- General Surgery
- Kidney and Pancreas Transplantation
- Liver Transplantation
Professor - Med Center Line, Surgery - Multi-Organ Transplantation
Director Adult Kidney and Pancreas Transplant Program, Stanford University School of Medicine (2001 - Present)
Residency:University of Montreal (1991) Canada
Medical Education:University of Montreal (1986) Canada
Fellowship:California Pacific Medical Center (1995) CA
Internship:University of Montreal (1987) Canada
Board Certification: General Surgery, American Board of Surgery (1996)
Board Cerification, American Board of Surgery, General Surgery (1996)
M. Sc., Mc Gill University, Transplant Immunology (1995)
., California Pacific Med Center, Multi-Organ Transplantation (1995)
FRCSC, University of Montreal, General Surgery (1991)
MD, Univerty of Montreal (1986)
Current Research and Scholarly Interests
My research interest is centered on the improvement of clinical immunosuppression. This involves the evaluation of new immunosuppressive drugs that are potentially more efficacious and/or less toxic or better monitoring of the effect of these drugs. We are participating in the drug development process from phase1 to phase 3 studies. I participate to trial design and data analysis of some of these trials. The ultimate goal is to achieve tolerance, a state that would obviate the need for any drugs. I am a clinical investigator in a multidisciplinary trial aimed at inducing tolerance after kidney transplantation. My other interests include the development and study of efficacy of strategies to desensitized organ transplant recipients and expending our capabilities to tailor the immunosuppression needs of specific patients through new immune-monitoring tests. Ultimately these research projects are aimed at improving the outcomes of organ transplant recipients.
Combined Blood Stem Cell and Kidney Transplant of One Haplotype Match Living Donor Pairs.
The Stanford Medical Center Program in Multi-Organ Transplantation and the Division of Bone marrow Transplantation are enrolling patients into a research study to determine if donor stem cells given after a living related one Haplotype match kidney transplantation will change the immune system such that immunosuppressive drugs can be completely withdrawn.
- Independent Studies (5)
Chimerism, Graft Survival, and Withdrawal of Immunosuppressive Drugs in HLA Matched and Mismatched Patients After Living Donor Kidney and Hematopoietic Cell Transplantation.
American journal of transplantation
2015; 15 (3): 695-704
Thirty-eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34(+) hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti-thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34(+) cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long-term graft survival in all patients.
View details for DOI 10.1111/ajt.13091
View details for PubMedID 25693475
Longitudinal study of living kidney donor glomerular dynamics after nephrectomy
JOURNAL OF CLINICAL INVESTIGATION
2015; 125 (3): 1311-1318
Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors.We enrolled 21 adult living kidney donors to undergo detailed long-term clinical, physiological, and radiological evaluation pre-, early post- (median, 0.8 years), and late post- (median, 6.3 years) donation. A morphometric analysis of glomeruli obtained during nephrectomy was performed in 19 subjects.Donors showed parallel increases in single-kidney renal plasma flow (RPF), renocortical volume, and glomerular filtration rate (GFR) early after the procedure, and these changes were sustained through to the late post-donation period. We used mathematical modeling to estimate the glomerular ultrafiltration coefficient (Kf), which also increased early and then remained constant through the late post-donation study. Assuming that the filtration surface area (and hence, Kf) increased in proportion to renocortical volume after donation, we calculated that the 40% elevation in the single-kidney GFR observed after donation could be attributed exclusively to an increase in the Kf. The prevalence of hypertension in donors increased from 14% in the early post-donation period to 57% in the late post-donation period. No subjects exhibited elevated levels of albuminuria.Adaptive hyperfiltration after donor nephrectomy is attributable to hyperperfusion and hypertrophy of the remaining glomeruli. Our findings point away from the development of glomerular hypertension following kidney donation.Not applicable. FUNDING. NIH (R01DK064697 and K23DK087937); Astellas Pharma US; the John M. Sobrato Foundation; the Satellite Extramural Grant Foundation; and the American Society of Nephrology.
