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1.
Khirurgiia (Mosk) ; (5): 12-19, 2020.
Article in Russian | MEDLINE | ID: mdl-32500684

ABSTRACT

OBJECTIVE: To compare different clinical and morphometric features of patients undergoing TPAIT for prediction of postoperative outcomes. MATERIAL AND METHODS: A retrospective review enrolled patients who underwent TPAIT for the period from January 2007 to October 2017. Morphometric parameters were analyzed using preoperative CT scans and patients were grouped to examine association of these characteristics with postoperative morbidity. Sarcopenia was defined as the presence of a TPA in the lowest sex-specific quartile. The impact of sarcopenia on pancreatic islet features, perioperative blood transfusion, ICU- and hospital-stay, complications, repeated admission within 90 days and islet function was assessed. RESULTS: A total of 34 patients were included in this study (12 males and 24 females). At the time of diagnosis, mean age of patients was 43.1 years. Mean body mass index (BMI) in sarcopenic patients was 24.9 kg/m2, mean BMI in those without sarcopenia - 24.8 kg/m2 (p=1.00). Various surgical complications were observed in 11 patients (32.3%). Patients with sarcopenia experienced more complications (83.3%) compared with patients without sarcopenia (50%). However, differences were not significant (p=0.31). Islet characteristics (islet numbers, purity), readmission, ICU- and hospital-stay, incidence of blood transfusion and islet function were also similar in both groups. CONCLUSION: Sarcopenia is not a predictor of postoperative complications and islet cell function in chronic pancreatitis patients following TPAIT.


Subject(s)
Islets of Langerhans Transplantation , Pancreatectomy , Pancreatitis, Chronic/surgery , Sarcopenia/physiopathology , Adipose Tissue/physiopathology , Adult , Female , Humans , Male , Pancreatitis, Chronic/complications , Pancreatitis, Chronic/physiopathology , Retrospective Studies , Sarcopenia/complications , Transplantation, Autologous , Treatment Outcome
2.
Case Rep Surg ; 2018: 4965459, 2018.
Article in English | MEDLINE | ID: mdl-29682387

ABSTRACT

INTRODUCTION: Encapsulating peritoneal sclerosis (EPS) is a clinical syndrome of progressive fibrotic change in response to prolonged, repetitive, and typically severe insult to the peritoneal mesothelium, often occurring in the setting of peritoneal dialysis (PD). Clear guidelines for successful management remain elusive. We describe the successful surgical management of EPS in a 28-year-old male s/p deceased donor kidney transplant for end-stage renal disease (ESRD) secondary to focal segmental glomerulosclerosis (FSGS). This patient received PD for 7 years but changed to hemodialysis (HD) in the year of transplant due to consistent signs and symptoms of underdialysis. EPS was visualized at the time of transplant. Despite successful renal transplantation, EPS progressed to cause small bowel obstruction (SBO) requiring PEG-J placement for enteral nutrition and gastric decompression. The patient subsequently developed a chronic gastrocutaneous fistula necessitating chronic TPN and multiple admissions for pain crises and bowel obstruction. He was elected to undergo surgical intervention due to deteriorating quality of life and failure to thrive. Surgical management included an exploratory laparotomy with extensive lysis of adhesions (LOA), repair of gastrocutaneous fistula, and end ileostomy with Hartmann's pouch. Postoperative imaging confirmed resolution of the SBO, and the patient was transitioned to NGT feeds and eventually only PO intake. He is continuing with PO nutrition, gaining weight, and free from dialysis. CONCLUSION: Surgical intervention with LOA and release of small intestine can be successful for definitive management of EPS in the proper setting. In cases such as this, where management with enteral nutrition fails secondary to ongoing obstructive episodes, surgical intervention can be pursued in the interest of preserving quality of life.

