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Rakesh Sindhi

Publications and source records attributed to Rakesh Sindhi.

At least 19 recordsLinked to original sources
PubMed2007

Persistent donor-specific alloreactivity may portend delayed liver rejection during drug minimization in children.

Immunoreactivity, immunosuppression requirement and liver graft function was assessed serially for its relationship to delayed/recurrent acute cellular rejection (ACR) after the first 60 days in 36 pediatric primary liver transplant (LTx) recipients. Subjects were classified as rejectors (n=20) or Non-Rejectors (n=16) based on the presence/absence of biopsy-proven ACR in the first 60 days. All children received anti-lymphocyte induction and steroid-free Tacrolimus or Sirolimus monotherapy, as reported previously. Median age was 4 years (0.45-18) and follow-up was 570 days (106-1144). Compared with non-rejectors, rejectors 1. took significantly longer to achieve reduced donor-specific alloreactivity by MLR (p=0.049), and "low" TAC/SRL whole blood requirements defined as TAC levels < or = 8 ng/ml (p=0.0048), 2. experienced significantly greater variation in time to achieve reduced donor-specific immunoreactivity (SEM 0.8 vs 3.85, p=0.0048), and 3. experienced greater ACR incidence during minimization of immunosuppression (35% versus 6%, p=0.032). Serial monitoring of immunoreactivity may increase the safety with which immunosuppression is minimized in pediatric LTx.

Adolescent↗
PubMed2006

Individualizing combination of two antiproliferative immunosuppressants with pharmacodynamic modeling of stimulated lymphocyte responses.

BACKGROUND: Unpredictable serious adverse events (SAE) of immunosuppression, e.g. nephrotoxicity, with the nephrotoxic immunosuppressants have fostered interest in alternative regimens, which contain two antiproliferative agents, and individualized therapy. However, titration of such combinations to individual needs is not understood. SPECIFIC AIM: To determine concentration (C) mixtures of mycophenolate mofetil (MMF) and sirolimus (SRL), which produce half-maximal inhibitory effect (EC(50)) on human lymphocytes from individual subjects. METHODS: Concentration mixtures of MMF (0-5 mug/ml) and SRL (0-30 ng/ml) were incubated with whole blood from each of five healthy human subjects. The intracellular cytokines IL-2, TNF-alpha, and IFN-gamma were measured in PMA-ionomycin-stimulated T-cells (CD4+), while CD54, CD95, CD86, CD25, CD69, and CD71 were measured in pokeweed mitogen-stimulated B-cells, by flow cytometry. Pharmacodynamic (PD) relationships were evaluated using Hill equations modified for single and multidrug regimens, and expressed as EC(50) for each target receptor. RESULTS: No change was seen in the expression of the T-cell cytokines with either MMF or SRL. Each B-cell receptor was inhibited with increasing concentrations of either MMF or SRL. Each B-cell receptor was also inhibited half-maximally at lower concentrations of MMF in the presence of SRL, than with either agent alone, for the test population of five subjects together, and for each of five individual subjects. However, each subject showed distinctly different amounts of MMF and SRL that needed to be present together, in order to produce an identical inhibitory effect on lymphocyte function. CONCLUSIONS: PD analysis of biological effect can potentially predict optimal concentration mixtures of two immunosuppressants for individual recipients, and enhance rejection prophylaxis and safety. While this holds promise for drug development efforts, clinical application must await correlation of lymphocyte markers with post-transplant clinical outcomes.

Antigens, CD↗
PubMed2005

Reduced immunosuppression in pediatric liver-intestine transplant recipients with CD8+CD28- T-suppressor cells.

Twelve pediatric liver (n = 7), liver-kidney (n = 1), and small bowel (n = 4) transplant recipients, median age 6.5 years (1-21), who received rabbit anti-human thymocyte globulin (rATG) and steroid-free tacrolimus/sirolimus, were screened for the presence of CD8+CD28- T suppressor cells. Four control liver transplant recipients, median age 15 years (5-20), in whom conventional immunosuppression without rATG was successfully discontinued for at least 1 year, were also screened as a reference population. Median time to CD8+CD28- T-suppressor cells analysis was 16 months (2-24) in rATG subjects and 168 months (16-228) in no-immunosuppression subjects. Nine of 16 patients demonstrated the presence of CD8+CD28- T-suppressor cells in the circulation, whereas seven patients did not. CD8+CD28- T-suppressor cells were present in 4/4 children with no immunosuppression, and absent from three of four subjects with acute cellular rejection, all of whom experienced more than one acute cellular rejection episode. In the reduced immunosuppression group (n = 8), four children demonstrated presence of CD8+CD28- T-suppressor cells in the circulation and four did not. The presence of donor-specific T-suppressor cells in the circulation may characterize transplant recipients, in whom graft function can be maintained with minimal or no immunosuppression. Such assays may also permit safe evaluation of prospective immunosuppression withdrawal strategies.

