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Biomedical subjects

R Sindhi

Publications and source records attributed to R Sindhi.

At least 19 recordsLinked to original sources
PubMed2006

Elective liver transplantation for the treatment of classical maple syrup urine disease.

An 8.5-year-old girl with classical maple syrup urine disease (MSUD) required liver transplantation for hypervitaminosis A and was effectively cured of MSUD over an 8-year clinical follow-up period. We developed a collaborative multidisciplinary effort to evaluate the effects of elective liver transplantation in 10 additional children (age range 1.9-20.5 years) with classical MSUD. Patients were transplanted with whole cadaveric livers under a protocol designed to optimize safe pre- and post-transplant management of MSUD. All patients are alive and well with normal allograft function after 106 months of follow-up in the index patient and a median follow-up period of 14 months (range 4-18 months) in the 10 remaining patients. Leucine, isoleucine and valine levels stabilized within 6 hours post-transplant and remained so on an unrestricted protein intake in all patients. Metabolic cure was documented as a sustained increase in weight-adjusted leucine tolerance, normalization of plasma concentration relationships among branched-chain and other essential and nonessential amino acids, and metabolic and clinical stability during protein loading and intercurrent illnesses. Costs and risks associated with surgery and immune suppression were similar to other pediatric liver transplant populations.

Adolescent↗
PubMed2003

Sirolimus in pediatric transplant recipients.

The side effects of calcineurin inhibitors (CI) have a unique spectrum in pediatric recipients of organ transplants. These include a lifelong risk of mortality due to sepsis, a nearly 5% risk of renal failure from protracted exposure to CI, and a significantly higher risk of posttransplant lymphoproliferative disorder (PTLD) when compared with adults (10% versus 2%). This led us to explore the use of the new antiproliferative immunosuppressant sirolimus (SRL) for rescue and primary immunosuppression in recipients of pediatric abdominal and thoracic organs at the Children's Hospital of Pittsburgh. Following initial success with SRL in 50 such children, we also explored its use for the elimination of tacrolimus (TAC) in patients experiencing toxicity and for maintenance immunosuppression in steroid-sparing regimens in liver transplantation. These early results suggest that sirolimus may hold promise as a primary immunosuppressive agent under defined protocol conditions. The salient features of our experience with SRL in over 85 children are summarized here.

Bone Marrow Transplantation↗
PubMed2001

Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus.

AIMS: The role of sirolimus (SRL) as a rescue agent (n=42) and as a component of primary immunosuppression (n=8) was evaluated in a mixed population of 50 transplanted children receiving tacrolimus (liver: 26, heart: 5, intestinal: 5, liver-intestine: 9, lung: 1, bone marrow: 1, liver-kidney: 1, multivisceral: 1). Rescue indications for tacrolimus (TAC) failure were recurrent acute rejection and acute rejection complicating withdrawal of immunosuppression in posttransplant lymphoproliferative disorder (PTLD). Rescue indications for TAC toxicity were nephrotoxicity, pancreatitis, seizures, hypertrophic cardiomyopathy, and graft-versus-host disease. RESULTS: Mean age at rescue was 11.5 years and mean follow-up was 204 (range 18-800) days. As primary immunosuppression, SRL+TAC prevented early acute rejection in 7/8 children. The indication for rescue resolved in 33/42 children. In children with TAC toxicity, this was associated with decrease in TAC doses by 50%, significant improvements in renal function, and continuing decline in Epstein-Barr virus (EBV) viral load in PTLD patients. Serious adverse events led to discontinuation of SRL in 9/42 rescue patients, 3 of them also experienced acute rejection. Three additional children also experienced acute rejection on SRL therapy (overall incidence 6/50, 12%). Pharmacokinetic analysis in the first week of SRL administration suggested a short half-life (11.8+/-5.5 hr, n=21). CONCLUSIONS: SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.

Acute Disease↗
PubMed2001

Cytokines and cell surface receptors as target end points of immunosuppression with cyclosporine A.