3.
Am J Transplant ; 14(5): 1152-1163, 2014 May.
Article in English | MEDLINE | ID: mdl-24698514

ABSTRACT

The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated by: (1) identifying specific CNIT molecular pathways that associate with allograft injury (cross-sectional study) and (2) assessing the contribution of the identified CNIT signature in the progression to CAD with IF/TA (longitudinal study). Kidney biopsies from well-selected transplant recipients with histological diagnosis of CNIT (n = 14), acute rejection (n = 13) and CAD with IF/TA (n = 10) were evaluated. Normal allografts (n = 18) were used as controls. To test CNIT contribution to CAD progression, an independent set of biopsies (n = 122) from 61 KT patients collected at 3 and ~12 months post-KT (range = 9-18) were evaluated. Patients were classified based on 2-year post-KT graft function and histological findings as progressors (n = 30) or nonprogressors to CAD (n = 31). Molecular signatures characterizing CNIT samples were identified. Patients classified as progressors showed an overlap of 7% and 22% with the CNIT signature at 3 and at ~12 months post-KT, respectively, while the overlap was <1% and 1% in nonprogressor patients, showing CNIT at the molecular level as a nonimmunological factor involved in the progression to CAD.


Subject(s)
Biomarkers/blood , Calcineurin Inhibitors/adverse effects , Gene Expression Profiling , Graft Rejection/classification , Kidney Failure, Chronic/surgery , Kidney Transplantation , Adult , Allografts , Area Under Curve , Cross-Sectional Studies , Disease Progression , Female , Follow-Up Studies , Graft Rejection/blood , Graft Rejection/drug therapy , Graft Rejection/genetics , Humans , Kidney Failure, Chronic/complications , Longitudinal Studies , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Postoperative Complications , Prognosis , Prospective Studies
4.
Transplant Proc ; 43(9): 3285-7, 2011 Nov.
Article in English | MEDLINE | ID: mdl-22099778

ABSTRACT

BACKGROUND: Nanofiber scaffolds could improve islet transplant success by physically mimicking the shape of extracellular matrix and by acting as a drug-delivery vehicle. Scaffolds implanted in alternate transplant sites must be prevascularized or very quickly vascularized following transplantation to prevent hypoxia-induced islet necrosis. The local release of the S1P prodrug FTY720 induces diameter enlargement and increases in length density. The objective of this preliminary study was to evaluate length and diameter differences between diabetic and nondiabetic animals implanted with FTY720-containing electrospun scaffolds using intravital imaging of dorsal skinfold window chambers. METHODS: Electrospun mats of randomly oriented fibers we created from polymer solutions of PLAGA (50:50 LA:GA) with and without FTY720 loaded at a ratio of 1:200 (FTY720:PLAGA by wt). The implanted fiber mats were 4 mm in diameter and ∼0.2 mm thick. Increases in length density and vessel diameter were assessed by automated analysis of images over 7 days in RAVE, a Matlab program. RESULTS: Image analysis of repeated measures of microvessel metrics demonstrated a significant increase in the length density from day 0 to day 7 in the moderately diabetic animals of this preliminary study (P < .05). Furthermore, significant differences in length density at day 0 and day 3 were found between recently STZ-induced moderately diabetic and nondiabetic animals in response to FTY720 local release (P < .05, Student t test). CONCLUSIONS: Driving the islet revascularization process using local release of factors, such as FTY720, from biodegradable polymers makes an attractive system for the improvement of islet transplant success. Preliminary study results suggest that a recently induced moderately diabetic state may potentiate the mechanism by which local release of FTY720 from polymer fibers increases length density of microvessels. Therefore, local release of S1P receptor-targeted drugs is under further investigation for improvement of transplanted islet function.


Subject(s)
Diabetes Mellitus, Experimental/therapy , Immunosuppressive Agents/administration & dosage , Lactic Acid/chemistry , Polyglycolic Acid/chemistry , Propylene Glycols/administration & dosage , Sphingosine/analogs & derivatives , Animals , Automation , Biocompatible Materials/chemistry , Drug Delivery Systems , Extracellular Matrix/metabolism , Fingolimod Hydrochloride , Hypoxia , Image Processing, Computer-Assisted , Male , Materials Testing , Mice , Mice, Inbred C57BL , Microvessels , Nanofibers/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Polymers/chemistry , Sphingosine/administration & dosage , Streptozocin/chemistry , Tissue Scaffolds
5.
Am J Transplant ; 9(8): 1846-52, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19538490

