admissions due to infections, but no difference in malignancy, graft or patient outcome. LPF testing prospectively identified a cohort who incurred a higher burden of infection. Further studies are required to determine the predictive value of LPF for acute rejection, infection and cancer, and to determine whether adjustments to therapy on the basis of LPF can lead to improved outcomes.

Sildenafil Citrate Treatment for Erectile Dysfunction After Kidney Transplantation

Objective Our goal was to analyze the morbidity of organic erectile dysfunction (ED) in kidney-transplant patients and to evaluate the efficacy and reliability of sildenafil citrate treatment. Method Sixty-five ED patients with normal graft function for 3 to 12 months after kidney transplantation were involved in our study. Erectile dysfunction was diagnosed in all the patients by the International Index of Erectile Dysfunction (IIEF). Among them, 10 patients were in light degree; 32 patients in moderate degree, and 23 patients in severe degree according to IIEF score. All of the patients underwent medical history, physical and chemical examinations. In each patient, the IIEF score, blood urea nitrogen, creatinine, and trough concentrations of cyclosporine were compared before and after taking sildenafil citrate at an initial dose of 50 mg every night. Results Twenty-six patients without ED before transplantation suffered ED after the operation, and 32 patients with ED before transplantation noticed worsening. Taking sildenafil citrate was effective in 53 patients (81.54%). There were no statistical differences in blood urea nitrogen, creatinine, or trough concentrations of cyclosporine in patients before and after sildenafil treatment. Conclusions The morbidity of organic erectile dysfunction increased after transplantation. Sildenafil citrate treatment for ED in kidney-transplant patients was effective and safe. Graft function and trough concentrations of cyclosporine were not affected by sildenafil citrate.

Blood Cyclosporine Level Soon After Kidney Transplantation is a Major Determinant of Rejection: Insights From the Mycophenolate Steroid-Sparing Trial

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C 0) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C 2) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C 0 levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C 2 levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.