Adolescent↗
PubMed2005

Evolutionary experience with immunosuppression in pediatric intestinal transplantation.

BACKGROUND/PURPOSE: Intestinal transplantation has developed to become the standard of care for patients with irreversible intestinal failure who are not responding to total parenteral nutrition. Once considered experimental, it has taken time and much effort for the procedure to become a clinical reality, with final acceptance primarily because of the vastly improved outcomes. Advances and novel modifications in immunosuppression have been at the forefront of these improvements. The authors review their evolutionary experience with intestinal transplantation, particularly relating changes in immunosuppression protocols to improved outcomes. METHODS: From July 1990 to December 2003, 122 children received 129 intestinal containing allografts (70 liver/intestine, 42 isolated intestine, 17 multivisceral). Mean age was 5.3 +/- 5.2 years, and 55% were boys. Indications for transplantation were mostly short gut syndrome. The allografts were cadaveric, ABO identical (except one), with no immunomodulation. Bone marrow augmentation was used in 29% of the recipients since 1995. T-cell lymphoctytotoxic crossmatch was positive in 24% cases. Immunosuppression protocols can be divided into 3 categories: (i) maintenance tacrolimus and steroids (n = 52, 1990-1995, 1997-1998); (ii) addition of induction therapy with cyclophosphamide (n = 16, 1995-1997) then daclizumab (n = 24, 1998-2001). A third immunosuppressive agent was added in either group where increased immunosuppression was indicated; (iii) pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). In this later group, if clinically stable at 60 to 90 days posttransplantation, and no recent rejection, the tacrolimus was weaned by decreasing frequency of dosing. RESULTS: The overall Kaplan-Meier patient/graft survival was 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years. Survival continues to improve, with 1-year patient/graft survival being 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively. Acute intestinal allograft rejection has decreased markedly in group (iii). The rate of infectious diseases, such as cytomegalovirus and Epstein-Barr virus, is lowest in group (iii). Graft-versus-host disease has not significantly increased with the latest protocol. Most importantly, the overall level of immunosuppression requirements has decreased markedly, with most patients in group (iii) being on monotherapy. Of these, most had their monotherapy weaned down to spaced doses, something never systematically attempted or achieved in pediatric intestinal transplantation. CONCLUSIONS: Intestinal transplantation has progressed markedly over the last 13 years. Although there have been modifications in all aspects of the procedure, the story of intestinal transplantation has been the evolution of successful immunosuppression regimens. Our latest pretreatment/induction conditioning and posttransplantation monotherapy strategy improves graft acceptance and lowers subsequent immunosuppression dosing requirements. It is expected this will overcome many of the complications related to the previously high immunosuppression requirements. Minimization of immunosuppression with avoidance of steroid therapy offers profound long-term benefits, especially in the pediatric population. The patients still remain challenging and complex in every aspect; however, these advances offer significant hope to both patients and caregivers alike.

Adolescent↗
PubMed2005

Carcinoma of donor origin after liver-intestine transplantation in a child.

Tumor-related complications after intestinal transplantation in children have been principally EBV driven post-transplant disorders. We describe the clinical course of a child, with a diagnosis of microvillus inclusion disease who received a liver and intestine allograft at the age of 9 months. His postoperative course was significant for multiple episodes of acute intestinal allograft rejection and eventually the development of post-transplant lymphoproliferative disorder (PTLD), which resolved. At 8 yr post-transplant he presented with masses in the intestine allograft mesentery and in the right lobe of the allograft liver, biopsy of which revealed a relatively undifferentiated tumor, suggestive of a carcinoma. In situ hybridization for X and Y chromosomes, revealed his tumor to be of donor origin. Treatment included debulking of the mesenteric mass with segmental enterectomy of the intestinal allograft, and stopping his immunosuppression for a period of 4 months; this resulted in complete resolution of his malignancy. Immunosuppression with tacrolimus and steroids was restarted because of intestinal allograft rejection; he died suddenly of unknown causes at 17 months post-diagnosis of carcinoma. The severely immunosuppressed state produced in this patient allowed for the development of an unusual donor derived carcinoma, which resolved spontaneously with withdrawal of immunosuppression. The mechanism of such regression of tumor may be related to restitution of immunologic competence, but is yet to be determined.

Child↗
PubMed2005

Sclerosing peritonitis after intestinal transplantation in children.