ABSTRACT

The purpose of this study is to explore the relationship between coronary artery disease (CAD), transplantation status and subsequent mortality in end-stage renal disease (ESRD) patients undergoing evaluation for renal transplantation. Two hundred fifty-three ESRD patients at high risk for CAD underwent coronary angiography as part of a renal transplant evaluation. The cohort was divided into three groups: Group 1 (n = 127) had no vessels with >or=50% stenosis, Group 2 (n = 56) had one vessel with >or=50% stenosis and Group 3 (n = 70) had two or more vessels with >or=50% stenosis. Long-term survival was determined; median follow-up was 3.3 years. The baseline characteristics were similar except for older age and higher proportion of diabetes mellitus, dyslipidemia and peripheral vascular disease in Groups 2 and 3 patients as compared to Group 1. Survival was worse in Group 3 compared to Group 1 (p < 0.0001). Each of the three subgroups had better survival with renal transplantation than those who did not undergo transplantation (p < 0.0001). Although the degree of CAD is related to subsequent mortality, transplantation is associated with better survival regardless of the extent and severity of CAD. Thus, the presence of CAD should not exclude ESRD patients from consideration for this therapy.


Subject(s)
Coronary Disease/physiopathology , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/surgery , Kidney Transplantation , Patient Selection , Severity of Illness Index , Coronary Angiography , Coronary Disease/diagnostic imaging , Coronary Disease/etiology , Diabetes Complications/complications , Dyslipidemias/complications , Female , Follow-Up Studies , Humans , Male , Middle Aged , Peripheral Vascular Diseases/complications , Prevalence , Retrospective Studies , Survival Rate
6.
Am J Transplant ; 9(4 Pt 2): 894-906, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19341414

ABSTRACT

Although the number of candidates on the kidney transplant waiting list at year-end rose from 40 825 to 76 070 (86%) between 1998 and 2007, recent growth principally reflects increases in the number of patients in inactive status. The number of active patients increased by 'only' 4510 between 2002 and 2007, from 44 263 to 48 773. There were 6037 living donor and 10 082 deceased donor kidney transplants in 2007. Patient and allograft survival was best for recipients of living donor kidneys, least for expanded criteria donor (ECD) deceased donor kidneys, and intermediate for non-ECD deceased donor kidneys. The total number of pancreas transplants peaked at 1484 in 2004 and has since declined to 1331. Among pancreas recipients, those with simultaneous pancreas-kidney (SPK) transplants experienced the best pancreas graft survival rates: 86% at 1 year and 53% at 10 years. Between 1998 and 2006, among diabetic patients with end-stage renal disease (ESRD) who were under the age of 50 years, 23% of all and 62% of those waitlisted received a kidney-alone or SPK transplant. In contrast, 6% of diabetic patients aged 50-75 years with ESRD were transplanted, representing 46% of those waitlisted from this cohort. Access to kidney-alone or SPK transplantation varies widely by state.


Subject(s)
Diabetic Nephropathies/surgery , Kidney Failure, Chronic/surgery , Kidney Transplantation/statistics & numerical data , Pancreas Transplantation/statistics & numerical data , Waiting Lists , Adult , Aged , Cadaver , Cohort Studies , Family , Humans , Living Donors/statistics & numerical data , Middle Aged , Patient Selection , Racial Groups , Tissue Donors/statistics & numerical data , Transplantation, Homologous/statistics & numerical data , United States
7.
Am J Transplant ; 8(2): 355-65, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18093266

ABSTRACT

Improvements in human immunodeficiency virus (HIV)-associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9-4.9). One- and 3-year liver recipients' survival was 91% and 64%, respectively; kidney recipients' survival was 94%. One- and 3-year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999-2004 transplants in the national database. CD4+ T-cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1- and 3-year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28-75%) and 70% (48-92%), respectively. Two-thirds of hepatitis C virus (HCV)-infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV-related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV-infected patients cared for at centers with adequate expertise.