View details for DOI 10.1172/JCI78885
View details for Web of Science ID 000350616500041
View details for PubMedID 25689253
A Preconditioning Regimen With a PKC epsilon Activator Improves Islet Graft Function in a Mouse Transplant Model
2014; 23 (7): 913-919
BACKGROUND: Transplantation of islets isolated from deceased donor pancreata is an attractivemethod of β cell replacement therapy for patients with type 1 diabetes (T1D). However the loss of islet cell viability and function during the peritransplant period is a limiting factor to long-term islet engraftment. Activation of the isoenzyme PKCε may improve islet survival and function. The currentstudy assesses the effects of PKC εactivation on islet graft function in a syngeneic streptozotocininduced diabetic mouse model.METHODS: Islets were isolated from wild-type BALB/c mice preconditioned with either a PKCεactivator (ψεRACK) or a TAT carrier control peptide. Islets were further treated with the same agents during isolation, purification, and incubation prior to transplantation. 275 islet equivalents were transplanted under the kidney capsule of streptozotocin-induced diabetic BALB/c mice. Islet function was assessed by measurement of blood glucose levels every 3 days for 42 days after transplant and through an intra peritoneal glucose tolerance test (IPGTT).RESULTS: The time for return to euglycemia in mice transplanted with islets treated with ψεRACK was improved at 14 +/- 6 days versus 21+/- 6 days with TAT-treated islets. The IPGTT showed a 50% reduction in the area under the curve associated with an improved insulin response in mice transplanted with ψεRACK-treated islets compared to TAT-treated islets.CONCLUSION: A preconditioning regimen using PKCε agonist before pancreatic recovery and during islet isolation improves islet graft function and resistance to high glucose stress after transplantation.
View details for DOI 10.3727/096368913X665567
View details for Web of Science ID 000337989700010
View details for PubMedID 23562311
Uniform Long-Term Graft Survival in a Clincial Trial of the Induction of Tolerance to Kidney Transplants.
WILEY-BLACKWELL. 2013: 200-200
View details for Web of Science ID 000318240300549
Evaluating Deceased Donor Registries: Identifying Predictive Factors of Donor Designation
2013; 79 (3): 235-241
The objectives of this study were to evaluate and compare the performance of the deceased donor registries of the 50 states and the District of Columbia and to identify possible predictive factors of donor designation. Data were collected retrospectively by Donate Life America using a questionnaire sent to Donor Designation Collaborative state teams between 2007 and 2010. By the end of 2010, there were 94,669,081 designated donors nationwide. This accounted for 39.8 per cent of the U.S. population aged 18 years and over. The number of designated organ donors and registry-authorized recovered donors increased each year; however, the total number of recovered donors in 2010 was the lowest since 2004. Donor designation rate was significantly higher when license applicants were verbally questioned at the Department of Motor Vehicles (DMV) regarding their willingness to register as a donor and when DMV applicants were not given an option on DMV application forms to contribute money to support organ donation, compared with not being questioned verbally, and being offered an option to contribute money. State registries continue to increase the total number of designated organ donors; however, the current availability of organs remains insufficient to meet the demand. These data suggest that DMV applicants who are approached verbally regarding their willingness to register as a donor and not given an option on DMV application forms to contribute money to support organ donation might be more likely to designate themselves to be a donor.
View details for Web of Science ID 000315606500003
View details for PubMedID 23461946
Desensitization Combined With Paired Exchange Leads to Successful Transplantation in Highly Sensitized Kidney Transplant Recipients: Strategy and Report of Five Cases
2013; 45 (1): 82-87
Sensitization remains a major barrier to kidney transplantation. Sensitized patients comprise 30% of the kidney transplant waiting list but fewer than 15% of highly sensitized patients are transplanted each year. Options for highly sensitized patients with an immunologically incompatible living donor include desensitization or kidney paired donation (KPD). However, these options when used alone may still not be sufficient to allow a compatible transplant for recipients who are broadly sensitized with cumulative calculated panel-reactive antibody (cPRA) > 95%. We describe in this report the combined use of both desensitization and KPD to maximize the likelihood of finding a compatible match with a more immunologically favorable donor through a kidney exchange program. This combined approach was used in five very highly sensitized patients, all with cPRA 100%, who ultimately received compatible living and deceased donor kidney transplants. We conclude that early enrollment in paired kidney donor exchange and tailored desensitization protocols are key strategies to improve care and rates of kidney transplantation in highly sensitized patients.