Long-term graft dysfunction and/or graft loss after intestinal transplantation (ITx) is a significant concern. Sclerosing peritonitis (SP) is a manifestation of chronic allograft failure and its presence may also include classic arterial obliterative arteriopathy (OA) as in chronic rejection. We describe the clinical presentation and management of SP occurring after ITx in children. Case records of 121 children undergoing ITx from 1990 to 2003 were reviewed. Three children (2.4%) presented with SP of the intestine allograft at a mean time of 6.6 yr following ITx as follows: age at Tx (yr) 8.2, and 3.7, with indication for ITx being gastroschisis in two and midgut volvulus in one patient. Type of ITx was isolated intestine in one and liver/intestine in two patients. Gross findings of SP included fibrosis/strictures; microscopically SP showed fibrosis/serositis, and fibrous adhesions; one patient had evidence of chronic allograft vasculopathy. All patients presented with clinical signs and symptoms of bowel obstruction and gastrointestinal contrast studies confirmed distal ileal obstruction (DIO). Operative findings confirmed SP and DIO in all patients; all patients were initially treated with distal segmental intestine allograft resection and lysis of the fibrous peel. All three patients recovered, although two required repeat laparotomy, there is only one long-term survival. SP after ITx may be a different manifestation of long-term intestine allograft degeneration. Surgical resection appears to offer palliation.

Child↗
PubMed2005

Replacing calcineurin inhibitors with mTOR inhibitors in children.

A highly selected subject group comprising pediatric recipients of liver (n = 36) and small intestine alone (n = 1) or multivisceral graft (n = 2) were converted to sirolimus maintenance therapy for tacrolimus-related side effects (n = 32) or by primary intent (n = 7). Indications were nephrotoxicity (n = 14), primary intent (n = 7), post-transplant lymphoproliferative disorder (n = 6), seizures (n = 4), recurrent acute rejection (n = 2), and cardiomyopathy (n = 1). Thirty subjects (78%) experienced successful conversion, with one subject requiring atorvastatin for hypercholesterolemia and hypertriglyceridemia. Nine subjects (22%) were converted back to tacrolimus for serious adverse events including acute rejection (n = 2), elevated liver function tests (n = 1), severe leucopenia (n = 1), non-compliance (n = 2), recurrent malignancy/death (n = 1), steatohepatitis (n = 1), and thrombocytopenic thrombotic purpura (n = 1). Among subjects with nephrotoxicity, significant benefit was seen only in those subjects with shorter time to rescue after transplantation (n = 8 of 14 subjects). Additional benefits included a significant decrease in mean serum creatinine from pretransplant values for the entire population, and elimination of antihypertensive treatment in all five subjects receiving it prior to conversion. Hemoglobin, serum cholesterol and triglycerides, white cell counts and platelets remained within normal limits for the duration of follow-up (36 month). Conversion from tacrolimus to sirolimus is successful in selected pediatric liver and intestine recipients. Chronic nephrotoxicity may be ameliorated by early conversion. Improvement in renal function and hypertension management, and absence of sirolimus-related adverse events argue for prospective evaluation of regimens in which mTOR inhibitors are used without calcineurin inhibitors in children.

Calcineurin Inhibitors↗
PubMed2005

Enhanced donor-specific alloreactivity occurs independently of immunosuppression in children with early liver rejection.

UNLABELLED: To determine whether early acute cellular rejection (ACR) is associated with sub-optimal immunosuppression in children with liver transplants (LTx). METHODS: Twenty-five children with primary LTx after pre-transplant rabbit anti-thymocyte globulin (rATG), and steroid-free tacrolimus (TAC) were evaluated. Mitogen-stimulated T- and B-cell responses and mixed lymphocyte response to donor and third-party antigens were performed at several time points between two consecutive TAC doses. TAC concentrations (C) associated with half-maximal effect (EC(50)) on lymphocytes was determined by pharmacodynamic equations. RESULTS: Mean age was 7.2 +/- 6.2 years, mean time to lymphocyte function studies was 25 +/- 19 days. Acute rejection occurred at a mean interval of 31 +/- 19 days after LTx. Rejectors (n = 16) demonstrated significantly higher EC(50) of TAC for the intra-cellular IFN-gamma in T cells (p = 0.005) and its CD8+ sub-population (p = 0.027) as well as the co-stimulatory/activation receptor CD54 on B cells (p = 0.0001). The response of recipient lymphocytes to donor antigen was significantly higher in rejectors, compared with non-rejectors (p = 0.015). The patient groups demonstrated no differences in third-party MLR, or in C of TAC. CONCLUSIONS: Independent of the amount of immunosuppressant, ACR of liver allografts in children is associated with enhanced donor-specific alloreactivity. This is accompanied by a cytotoxic T-cell sub-population with increased requirement for TAC.