Subject(s)
HIV Infections/complications , Kidney Transplantation/statistics & numerical data , Liver Transplantation/statistics & numerical data , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Cadaver , Female , Follow-Up Studies , Graft Rejection/epidemiology , HIV Infections/drug therapy , Humans , Kidney Transplantation/immunology , Liver Transplantation/immunology , Living Donors , Male , Middle Aged , Time Factors , Tissue Donors/statistics & numerical data , Treatment Outcome , Viral Load
8.
Am J Transplant ; 7(5 Pt 2): 1359-75, 2007.
Article in English | MEDLINE | ID: mdl-17428285

ABSTRACT

Kidney and pancreas transplantation in 2005 improved in quantity and outcome quality, despite the increasing average age of kidney graft recipients, with 56% aged 50 or older. Geography and ABO blood type contribute to the discrepancy in waiting time among the deceased donor (DD) candidates. Allocation policy changes are decreasing the median times to transplant for pediatric recipients. Overall, 6% more DD kidney transplants were performed in 2005 with slight increases in standard criteria donors (SCD) and expanded criteria donors (ECD). The largest increase (39%) was in donation after cardiac death (DCD) from non-ECD donors. These DCD, non-ECD kidneys had equivalent outcomes to SCD kidneys. 1-, 3- and 5-year unadjusted graft survival was 91%, 80% and 70% for non-ECD-DD transplants, 82%, 68% and 53% for ECD-DD grafts, and 95%, 88% and 80% for living donor kidney transplants. In 2005, 27% of patients were discharged without steroids compared to 3% in 1999. Acute rejection decreased to 11% in 2004. There was a slight increase in the number of simultaneous pancreas-kidney transplants (895), with fewer pancreas after kidney transplants (343 from 419 in 2004), and a stable number of pancreas alone transplants (129). Pancreas underutilization appears to be an ongoing issue.


Subject(s)
Kidney Transplantation/statistics & numerical data , Pancreas Transplantation/statistics & numerical data , Graft Rejection/drug therapy , Graft Rejection/epidemiology , Graft Survival , Humans , Immunosuppression Therapy/methods , Kidney Transplantation/mortality , Kidney Transplantation/trends , Living Donors/statistics & numerical data , Pancreas Transplantation/trends , Patient Selection , Survival Analysis , Tissue Donors/statistics & numerical data , United States
9.
Transplant Proc ; 39(1): 55-63, 2007.
Article in English | MEDLINE | ID: mdl-17275474

ABSTRACT

Among recipients of deceased donor kidney transplants, African-Americans experience a more rapid rate of kidney allograft loss than non-African-Americans. The purpose of this study was to characterize and quantify the HLA-A, -B, and -DRB1 allele mismatches and amino acid substitutions at antigen recognition sites among African-American and non-African-American recipients of deceased donor kidney transplants matched at the antigen level. In recipients with zero HLA antigen mismatches, the degree of one or two HLA allele mismatches for both racial groups combined was 47%, 29%, and 11% at HLA-DRB1, HLA-B, and HLA-A, respectively. There was a greater number of allele mismatches in African-Americans than non-African-Americans at HLA-A (P < .0001), -B (P = .096), and -DRB1 loci (P < .0001). For both racial groups, the HLA allele mismatches were predominantly at A2 for HLA-A; B35 and B44 for HLA-B; but multiple specificities for HLA-DRB1. The observed amino acid mismatches were concentrated at a few functional positions in the antigen binding site of HLA-A and -B and -DRB1 molecules. Future studies are ongoing to assess the impact of these HLA mismatches on kidney allograft loss.


Subject(s)
Black People , HLA-A Antigens/genetics , HLA-B Antigens/genetics , HLA-DR Antigens/genetics , Histocompatibility Testing , Kidney Failure, Chronic/surgery , Kidney Transplantation/immunology , White People , Amino Acid Substitution , Black People/genetics , Cadaver , Cause of Death , DNA/genetics , DNA/isolation & purification , HLA-DRB1 Chains , Humans , Kidney Failure, Chronic/etiology , Prospective Studies , Tissue Donors , Transplantation, Homologous , United States , White People/genetics
10.
Transplant Proc ; 37(8): 3438-40, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16298621

