Protopic
Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience.

Tan HP, Kaczorowski DJ, Basu A, Khan A, McCauley J, Marcos A, Fung JJ, Starzl TE, Shapiro R.

The Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, UPMC Montefiore, Suite NE 758.1, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA. tanhp upmc.edu

BACKGROUND: End-stage renal disease (ESRD) is an increasing problem in patients infected with the human immunodeficiency virus (HIV). The use of highly active antiretroviral therapy (HAART) has decreased the morbidity associated with HIV and has prompted renewed interest in renal transplantation. METHODS: We performed four cases of deceased donor renal transplantation in HIV+ recipients and three cases where laparoscopic live donor nephrectomy (LLDN) was utilized to obtain the kidney for transplantation into living-related HIV+ recipients. In the four deceased donor cases, conventional tacrolimus-based immunosuppression, without antibody induction was used. In the three living-related cases, the immunosuppressive regimen was based on two principles: recipient pretreatment and minimal posttransplant immunosuppression. Alemtuzumab 30 mg (Campath 1-H) was used for preconditioning followed by low-dose tacrolimus monotherapy. RESULTS: Of the four deceased donor cases, one patient continues to have good graft function, and another is not yet on dialysis but has significant graft dysfunction. Rejection was observed in three patients (75%). Infectious complications occurred in one patient (25%), all non-acquired immunodeficiency syndrome (AIDs) defining. In the three living-related cases, all had good graft function, and none have experienced acute rejection. HIV viral loads remain undetectable. CD4 counts are slowly recovering. No infectious or surgical complications occurred. There were no deaths in either group. CONCLUSIONS: These data suggest that living-related donor renal transplantation with steroid-free tacrolimus monotherapy in a "tolerogenic" regimen can be efficacious. However, long-term follow-up is needed to confirm this observation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15591960&dopt=Abstract tacrolimus Protopic



Protopic
Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis.

Mollee P, Morton AJ, Irving I, Durrant S.

Bone Marrow Transplant Unit, Royal Brisbane Hospital, Brisbane, Australia. durrants health.qld.gov.au

We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion, concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11328304&dopt=Abstract tacrolimus Protopic



Protopic
Reasons why some children receiving tacrolimus therapy require steroids more than 5 years post liver transplantation.

Jain A, Mazariegos G, Kashyap R, Marsh W, Khanna A, Iurlano K, Fung J, Reyes J.

Thomas E. Starzl Transplantation Institute, Department of Surgery and Department of Pharmaceutical Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

Tacrolimus is a potent immunosuppressive agent and has been used in liver transplantation (LTx) for nearly a decade. More than 70% of children can be maintained on tacrolimus monotherapy, without steroids, by the end of 1 yr post-Tx. This freedom from steroids does not appear to change significantly in subsequent years. The use of steroids has obvious metabolic and cosmetic disadvantages, besides affecting linear growth in children. The present study identifies why some children still require steroid therapy after successful LTx. One hundred and sixty-six consecutive pediatric patients who had undergone primary LTx between October 1989 and December 1992, were included in this study. Follow-up ranged from 6 to 9 yr (mean 7.5 +/- 0.8 yr). One hundred and forty-one children were alive in November 1998 and these patients constituted the study group. Their current rate of prednisone use, reason for prednisone use, and prednisone dose were examined retrospectively. Of the 141 patients, 139 (98.5%) had stopped taking steroids at some time-point after LTx. Thirteen patients (9%) were off immunosuppression altogether (group I), 97 were undergoing tacrolimus monotherapy (group II), and the remaining 31 were receiving therapy with steroids and tacrolimus (group III). The mean prednisone dose at the last follow-up was 6.5 +/- 4.9 mg/day (median 5.0 mg/day). In group III, two children were never weaned off steroids because of inadequate follow-up (both lived outside the country), and the remaining 29 children completely stopped steroid therapy at some time-point after LTx; however, prednisone was re-introduced for clinically suspected or biopsy-proven rejection in 24. Seven children in group III had completely stopped immunosuppressive therapy either as part of an immunosuppression reduction protocol (n = 3) or for suspected or proven post-transplant lymphoproliferative disorder (PTLD) (n = 4). In eleven of the 18 children in group III, requirement of steroid for rejection was thought to be related, in part, to non-compliance. In three children in group III, steroids were re-introduced for renal dysfunction, and two of these patients subsequently received a kidney Tx. In one child with cerebral ischemia, steroids were used to reduce brain edema, and another child had features of auto-immune hepatitis. Hence, almost all children can be weaned off steroids when tacrolimus is used as primary immunosuppression after primary LTx. However, approximately 22% of children may need re-institution of steroids because of late acute rejection or renal dysfunction. The concomitant use of other non-steroidal immunosuppressive agents with tacrolimus may further reduce the dose and rate of steroid use.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11328546&dopt=Abstract tacrolimus Protopic



Protopic
Therapeutic drug monitoring of tacrolimus in pediatric liver transplant patients.