Adolescent↗
PubMed2005

Intestinal transplantation under tacrolimus monotherapy after perioperative lymphoid depletion with rabbit anti-thymocyte globulin (thymoglobulin).

Modifications in the timing and dosage of immunosuppression can ameliorate the morbidity and mortality that has prevented widespread use of intestinal transplantation (ITx) in children. Thirty-six patients receiving ITx, aged 5 months to 20 years were given 2-3 mg(kg of rabbit anti-thymocyte globulin (rATG, thymoglobulin) just before ITx, and 2-3 mg(kg postoperatively (total 5 mg(kg). Twice daily doses of tacrolimus (TAC) were begun enterally within 24 h after graft reperfusion with reduction of dose quantity or frequency after 3 months. Prednisone or other agents were given to treat breakthrough rejection. After 8-28 months follow-up (mean 15.8 +/- 5.3), 1- and 2-year patient and graft survival is 100% and 94%, respectively. Despite a 44% incidence of acute rejection in the first month, 16 of the 34 (47%) survivors are on TAC (n = 14) or sirolimus (n = 2) monotherapy; 15 receive TAC plus low dose prednisone; one each receive TAC plus sirolimus, TAC plus azathioprine and TAC plus sirolimus and prednisone. There was a low incidence of immunosuppression-related complications. This strategy of immunosuppression minimized maintenance TAC exposure, facilitated the long-term control of rejection, decreased the incidence of opportunistic infections, and resulted in a high rate of patient and graft survival.

Adolescent↗
PubMed2005

Immunosuppressant strategies for intestinal transplantation: a review of a tolerogenic regimen.

Intestinal, combined liver-intestinal, and multivisceral transplantation are now considered the standard of care for children and adults with permanent intestinal failure. Early attempts at intestinal transplantation were discouraging because of the high incidence of technical complications, rejection, and infection. Advances in the field of transplantation, including the introduction of tacrolimus, improved surgical techniques, and improvements in postoperative care, have led to a renewed interest in intestinal transplantation since 1990. The most significant achievement, however, has been the effective control of rejection and life-threatening infections. This article focuses on the experience to date of innovative strategies that induce lymphocyte depletion and reduction in the incidence of rejection. In this setting, low-maintenance immunosuppression is clinically achievable with an acceptable rate of allograft rejection. Subsequently, the long-term complications of immunosuppression are significantly reduced with achievement of better long-term survival, and an overall improvement in the quality of life.

Graft Rejection↗
PubMed2004

Transient posttransplant graft-versus-host lymphadenopathy.

There is sparse information in humans on graft-versus-host (GVH) lymphadenopathy. A 15-month-old male received a liver and small bowel transplant for short bowel after gastroschisis. At 21 days he developed a GVH-like skin rash. Flow cytometry demonstrated 16.1% circulating donor cells. Polymerase chain reaction for Epstein-Barr virus was negative. Two months later, the rash recurred with diffuse lymphadenopathy. Lymph node biopsy showed effaced architecture without visible follicles, large numbers of CD79a(+) immunoblasts interspersed with smaller CD3(+) and CD8(+) cells, and prominent dendritic cell hyperplasia. Human herpes virus 8, cytomegalovirus, and EBER-1 probes were negative, as was polymerase chain reaction for human herpes virus 6. Allograft intestinal biopsies on days 10 and 24 had a similar infiltrate. The features appeared to be those of lymphocytes trafficking between the graft and host with a mixed lymphocyte reaction in situ, a GVH-type reaction without tissue damage. The reaction was self-limiting in the intestinal graft, and the lymphadenopathy resolved with some decrease in immunosupression. Circulating donor cells fell to 2.5% by day 62, and the child has been rejection free on low-dose immunosuppression.

Diagnosis, Differential↗
PubMed2004

Multiparametric effect: concentration analyses.

Immunosuppressant drug toxicity currently competes with acute rejection, as the major cause of efficacy failure of potent new agents in clinical transplantation. The development of mechanistic drug targets as surrogate endpoints for use in the clinic has been facilitated by fluorescent imaging techniques which measure multiple cytokines and cell surface receptors on stimulated (peripheral blood) lymphocyte responses. However, the promise of delivering customized drug therapy to the transplant recipient remains unfulfilled. In this brief review, computational algorithms that can relate multiparametric effects to clinical drug concentrations of immunosuppressants are discussed. Based on Hill equations, these pharmacodynamic modeling techniques have been used to simulate single-agent effects, combination regimen effects, as well as the individual response to combination regimens. The potential implications of these models crystallize the clinical challenges confronting practitioners of clinical, post-transplant immunosuppression.