View details for DOI 10.1016/j.transproceed.2012.08.007
View details for Web of Science ID 000315007200013
Chain Transplantation: Initial Experience of a Large Multicenter Program
AMERICAN JOURNAL OF TRANSPLANTATION
2012; 12 (9): 2429-2436
We report the results of a large series of chain transplantations that were facilitated by a multicenter US database in which 57 centers pooled incompatible donor/recipient pairs. Chains, initiated by nondirected donors, were identified using a computer algorithm incorporating virtual cross-matches and potential to extend chains. The first 54 chains facilitated 272 kidney transplants (mean chain length = 5.0). Seven chains ended because potential donors became unavailable to donate after their recipient received a kidney; however, every recipient whose intended donor donated was transplanted. The remaining 47 chains were eventually closed by having the last donor donate to the waiting list. Of the 272 chain recipients 46% were ethnic minorities and 63% of grafts were shipped from other centers. The number of blood type O-patients receiving a transplant (n = 90) was greater than the number of blood type O-non-directed donors (n = 32) initiating chains. We have 1-year follow up on the first 100 transplants. The mean 1-year creatinine of the first 100 transplants from this series was 1.3 mg/dL. Chain transplantation enables many recipients with immunologically incompatible donors to be transplanted with high quality grafts.
View details for DOI 10.1111/j.1600-6143.2012.04156.x
View details for Web of Science ID 000307945000021
View details for PubMedID 22812922
Randomized Phase 2b Trial of Tofacitinib (CP-690,550) in De Novo Kidney Transplant Patients: Efficacy, Renal Function and Safety at 1 Year
AMERICAN JOURNAL OF TRANSPLANTATION
2012; 12 (9): 2446-2456
In this Phase 2b study, 331 low-to-moderate risk de novo kidney transplant patients (approximately 60% deceased donors) were randomized to a more intensive (MI) or less intensive (LI) regimen of tofacitinib (CP-690, 550), an oral Janus kinase inhibitor or cyclosporine (CsA). All patients received basiliximab induction, mycophenolic acid and corticosteroids. Primary endpoints were: incidence of biopsy-proven acute rejection (BPAR) with a serum creatinine increase of ?0.3 mg/dL and ?20% (clinical BPAR) at Month 6 and measured GFR at Month 12. Similar 6-month incidences of clinical BPAR (11%, 7% and 9%) were observed for MI, LI and CsA. Measured GFRs were higher (p < 0.01) at Month 12 for MI and LI versus CsA (65 mL/min, 65 mL/min vs. 54 mL/min). Fewer (p < 0.05) patients in MI or LI developed chronic allograft nephropathy at Month 12 compared with CsA (25%, 24% vs. 48%). Serious infections developed in 45%, 37% and 25% of patients in MI, LI and CsA, respectively. Anemia, neutropenia and posttransplant lymphoproliferative disorder occurred more frequently in MI and LI compared with CsA. Tofacitinib was equivalent to CsA in preventing acute rejection, was associated with improved renal function and less chronic allograft histological injury, but had side-effects at the doses evaluated.
View details for DOI 10.1111/j.1600-6143.2012.04127.x
View details for Web of Science ID 000307945000023
View details for PubMedID 22682022
Incidental kidney stones: a single center experience with kidney donor selection
2012; 26 (4): 558-563
The presence of kidney stones has been a relative contraindication for living donation. With the widespread use of more sensitive imaging techniques as part of the routine living donor workup, kidney stones are more frequently detected, and their clinical significance in this setting is largely unknown. Records from 325 potential kidney donors who underwent MRA or CT-angiography were reviewed; 294 proceeded to donation. The prevalence of kidney stones found incidentally during donor evaluation was 7.4% (24 of 325). Sixteen donors with stones proceeded with kidney donation. All incidental calculi were nonobstructing and small (median 2 mm; range 1-9 mm). Eleven recipients were transplanted with allografts containing stones. One recipient developed symptomatic nephrolithasis after transplantation. This recipient was found to have newly formed stones secondary to hyperoxaluria, suggesting a recipient-driven propensity for stone formation. The remaining ten recipients have stable graft function, postoperative ultrasound negative for nephrolithiasis, and no sequelae from stones. No donor developed symptomatic nephrolithiasis following donation. Judicious use of allografts with small stones in donors with normal metabolic studies may be acceptable, and careful follow-up in recipients of such allografts is warranted.