MacFarlane GD, Venkataramanan R, McDiarmid SV, Pirsch JD, Scheller DG, Ersfeld DL, Fitzsimmons WE.

DiaSorin Inc., 1990 Industrial Blvd., Stillwater, Minnesota 55082, USA. gordon.macfarlane diasorin.com

The clinical utility of tacrolimus monitoring in adults has been well documented. The present study compared tacrolimus monitoring in a pediatric population of 34 liver transplant patients in four US centers with an adult population of 111 patients in six US centers. Subjects (adult and pediatric) were evaluated, at defined intervals over 12 weeks post-transplantation (Tx), for tacrolimus trough concentrations and 12 additional laboratory chemistries. Pediatric patient and graft survival for the 12 weeks were 91% and 88%, respectively, as compared to 97% and 93%, respectively, for the adult population. The mean oral dosage of tacrolimus for pediatric patients was 0.13 +/- 0.1 mg/kg/day at week 1, increased to 0.30 +/- 0.3 mg/kg/day by week 3 and remained constant for the remainder of the study. These dosages were two- to three-fold higher than the dosage used in the adult population. In contrast, the mean whole-blood trough concentration, as determined by PRO-Tractrade mark II enzyme-linked immunosorbent assay (ELISA), decreased from 11.3 +/- 5.1 ng/mL at week 1 to 6.3 +/- 3.7 ng/mL by week 12 and was not significantly different from the trough concentration in adults. The incidence and distribution of the clinical end-points for the pediatric subjects (rejection, nephrotoxicity, death, re-Tx) were different from those observed in adults. The total percentage of pediatric subjects reaching any end-point was 74%, as compared to 54% in the adult population. These data indicate several differences between the adult and pediatric populations in their response to tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11328550&dopt=Abstract tacrolimus Protopic



Protopic
Hematologic abnormalities in children and young adults receiving tacrolimus-based immunosuppression following cardiothoracic transplantation.

Dobrolet NC, Webber SA, Blatt J, Michaels M, Kiaffas M, Kurland G, Boyle GJ.

Miami Children's Hospital, Division of Cardiology, 3200 SW 60th Court, Miami, FL 33155, USA. nancy.dobrolet mch.com

To define the incidence, course, and etiology of hematologic abnormalities in children on tacrolimus-based immunosuppression, we reviewed records of 106 transplant patients (70 heart, 16 heart and lung, 20 double lung), 0-21 yr of age, who were transplanted at the Children's Hospital of Pittsburgh from 1989 to 1997. Fifty-four of the 106 patients (51%) developed 65 abnormal hematologic episodes (32 anemia, nine neutropenia, nine thrombocytopenia, 15 simultaneous anemia and neutropenia with or without thrombocytopenia). Common etiologies included: infections, post-transplant lymphoproliferative disease, and medications. Eleven episodes (seven anemia, one neutropenia, and three simultaneous anemia and neutropenia) had unclear etiologies and process of elimination suggested an association with tacrolimus. Interventions included filgrastim (effective in 15 of 15 patients, with resolution of neutropenia in a median of 5 days) and epoetin alfa (effective in five of 16 patients, including four of four patients with anemia possibly related to tacrolimus). Five patients (two with neutropenia and three with simultaneous neutropenia and anemia) were switched to cyclosporin A (CsA); rapid resolution occurred in four of the five patients, suggesting a possible association of the hematologic abnormalities with tacrolimus. In summary, hematologic abnormalities are common in children on tacrolimus-based immunosuppression. Most of these hematologic abnormalities are caused by common etiologies; however, a sub-population exists where tacrolimus may be the etiologic agent. Anemia and neutropenia respond to treatment with epoetin alfa and filgrastim. After thorough investigation, a trial switch to CsA may be warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11328551&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus as a rescue immunosuppressant after heart transplantation.