Algorithms↗
PubMed2004

Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients.

To evaluate the pharmacokinetics of Sirolimus (SRL) and Tacrolimus (TAC) in pediatric transplant recipients. Fifty-one SRL and 55 TAC pharmacokinetic profiles were obtained from 20 male and 14 female recipients of liver alone (LTx, n = 23), small bowel alone, and with liver (SBTx, n = 11). The median age was 13.3 years (range 0.9-23.9). Whole blood concentrations of SRL and TAC were determined by liquid chromatography-mass spectrometry (LC-MS) and microparticulate enzyme immunoassay (MEIA-Abbott Laboratories, IL), respectively. Pharmacokinetic (PK) parameters were derived from noncompartmental model analysis. The half-life was estimated using the data points during the terminal disposition phase and area under the concentration (AUC) time curve was calculated within a dosing interval using the trapezoidal method. The dose of SRL or TAC did not correlate with the corresponding AUCs. Trough concentrations of SRL and TAC correlated well with AUC (r = 0.8544 and 0.8603, respectively). Half-life (h) did not differ significantly between different transplant groups for SRL and TAC (SRL: LTx: 21.2 h, SBTx: 19.3 h; TAC: LTx: 14.1 h, SBTx: 12.7 h). Serial PK analysis with the first measurement within 14 days after transplantation revealed no difference in AUC/dose/BSA for SRL, with time. During this period, SRL half-life increased significantly, from 11.2 +/- 1.0-20.1 +/- 3.1 h (n = 4; p = 0.02). After introduction of SRL, TAC half-life did not change (11.6 +/- 3.9-14.0 +/- 10.4, n = 10, P = 0.52) in all the groups analyzed together. TAC AUC/dose/BSA decreased significantly in LTx and SBTx patients (90.9 +/- 55.3 vs. 48.8 +/- 27.3). Trough concentration measurements provide good estimates of SRL and TAC exposure in pediatric transplant recipients. The short half-life of SRL in children may support twice-daily administration early after liver and small intestinal transplantation. During conversion of subjects from TAC to combined TAC and SRL, aggressive therapeutic drug monitoring must be used to individualize therapy and avoid serous adverse events.

Adolescent↗
PubMed2004

Graft versus host disease in intestinal transplantation.

Our aim was to analyze the clinical course and outcome of patients with graft vs. host disease (GVHD) after intestinal transplantation (ITx). All patients receiving ITx between May, 1990 and December, 2003 were retrospectively reviewed for evidence of GVHD. Two hundred and fifty patients underwent ITx during the study period. Graft vs. host disease was suspected clinically in 23 patients on the clinical basis of presentation such as skin rash, ulceration of oral mucosa, diarrhea, lymphadenopathy, or native liver dysfunction. Fourteen (eight children and six adults) patients (5.6% of total patient population) had GVHD confirmed by histopathological criteria including keratinocyte necrosis (n = 9), epithelial apoptosis of the native gastrointestinal tract (n = 4), and epithelial cell necrosis of oral mucosa (n = 1). Donor-cell tissue infiltration or extensive peripheral blood donor-cell chimerism was documented on seven occasions. The majority of cases of GVHD resolved with steroid administration and optimization of tacrolimus immunosuppression. The incidence of histologically proven GVHD after clinical intestinal transplantation is 6.5% (8/122) in children and 4.7% (6/128) in adults. Successful clinical management requires a high index of suspicion to minimize morbidity and mortality. Diagnostic and treatment strategies based on this experience are proposed.

Adolescent↗
PubMed2004

Pancreatic transplantation at the University of Pittsburgh.

Campath-1H preconditioning with tacrolimus monotherapy is an effective immunosuppressive regimen for pancreas transplantation, with acceptable patient and graft survival rates early after transplantation. Rejection rates are low under this protocol if the tacrolimus level is kept consistently >10 ng/ml. This immunosuppressive protocol, combined with recent technical refinements, has resulted in lower rates of thrombosis and overall complications. Pancreatic transplantation en-bloc with visceral grafts has the following unique features: Diabetes is a rare indication, and HLA matching is not required. The gland is immunologically protected by the simultaneously transplanted visceral organs. Disease gravity, surgical complexity and gut alloimmunity influence the overall pancreatic allograft survival. The current UNOS listing criteria and data registry should be modified for obvious logistic and scientific reasons.

Adolescent↗