View details for DOI 10.1111/j.1399-0012.2011.01567.x
View details for Web of Science ID 000307344400024
View details for PubMedID 22168332
Tolerance and Withdrawal of Immunosuppressive Drugs in Patients Given Kidney and Hematopoietic Cell Transplants
AMERICAN JOURNAL OF TRANSPLANTATION
2012; 12 (5): 1133-1145
Sixteen patients conditioned with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) were given kidney transplants and an injection of CD34+ hematopoietic progenitor cells and T cells from HLA-matched donors in a tolerance induction protocol. Blood cell monitoring included changes in chimerism, balance of T-cell subsets and responses to donor alloantigens. Fifteen patients developed multilineage chimerism without graft-versus-host disease (GVHD), and eight with chimerism for at least 6 months were withdrawn from antirejection medications for 1-3 years (mean, 28 months) without subsequent rejection episodes. Four chimeric patients have just completed or are in the midst of drug withdrawal, and four patients were not withdrawn due to return of underlying disease or rejection episodes. Blood cells from all patients showed early high ratios of CD4+CD25+ regulatory T cells and NKT cells versus conventional naive CD4+ T cells, and those off drugs showed specific unresponsiveness to donor alloantigens. In conclusion, TLI and ATG promoted the development of persistent chimerism and tolerance in a cohort of patients given kidney transplants and hematopoietic donor cell infusions. All 16 patients had excellent graft function at the last observation point with or without maintenance drugs.
View details for DOI 10.1111/j.1600-6143.2012.03992.x
View details for Web of Science ID 000303235100012
View details for PubMedID 22405058
Validity of Surrogate Measures for Functional Nephron Mass
2011; 92 (12): 1335-1341
Transplanted nephron mass is an important determinant of long-term allograft survival, but accurate assessment before organ retrieval is challenging. Newer radiologic imaging techniques allow for better determination of total kidney and cortical volumes.Using volume measurements reconstructed from magnetic resonance or computed tomography imaging from living donor candidates, we characterized total kidney (n=312) and cortical volumes (n=236) according to sex, age, weight, height, body mass index (BMI), and body surface area (BSA).The mean cortical volume was 204 mL (range 105-355 mL) with no significant differences between left and right cortical volumes. The degree to which existing anthropomorphic surrogates predict nephron mass was quantified, and a diligent attempt was made to derive a better surrogate model for nephron mass. Cortical volumes were strongly associated with sex and BSA, but not with weight, height, or BMI. Four prediction models for cortical volume constructed using combinations of age, sex, race, weight, and height were compared with models including either BSA or BMI.Among existing surrogate measures, BSA was superior to BMI in predicting renal cortical volume. We were able to construct a statistically superior proxy for cortical volume, but whether relevant improvements in predictive accuracy could be gained needs further evaluation in a larger population.
View details for DOI 10.1097/TP.0b013e31823705ef
View details for Web of Science ID 000298149200012
View details for PubMedID 22011765
The PROMISE Study: A Phase 2b Multicenter Study of Voclosporin (ISA247) Versus Tacrolimus in De Novo Kidney Transplantation
AMERICAN JOURNAL OF TRANSPLANTATION
2011; 11 (12): 2675-2684
Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic-pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high-dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r(2) = 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6-month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low- and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.