De Bonis M, Reynolds L, Barros J, Madden BP.

Department of Cardiothoracic Surgery, St. George's Hospital, Blackshaw Road, SW17 0QT, London, UK.

OBJECTIVE: The purpose of this retrospective study is to review our experience with tacrolimus as a rescue immunosuppressant for heart transplant recipients with refractory rejection or cyclosporine intolerance. METHODS: From June 1995 to November 1998, 15 cardiac transplant recipients were converted from our standard cyclosporine-based immunosuppressive regimen to a tacrolimus-based treatment. Each patient had been treated with cyclosporine, azathioprine and steroids. Six were switched to tacrolimus for persistent rejection, four for recurrent acute rejection and five for severe debilitating side-effects attributed to cyclosporine. All ten patients converted to tacrolimus because of rejection had been treated with high-dose methylprednisolone intravenously and four had also received anti-lymphocyte globulin (ALG; one patient) or anti-thymocyte globulin (ATG; three patients) preparations. RESULTS: The time between transplantation and conversion to tacrolimus ranged from 44 to 1866 (median, 380) days. The range of follow-up after conversion was 84-1379 (median, 806) days. Eleven patients are alive with a follow-up period of 764+/-435 (median, 820) days. Four patients died between 90 and 930 (median, 464) days after conversion. The average number of episodes of acute rejection/recipient decreased from 2.1+/-1.6 on the cyclosporine regimen to 0.2+/-0.4 on the tacrolimus regimen (P<0.001). When the incidence of acute rejection was normalized for follow-up times (episodes/100 patient-days), the results were 1.1+/-1.4 and 0.07+/-0.2, respectively (P<0.01). The persistent/recurrent rejection resolved in all ten patients who were converted to tacrolimus. None of the five cyclosporine intolerant patients converted to tacrolimus experienced rejection after the changeover. CONCLUSIONS: In our experience, conversion from a cyclosporine-based to a tacrolimus-based maintenance immunosuppression has been shown to be an effective and safe approach to the management of patients with persistent or recurrent cardiac allograft rejection or those with cyclosporine intolerance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11343954&dopt=Abstract tacrolimus Protopic



Protopic
Effects of tacrolimus on hemispheric water content and cerebrospinal fluid levels of glutamate, hypoxanthine, interleukin-6, and tumor necrosis factor-alpha following controlled cortical impact injury in rats.

Stover JF, Schoning B, Sakowitz OW, Woiciechowsky C, Unterberg AW.

Department of Neurosurgery, Charite-Virchow Medical Center, Berlin, Germany. john.stover charite.de

OBJECT: Disturbance of calcium homeostasis contributes to evolving tissue damage and energetic impairment following traumatic brain injury (TBI). Calcium-mediated activation of calcineurin results in production of tissue-damaging nitric oxide and free oxygen radicals. Inhibition of calcineurin induced by the immunosuppressant tacrolimus (FK506) has been shown to reduce structural and functional damage after ischemia. The aims of the present study were to investigate time- and dose-dependent short-term antiedematous effects of tacrolimus following TBI. METHODS: A left temporoparietal contusion (controlled cortical impact injury [CCII]) was induced in 51 male Sprague-Dawley rats. Tacrolimus (1 or 3 mg/kg body weight) was administered by a single intraperitoneal injection at 5 minutes, 30 minutes, or 4 hours after CCII occurred. Control rats received physiological saline. Water contents of traumatized and nontraumatized hemispheres, as well as cerebrospinal fluid (CSF) levels of mediators reflecting tissue damage (the proinflammatory cytokines interleukin [IL]-6 and tumor necrosis factor [TNF]-alpha, the excitotoxin glutamate, and the adenosine triphosphate-degradation product hypoxanthine), were determined 24 hours after trauma. Although CSF levels of IL-6 and TNFalpha were completely suppressed by tacrolimus at all time points and at both concentrations, CSF levels of glutamate and hypoxanthine, as well as edema formation, were only marginally influenced. Significant reduction of cerebral water content was confined to nontraumatized hemispheres. In addition, the higher dose of tacrolimus failed to exert significant antiedematous effects on traumatized hemispheres. CONCLUSIONS: Under the present study design, the potency of tacrolimus in reducing edema formation following CCII seems limited. However, its immunosuppressive effects could be of value in influencing the posttraumatic inflammatory response known to aggravate tissue damage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11354410&dopt=Abstract tacrolimus Protopic