ABSTRACT

Currently there is minimal concern that islet allograft failure could result from the development of anti-human leukocyte antigen (HLA) antibodies reactive to the allograft. We report here a case of islet allograft failure where the recipient developed immunoglobulin G anti-HLA class I antibodies reactive to HLA antigens present in two of the three islet cell donors. The patient had no detectable anti-HLA antibodies prior to the transplant but these antibodies were detected approximately 4 months posttransplant. Of concern, these antibodies developed despite induction with anti-IL2R antibodies (Zenapex) prior to intraportal islet cell infusion, low-dose tacrolimus (12-hour troughs 3 to 5 ng/mL) and rapammune (target troughs 12 to 15 ng/mL). The patient was not presensitized with blood products or a previous allograft. Her husband, however, shared antigens present in one of the islet donors and the recipient could have been presensitized to her husband during her two pregnancies. This case clearly demonstrates that islet allografts can lead to development of anti-HLA antibodies, which can cause islet allograft failure, as is the case with solid organ transplants, and hence emphasizes the need to monitor for such antibodies pre- and posttransplant. Additionally it appears that currently recommended immunosuppression may not be sufficient to inhibit a humoral response to both alloantigens and autoantigens.


Subject(s)
Antibodies, Anti-Idiotypic/blood , Histocompatibility Antigens Class I/immunology , Islets of Langerhans Transplantation/immunology , Adult , B-Lymphocytes/immunology , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/surgery , Female , Histocompatibility Testing , Humans , Insulin/therapeutic use , T-Lymphocytes/immunology , Transplantation, Homologous , Treatment Failure
11.
Pediatr Transplant ; 8(2): 171-7, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15049798

ABSTRACT

Immunosuppression with SRL may provide an opportunity to avoid long-term exposure to the nephrotoxicity of CNI. Thus, we have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients (median age 15.5 yr, IQR 8.5, range 1.3-21.7). The recipients were treated with daclizumab every 2 wk for the first 2 months, prednisone on a tapering schedule, MMF at 1200 mg/m(2)/day and SRL given b.i.d. The SRL was dosed to achieve defined target whole blood 12-h trough levels. We performed 24 SRL PK profiles in 13 stable pediatric renal transplant recipients at 1 and 3 months post-transplant. Half-life (T(1/2)) and terminal T(1/2) were 9.7 (7.1-24.6) and 10.8 (4.4-95.2) hours (median, range) respectively at month 1, and were 9.6 (5-17.8) and 12.1 (4.7-71.0) hours respectively at month 3. SRL trough levels correlated with AUC (r(2) = 0.84, p < 0.001). There was no relationship between SRL and mycophenolic acid (MPA) AUC values (r(2) = 0.04). During the first 3 months post-transplant only one patient experienced severe neutropenia and another patient had subclinical (histologic) evidence of a mild acute rejection episode with no change in renal function. We conclude that the T(1/2) of SRL in pediatric renal transplant recipients not treated with CNI is much shorter than what has been reported for adults, due to rapid metabolism. We conclude that children require SRL dosing every 12 h, higher doses and frequent drug monitoring to achieve target SRL concentrations.


Subject(s)
Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Sirolimus/pharmacokinetics , Adolescent , Adult , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Area Under Curve , Child , Child, Preschool , Daclizumab , Drug Monitoring , Female , Follow-Up Studies , Graft Rejection/etiology , Half-Life , Humans , IMP Dehydrogenase/antagonists & inhibitors , Immunoglobulin G/therapeutic use , Immunosuppressive Agents/therapeutic use , Infant , Male , Mycophenolic Acid/therapeutic use , Neutropenia/chemically induced , Prednisone/therapeutic use , Receptors, Interleukin-2/immunology , Sirolimus/therapeutic use
13.
J Clin Pharmacol ; 41(5): 542-51, 2001 May.
Article in English | MEDLINE | ID: mdl-11361051