View details for DOI 10.1111/j.1600-6143.2011.03763.x
View details for Web of Science ID 000297411800019
View details for PubMedID 21943027
- Induced Immune Tolerance for Kidney Transplantation NEW ENGLAND JOURNAL OF MEDICINE 2011; 365 (14): 1359-1360
Living donor evaluation and exclusion: the Stanford experience
2011; 25 (5): 697-704
The proportion of prospective living donors disqualified for medical reasons is unknown. The objective of this study is to delineate and quantify specific reasons for exclusion of prospective living donors from kidney donation.All adult prospective kidney donors who contacted our transplant program between October 1, 2007 and April 1, 2009 were included in our analysis (n?=?484). Data were collected by review of an electronic transplant database.Of the 484 prospective donors, 39 (8%) successfully donated, 229 (47%) were excluded, 104 (22%) were actively undergoing evaluation, and 112 (23%) were withdrawn before evaluation was complete. Criteria for exclusion were medical (n?=?150), psychosocial (n?=?22), or histocompatibility (n?=?57) reasons. Of the 150 prospective donors excluded for medical reasons, 79% were excluded because of obesity, hypertension, nephrolithiasis, and/or abnormal glucose tolerance. One hundred and forty-seven (61%) intended recipients had only one prospective living donor, of whom 63 (42%) were excluded.A significant proportion of prospective living kidney donors were excluded for medical reasons such as obesity (body mass index >30), hypertension, nephrolithiasis, and abnormal glucose tolerance. Longer-term studies are needed to characterize the risks to medically complex kidney donors and the potential risks and benefits afforded to recipients.
View details for DOI 10.1111/j.1399-0012.2010.01336.x
View details for Web of Science ID 000296262300018
View details for PubMedID 21044160
12-MONTH RESULTS OF TOFACITINIB (CP-690,550)-BASED CNI-FREE IMMUNOSUPPRESSION IN A PHASE 2B STUDY IN DE NOVO KIDNEY TRANSPLANT PATIENTS
WILEY-BLACKWELL. 2011: 97-97
View details for Web of Science ID 000294869600332
Managing Finances of Shipping Living Donor Kidneys for Donor Exchanges
AMERICAN JOURNAL OF TRANSPLANTATION
2011; 11 (9): 1810-1814
Kidney donor exchanges enable recipients with immunologically incompatible donors to receive compatible living donor grafts; however, the financial management of these exchanges, especially when an organ is shipped, is complex and thus has the potential to impede the broader implementation of donor exchange programs. Representatives from transplant centers that utilize the National Kidney Registry database to facilitate donor exchange transplants developed a financial model applicable to paired donor exchanges and donor chain transplants. The first tenet of the model is to eliminate financial liability to the donor. Thereafter, it accounts for the donor evaluation, donor nephrectomy hospital costs, donor nephrectomy physician fees, organ transport, donor complications and recipient inpatient services. Billing between hospitals is based on Medicare cost report defined costs rather than charges. We believe that this model complies with current federal regulations and effectively captures costs of the donor and recipient services. It could be considered as a financial paradigm for the United Network for Organ Sharing managed donor exchange program.
View details for DOI 10.1111/j.1600-6143.2011.03690.x
View details for Web of Science ID 000294360400009
View details for PubMedID 21831153
Changes in T Cell Subsets in 12 Patients Enrolled in a Tolerance Induction Protocol with Combined Kidney and Hematopoietic Cell Transplantation.