Targets of cyclosporine (CsA) were identified from an array of stimulated lymphocyte responses (sLR) comprising 34 stimulation conditions in whole blood from 3 normal human volunteers (NHV) containing clinically relevant CsA concentrations (0-1200 ng/ml) in vitro. In whole blood from 5 additional NHV, selected targets (intracellular interleukin-2 [IL-2], tumor-necrosis factor-alpha [TNF-alpha], and interferon-gamma [IFN-gamma]) were measured in phorbol myristate acetate (PMA)-ionomycin-stimulated T lymphocytes. Effect:concentration relationships were analyzed with E(max) pharmacodynamic (PD) equations and expressed as the concentration associated with one-half maximal inhibitory effect (EC(50)). CsA demonstrated a rich matrix of inhibitory effects on T cells (CD3(+)), B cells (CD19(+)), dendritic cells (DC) (CD11c(+)), and basophils (CD123(+)) but not on monocytes (CD14(+)) (n = 3). PD analyses suggested that the EC(50) of CsA (1) for IL-2 in CD3(+) cells in NHV (n = 8) was similar to the EC(50) demonstrated by us previously in CD4(+) cells from transplanted patients (n = 13) (EC(50) = 260 ng/ml vs. 249 ng/ml), (2) for each cytokine was different under identical stimulation conditions (TNF-alpha, 324 ng/ml; IFN-gamma, 504 ng/ml), and (3) was relatively constant for a given cytokine under different stimulation conditions (e.g., PMA-ionomycin or the staphylococcal enterotoxin B [SEB] superantigen). In conclusion, inhibition of cytokine targets by CsA is concentration dependent. Further, a given CsA concentration may produce similar inhibitory effects across different stimulation conditions. Measurement of cytokine target expression may, therefore, allow effect-controlled administration of CsA during clinical transplantation.

Adult↗
PubMed2001

Clinical intestinal transplantation: a decade of experience at a single center.

OBJECTIVE: To assess the long-term efficacy of intestinal transplantation under tacrolimus-based immunosuppression and the therapeutic benefit of newly developed adjunct immunosuppressants and management strategies. SUMMARY BACKGROUND DATA: With the advent of tacrolimus in 1990, transplantation of the intestine began to emerge as therapy for intestinal failure. However, a high risk of rejection, with the consequent need for acute and chronic high-dose immunosuppression, has inhibited its widespread application. METHODS: During an 11-year period, divided into two segments by a 1-year moratorium in 1994, 155 patients received 165 intestinal allografts under immunosuppression based on tacrolimus and prednisone: 65 intestine alone, 75 liver and intestine, and 25 multivisceral. For the transplantations since the moratorium (n = 99), an adjunct immunosuppressant (cyclophosphamide or daclizumab) was used for 74 transplantations, adjunct donor bone marrow was given in 39, and the intestine of 11 allografts was irradiated with a single dose of 750 cGy. RESULTS: The actuarial survival rate for the total population was 75% at 1 year, 54% at 5 years, and 42% at 10 years. Recipients of liver plus intestine had the best long-term prognosis and the lowest risk of graft loss from rejection (P =.001). Since 1994, survival rates have improved. Techniques for early detection of Epstein-Barr and cytomegaloviral infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, and most recently allograft irradiation may have contributed to the better results. CONCLUSION: The survival rates after intestinal transplantation have cumulatively improved during the past decade. With the management strategies currently under evaluation, intestinal transplant procedures have the potential to become the standard of care for patients with end-stage intestinal failure.

Adult↗
PubMed2000

Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine+rapamycin regimen.

BACKGROUND: Clinically, cyclosporine (CSA, Neoral) is titrated to concentrations, and not to pharmacological effect. METHODS: Intracellular interleukin- (IL) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry, after isolation from 14 renal transplant recipients receiving CSA+prednisone, and double-blind rapamycin (rapamycin:placebo=4:1). RESULTS: The proportion (%) of CD4+IL-2+ lymphocytes corresponding to CSA levels (mean+/-SD ng/ml) measured preoperatively (TO=O), and on postoperative day 8, before (356+/-63), and 2 hr after the morning dose (Cmax=1567+/-669), decreased from 39+/-16 to 15+/-8 and 3+/-1.6, respectively. Reciprocally, unresponsive lymphocytes (%CD4+IL-2-) increased with increasing CSA levels and predicted an EC50 of 249 ng/ml (CSA concentration at which CD4+IL-2- cells increased by 50% over baseline) in an Emax pharmacodynamic model. CONCLUSIONS: Clinically, the pharmacological effect of CSA is quantifiable, and lies in the upper end of the predicted range. In our Neoral-treated sample population, Cmax was associated with the least variable "cyclosporine effect." Such information could potentially individualize immunosuppression, and lead to rational dosing strategies.