ABSTRACT

The relationship between the dose of tacrolimus, trough tacrolimus blood concentration, and selected clinical endpoints (acute rejection, nephrotoxicity, and other toxicities) were examined in a prospective, multicenter clinical trial to validate the use of an enzyme-linked immunosorbent assay (ELISA) for monitoring whole-blood concentrations of tacrolimus in liver transplant patients. A total of 111 subjects from six transplant centers were evaluated over 12 weeks posttransplantation. In addition to trough tacrolimus blood concentrations, hematocrit, ALT, AST, GGTP, alkaline phosphatase, total bilirubin, serum creatinine, BUN, serum potassium, serum magnesium, blood glucose, and serum albumin were also measured. The relationship between trough tacrolimus blood concentrations and clinical endpoints was analyzed using both a logistic regression model and a Cox proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between increasing trough tacrolimus blood concentrations and decreasing risk of acute rejection was demonstrated over a 7-day time window. Nephrotoxicity and other toxicities also demonstrated statistically significant relationships with trough tacrolimus blood concentrations. The results of the Cox analysis were consistent with the logistic regression analysis. Using receiver operator characteristic curves, trough tacrolimus concentrations as measured by the ELISA method were able to differentiate the occurrence of nephrotoxicity and toxicity from nonevents. To minimize nephrotoxicity of tacrolimus, it is necessary to maintain trough blood concentrations below 15 ng/ml. This study demonstrates that the ELISA method used to measure tacrolimus blood concentrations in this study provides information of predictive value for managing the risk of nephrotoxicity, other toxicity, and rejection in liver transplant patients.


Subject(s)
Graft Rejection/chemically induced , Immunosuppressive Agents/blood , Immunosuppressive Agents/toxicity , Kidney Diseases/chemically induced , Liver Transplantation/physiology , Liver Transplantation/statistics & numerical data , Tacrolimus/blood , Tacrolimus/toxicity , Administration, Oral , Adult , Aged , Creatinine/blood , Dose-Response Relationship, Drug , Drug Administration Schedule , Endpoint Determination , Enzyme-Linked Immunosorbent Assay , Female , Graft Rejection/epidemiology , Humans , Immunosuppressive Agents/administration & dosage , Injections, Intravenous , Kidney/drug effects , Liver Function Tests , Liver Transplantation/mortality , Logistic Models , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , Risk Factors , Sensitivity and Specificity , Survival Rate , Tacrolimus/administration & dosage
15.
Clin Biochem ; 34(1): 17-22, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11239510

ABSTRACT

Mycophenolate mofetil is widely used in combination with either cyclosporine or tacrolimus for rejection prophylaxis in renal and heart transplant patients. Although not monitored routinely nearly to the degree that other agents such as cyclosporine or tacrolimus, there is an expanding body of experimental evidence for the utility of monitoring mycophenolic acid, the primary active metabolite of mycophenolate mofetil, plasma concentration as an index of risk for the development of acute rejection. The following are important experimentally-based reasons for recommending the incorporation of target therapeutic concentration monitoring of mycophenolic acid: (1) the MPA dose-interval area-under-the-concentration-time curve, and less precisely, MPA predose concentrations predict the risk for development of acute rejection; (2) the strong correlation between mycophenolic acid plasma concentrations and expression of important cell surface activation antigens, whole blood pharmacodynamic assays of lymphocyte proliferation and median graft rejection scores in a heart transplant animal model; (3) the greater than 10-fold interindividual variation of MPA area under the concentration time curve values in heart and renal transplant patients receiving a fixed dose of the parent drug; (4) drug-drug interactions involving other immunosuppressives are such that when switching from one to another (eg, from cyclosporine to tacrolimus or vice-versa) substantial changes in MPA concentrations can occur in patients receiving a fixed dose of the parent drug; (5) significant effects of liver and kidney diseases on the steady-state total and free mycophenolic acid area under the concentration time curve values; (6) the need to closely monitor mycophenolic acid when a major change in immunosuppression is planned such as steroid withdrawal. Current investigations are focused on determination of the most optimal sampling time and for mycophenolic acid target therapeutic concentration monitoring. Further investigations are needed to evaluate the pharmacologic activity of the newly described acyl glucuronide metabolite of mycophenolic acid which has been shown to inhibit, in vitro, inosine monophosphate dehydrogenase.