CD4-Positive T-Lymphocytes↗
PubMed2000

Split-liver transplantation: a comparison of ex vivo and in situ techniques.

BACKGROUND/PURPOSE: The expanding applicability of liver transplantation as treatment for end-stage liver disease has fostered a disproportionate increase in liver transplant candidates in the face of an unchanging pool of donor organs. This has resulted in disparities in pretransplant waiting times and deaths. The splitting of a liver allograft allows for the transplantation of 2 recipients, usually an adult and a child, thus providing a means to expand the cadaveric donor pool. METHODS: The authors present their results on the performance of an ex vivo (back table) split and in situ (in a hemodynamically stable cadaveric donor) split to evaluate safety, applicability, and effectiveness. Between November 1989 through April 1998, 54 split-liver transplant recipient operations were performed (24 pediatric and 30 adult). Thirty donors were procured: the ex vivo splitting yielded 25 grafts from 13 donors (donor age, 24.6+/-11 years), and the in-situ technique yielded 29 grafts from 17 donors (mean donor age of 25.5+/-10.4 years). Five donors involved interinstitutional sharing for which the left side of the graft was kept at the host hospital and the right side grafts were utilized at our center. RESULTS: Overall 1-year patient survival was 85%, with a graft survival of 72%. Patient survival was similar with ex vivo (74%) as compared with the in situ splitting group (96%; P = .06), as was graft survival in ex vivo (61 %) versus in situ (81%) splitting (P = .15). The pediatric population benefited most from the in situ technique, with a 1-year patient survival rate of 100% with the in situ technique versus the ex vivo technique survival rate of 64% at 1 year (P = .02). The 1-year graft survival comparing these 2 techniques was 83% for the in situ group versus 45% for the ex vivo group. Analysis of the program evolution of split-liver transplantation suggested a time-dependent learning curve, which was applicable to surgical splitting technique, implantation, and recipient selection. CONCLUSIONS: The principle of splitting livers from cadaveric donors is fundamentally sound and technically feasible. The authors' outcomes analysis using 2 different procurement techniques suggests that the in situ technique is clinically efficacious, can be used alternatively with the ex vivo technique, and is comparable to whole-liver allograft transplantation.

Adult↗
PubMed1999

Impact of segmental grafts on pediatric liver transplantation--a review of the United Network for Organ Sharing Scientific Registry data (1990-1996).

PURPOSE: The aim of this study was to assess the relative impact of segmental grafts from cadaveric and living donors on outcomes in 3,409 pediatric transplants (<18 years) between 1990 and 1996. METHODS: Analysis of the United Network for Organ Sharing (UNOS) Scientific registry data from 1990 to 1996 was performed. RESULTS: Liver grafts consisted of 2,636 whole grafts (WLG), 246 liver donor grafts (LDG), 89 split liver graft (SLG), and 438 reduced-size grafts (RSG). Although the number of pediatric transplants were unchanged between 1990 and 1996, segmental grafts made up an increasing proportion from 14.5% to 29.2%, and WLG decreased proportionately. The increase among segmental grafts occurred for LDG (threefold), followed by SLG (53%) and RSG (50%). One-year graft and patient survival rates for 3,409 transplants were 69.7% and 81.9%, respectively and were significantly higher (P<.001) in nonhospitalized patients than in hospitalized patients (79.8% and 91.3% v 61.0% and 73.7%). LDG graft survival (75.9%) was comparable with WLG(70.9%) but significantly better at 1 year than SLG (60.3%, P = .007) and RSG (61.1%, P = .001), even after excluding retransplants and ICU patients. Patient survival rates were not different statistically between groups. A separate analysis of outcomes in recipients less than 1 year of age suggested significantly better graft and patient survivals for LDG (83.3% and 89.4%) than for WLG (62.3% and 76.5%) and RSG (62.7% and 75%). CONCLUSIONS: Segmental liver grafts from cadaveric and living donors constitute an increasing proportion of pediatric transplants. Survival rates of cadaveric segmental graft are inferior to those of live donor segmental grafts even after adjustment for medical condition. Live donor grafts demonstrate consistently superior graft and patient outcomes in pediatric recipients less than 1 year of age, and should be promoted aggressively as a solution to the critical shortage of size matched grafts in small recipients.

Age Factors↗
PubMed1997

Solitary pancreas transplantation. Experience with 62 consecutive cases.

OBJECTIVE: To determine the safety and efficacy of solitary pancreas transplantation in the treatment of IDDM. RESEARCH DESIGN AND METHODS: A single-center retrospective case series of 62 consecutive solitary pancreas transplants (20 sequential pancreas after kidney, 42 pancreas transplants alone) performed in 57 adult IDDM patients was studied. Indications for solitary pancreas transplantation were 1) the presence of two or more overt diabetic complications and/or 2) glucose hyperlability with hypoglycemic unawareness and impaired quality of life. The recipient group consisted of 31 men and 26 women with a mean age of 38 years (range 25-62) and a mean duration of diabetes of 26 years (range 14-52). Mean pretransplant glycohemoglobin level was 9.9 +/- 2.6%. Organ acceptance was restricted to ideal donors and man-dated a minimum of a two-antigen match (mean human leukocyte antigen ABDR match 2.7). The mean cold ischemia time was 16.6 h. Whole-organ pancreas transplantation was performed with bladder drainage by the duodenal segment technique. All patients were managed with either triple or quadruple immunosuppression. Monitoring included prospective urine cytology as well as cystoscopic transduodenal needle biopsies. RESULTS: The mean length of initial hospital stay was 18 days, and mean hospital charges were $106,341. The incidences of rejection, infection, and surgical complications were 70, 55, and 47%, respectively. Overall patient and graft survival rates were 86 and 52%, respectively, with a mean follow-up of 28 months. All patients with functioning grafts had excellent metabolic control (mean glycohemoglobin level 5.1%) and achieved good rehabilitation. CONCLUSIONS: Despite morbidity, solitary pancreas transplantation can be performed with improving success, can enhance quality of life, and can offer an opportunity to arrest secondary diabetic complications.

Adult↗
PubMed1997

Experience with enteric conversion after pancreatic transplantation with bladder drainage.

BACKGROUND: Bladder drainage by the duodenal segment technique is currently the preferred method of handling the exocrine secretions after vascularized pancreatic transplantation. Despite improving results, however, the management of metabolic and urologic complications associated with bladder drainage remains problematic. STUDY DESIGN: A retrospective survey was performed of a consecutive case series of 196 pancreatic transplantations in 186 patients with diabetes over an 80-month period. All patients underwent whole organ pancreatic transplantation with bladder drainage by the duodenal segment technique. RESULTS: A total of 25 conversions (13 percent) from bladder drainage to enteric drainage were performed in 24 patients (24 side-to-side duodenoenterostomies, one Roux-en-Y limb duodenoenterostomy). The mean time of enteric conversion after pancreatic transplantation was 22 +/- 18 months (range, 1 to 72 months). All but two of the enteric conversions were performed at least 6 months after pancreatic transplantation. Indications for enteric conversion included dehydration with intractable metabolic acidosis (n = 18; 9 percent), urologic complications (n = 5; 3 percent), or problems with the duodenal segment (n = 2; 1 percent). The mean length of hospitalization for enteric conversion was 12 +/- 7 days (range, 6 to 30 days). All patients experienced improvement in their symptoms after enteric conversion. Anastomotic leaks developed postoperatively in five patients; two were managed operatively and three were managed nonoperatively. Oral bicarbonate supplementation was eliminated in all but one patient after enteric conversion. Patient survival is 100 percent and pancreatic graft survival (insulin independence) is 96 percent after a mean follow-up of 22 months after enteric conversion. CONCLUSIONS: Enteric conversion after pancreatic transplantation with bladder drainage is a safe and effective therapy for refractory problems related to the duodenal segment, altered physiologic function, or urologic complications and should be considered after 6 months for patients with persistent side effects.

Adult↗
PubMed1997

Bench reconstruction of pancreas for transplantation: experience with 192 cases.