Subject(s)
Heart Transplantation/methods , Kidney Transplantation/methods , Mycophenolic Acid/pharmacokinetics , Mycophenolic Acid/therapeutic use , Area Under Curve , Graft Rejection/drug therapy , Humans , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/pharmacology , Time Factors , Treatment Outcome
17.
Cell Transplant ; 9(4): 453-62, 2000.
Article in English | MEDLINE | ID: mdl-11038062

ABSTRACT

Isolated canine islets transplanted to hyperglycemic rats fail to restore euglycemia in almost all cases, although the grafted islet tissue appears to be morphologically intact for up to 48 h following transplantation. Cytokines typically produced in the xenograft environment (e.g., IL-1 and TNF) inhibit insulin biosynthesis and secretion from isolated pancreatic islets, and are associated with the production of nitric oxide (NO). To further define the relationship between NO production and islet xenotransplantation, the inhibition of NO in a splenocyte/islet coculture system, and the in vivo effect of this inhibition on canine islet xenotransplantation, was investigated. Splenocytes (SPLC) from Lewis rats were cocultured with canine islets (freshly isolated or cultured 7 days), supernatant removed, and NO concentration (NO2) determined by optical density (Griess reaction, 550 nm, expressed as nmol nitrite/10(6) cells/18 h). Lipopolysaccharide (LPS) was used as a positive control of SPLC production of NO. Stimulation by LPS resulted in maximal NO production (2.20 +/- 0.16 nmol/10(6) cells/18 h, p < 0.001 compared to baseline values of 0.73 +/- 0.04 nmol/10(6) cells/18 h). In the presence of NO inhibitors (NMA, polymyxin B, hydrocortisone, aminoguanidine, DMSO), nitrite levels did not significantly rise above unstimulated values. Freshly isolated canine islets did stimulate NO production (1.26 +/- 0.12 nmol/10(6) cells/18 h, p < 0.001). In contrast, cultured canine islets did not stimulate NO production (0.84 +/- 0.09 nmol/10(6) cells/18 h). Transplantation of freshly isolated canine islets to STZ-diabetic recipient Lewis rats resulted in amelioration of hyperglycemia in only 50% (n = 6) of recipients 12 h posttransplant, with a return to hyperglycemia at all subsequent time points. Transplantation of 7-day cultured canine islets resulted in amelioration of hyperglycemia in 88% of recipients 12 h posttransplant and 63% of recipients 24 h posttransplant [p = 0.028, mean survival time (MST) = 1.0 days, n = 8]. Transplantation of canine islet xenografts with aminoguanidine therapy (BID, n = 11) resulted in amelioration of hyperglycemia in 100% of recipients at 12 h posttransplant, decreasing to 82% by 24 h following transplantation (p = 0.002, MST = 0.9 days). These results demonstrate that freshly isolated canine islets are potent stimulators of NO production by rat SPLC in vitro, and that culture of canine islets, or addition of NO inhibitors, abrogates stimulated NO production. These results also demonstrate a statistically significant improvement (p < 0.001) in early function of canine islet xenografts following 7 days of islet culture prior to transplant, and following recipient treatment with aminoguanidine. These studies suggest that the production of NO in the microenvironment of the graft site may adversely affect engraftment and function of canine islets, and suggest that the abrogation of islet-stimulated NO production may improve engraftment following islet xenotransplantation.


Subject(s)
Diabetes Mellitus, Experimental/surgery , Graft Survival , Islets of Langerhans Transplantation , Islets of Langerhans/metabolism , Nitric Oxide/metabolism , Transplantation, Heterologous , Animals , Coculture Techniques , Dogs , Guanidines/pharmacology , Islets of Langerhans/cytology , Lipopolysaccharides/pharmacology , Liver/surgery , Male , Mice , Mice, Nude , Nitric Oxide/antagonists & inhibitors , Nitrites/metabolism , Rats , Rats, Inbred Lew , Rats, Nude , Spleen/cytology , Spleen/metabolism
19.
Ther Drug Monit ; 22(1): 14-9, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10688251

ABSTRACT

Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.


Subject(s)
Graft Rejection/immunology , Immunosuppressive Agents/pharmacokinetics , Mycophenolic Acid/pharmacokinetics , Transplantation/physiology , Area Under Curve , Drug Interactions , Drug Monitoring , Humans , Kidney Diseases/metabolism
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