UNLABELLED: Whole organ pancreaticoduodenal transplantation with bladder drainage by the duodenal segment technique is currently the preferred method of vascularized pancreas transplantation but is associated with a finite risk of surgical complications. Meticulous bench reconstruction of the pancreaticoduodenal allograft may minimize complications following transplantation. Over a 6.5-yr period, 192 pancreas transplants were performed in 181 diabetic patients by the same transplant team. A retrospective review was performed in order to describe a stepwise approach to bench preparation of the pancreaticoduodenal allograft that has developed from this experience. In this series of 192 consecutive pancreaticoduodenal reconstructions, no procured pancreas was deemed non-usable solely from an anatomic standpoint. The mean backtable pancreas preparation time was 2 h. The operative complication rate 19%, the incidence of technical graft loss was 6.8%, and there was no mortality related to technical problems. CONCLUSIONS: Using a standardized approach, meticulous bench reconstruction of the pancreaticoduodenal allograft: 1) can be performed in virtually any anatomic setting; 2) decrease complications following transplantation; 3) improves initial allograft function; and 4) minimizes organ wastage.

Diabetes Mellitus↗
PubMed1996

Combined liver/small bowel transplantation using a blood group compatible but nonidentical donor.

A successful liver/small intestinal transplantation with a blood group O donor to a blood type A recipient is described. Mild graft versus host disease developed, manifested by hemolysis, but did not result in graft loss or patient mortality. This suggests that minor ABO incompatibility may be tolerated with intestinal transplantation, despite the transplantation of large amounts of lymphoid tissue.

ABO Blood-Group System↗
PubMed1996

Humoral graft-versus-host disease after pancreas transplantation with an ABO-compatible and Rh-nonidentical donor. Case report and a rationale for preoperative screening.

Severe hemolysis and graft ischemia complicating solitary pancreas transplantation with an ABO-compatible, Rh-negative, anti-D-positive donor to Rh-positive recipient is described in this article. A brief review of the literature is presented. A rationale for preoperative screening for red cell antibodies during solid organ transplantation in this special setting is discussed.

ABO Blood-Group System↗
PubMed1996

Analysis of early readmissions after combined pancreas-kidney transplantation.

Combined pancreas-kidney transplantation (PKT) has become generally accepted as an effective treatment option, but controversy exists regarding the early morbidity rate of the procedure. To address this issue, we retrospectively analyzed all readmissions occurring in the first 3 months after PKT. Over a 5-year period, we performed 98 PKTs with bladder drainage. The mean recipient age was 36.6 years, with a mean pretransplant duration of diabetes of 23.5 years. All patients received quadruple immunosuppression with antilymphocyte induction therapy. The mean length of initial hospital stay was 20 days. One hundred forty-five readmissions occurred in 73 patients (74.5%), with the initial readmission occurring at a mean of 8.5 days after hospital dismissal and 28 days after PKT. Twenty-five patients (25.5%) had no readmissions, 35 (36%) had one readmission, 17 (17%) had two readmissions, and the remaining 21 patients (21.5%) had three or more readmissions in the first 3 months. The mean number of readmissions was 1.5 per patient. Forty-seven patients (48%) were readmitted within 1 week, and all but one initial readmission occurred within 1 month of hospital dismissal. Causes of readmission included rejection (51), infection (32), pancreas-specific morbidity (such as dehydration, hematuria, or pancreatitis; 50), and miscellaneous causes (12). Thirteen patients (13%) underwent reoperation during readmission. The mean length of hospital stay during readmission was 7.6 days. The mean total length of hospitalization in the first 3 months after PKT was 31 days. Over the span of 5 years, no changes have occurred either in the incidence, timing, causes, or duration of readmissions. The patient survival rate is 96%, the kidney graft survival rate is 90%, and the pancreas graft survival rate is 88% after a mean follow-up of 2.6 years. Mean rehabilitation time (return to work or normal activity) after PKT was 4.0 months. In conclusion, PKT is associated with a fixed morbidity characterized by early readmission (within 1 week) in nearly half of patients and pancreas-specific morbidity as the cause in 35% of readmissions. During evaluation, prospective candidates should be counseled regarding the unique morbidity of PKT. Successful management strategies must emphasize the intensity of early follow-up and recognize the propensity toward immunologic, metabolic, exocrine, and urologic side effects.

Adult↗