WILEY-BLACKWELL. 2011: 177-177
View details for Web of Science ID 000289318400491
C1q-Fixing Human Leukocyte Antigen Antibodies Are Specific for Predicting Transplant Glomerulopathy and Late Graft Failure After Kidney Transplantation
2011; 91 (3): 342-347
Human leukocyte antigen (HLA) antibodies, especially those that fix complement, are associated with antibody-mediated rejection and graft failure. The C1q assay on single antigen beads detects a subset of HLA antibodies that can fix complement and precede C4d deposition. The aim of this study was to determine whether C1q-fixing antibodies distinguish de novo donor-specific antibodies (DSA) that are clinically relevant and harmful.We retrospectively studied 31 of 274 kidney transplant recipients who had pretransplant and concurrent biopsy and serum specimens, 13 with C4d-positive and 18 with C4d-negative staining. We measured IgG and C1q DSA pretransplant and at the time of biopsy using single antigen bead assays. We identified 13 recipients who developed de novo DSA by IgG or C1q and examined associations with C4d deposition, transplant glomerulopathy, and graft failure.Testing for DSA by IgG is more sensitive for C4d deposition (IgG: 100%, 95% confidence interval [CI] 0.60-1; C1q: 75%, 95% CI 0.36-0.96). Testing for DSA by C1q is more specific for transplant glomerulopathy (C1q: 81%, 95% CI 0.57-0.94; IgG: 67%, 95% CI 0.43-0.85) and graft loss (C1q: 79%, 95% CI 0.54-0.93; IgG: 63%, 95% CI 0.39-0.83). Absence of de novo DSA by IgG and C1q has a high negative predictive value for the absence of C4d deposition (IgG: 100%, 95% CI 0.73-1; C1q: 88%, 95% CI 0.62-0.98), transplant glomerulopathy (IgG: 100%, 95% CI 0.73-1; C1q: 100%, 95% CI 0.77-1), and graft failure (IgG: 86%, 95% CI 0.56-0.97; C1q: 88%, 95% CI 0.62-0.98).Monitoring patients with the C1q assay, which detects antibodies that fix complement, offers a minimally invasive means of identifying patients at risk for transplant glomerulopathy and graft loss.
View details for DOI 10.1097/TP.0b013e318203fd26
View details for Web of Science ID 000286624400014
View details for PubMedID 21116220
- Debate: PRO Position Formal Assessment of Donor Kidney Function Should Be Mandatory AMERICAN JOURNAL OF NEPHROLOGY 2011; 33 (3): 198-200
Population Pharmacokinetic Analysis of Mycophenolic Acid Coadministered With Either Tasocitinib (CP-690,550) or Tacrolimus in Adult Renal Allograft Recipients
THERAPEUTIC DRUG MONITORING
2010; 32 (6): 778-781
Tasocitinib (CP-690,550) is an orally active Janus kinase inhibitor that is in development for prophylaxis of acute rejection after kidney transplantation and for the treatment of select autoimmune diseases. The current study was conducted to evaluate the systemic exposure of mycophenolic acid (MPA) in de novo kidney transplant patients when coadministered with tasocitinib compared with exposure in patients receiving tacrolimus, which has no effect on MPA pharmacokinetics. Plasma MPA concentrations were obtained from 17 adult patients who received either 15 mg or 30 mg tasocitinib twice daily (eight patients) or tacrolimus (nine patients) after kidney transplantation. All patients also received concomitant mycophenolate mofetil, prednisone, and basiliximab induction. The median mycophenolate mofetil dose was 1000 mg twice daily. A two-compartment population pharmacokinetic model estimating oral clearance, between-patient variability in oral clearance, central volume of distribution, and residual variability in combination with historical estimates of first-order absorption rate constant, intercompartmental clearance, and peripheral volume of distribution adequately described the sparse MPA data. Based on individual estimates oral clearance from the population pharmacokinetic model, mean steady-state area under the concentration-time curve values for a mycophenolate mofetil dose of 1000 mg twice daily were 63 mg·hr/L (22%) and 59 mg·hr/L (36%) for the tasocitinib and tacrolimus groups, respectively. These results indicate that tasocitinib does not influence systemic MPA exposure.
View details for DOI 10.1097/FTD.0b013e3181f361c9
View details for Web of Science ID 000284103400017
View details for PubMedID 20926996
Effects of aging on glomerular function and number in living kidney donors
2010; 78 (7): 686-692
To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (? 55 years) compared to 33 younger (? 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.
View details for DOI 10.1038/ki.2010.128
View details for Web of Science ID 000281824200011
View details for PubMedID 20463656
Imprecision of Creatinine-Based GFR Estimates in Uninephric Kidney Donors
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2010; 5 (3): 497-502
To ensure long-term safety of living kidney donors, it is now recommended that they be followed for at least 2 years after donation and that serum creatinine levels be monitored. Such levels are often subjected by clinical laboratories to estimating equations and are reported as estimated GFR (eGFR). The accuracy of such equations in uninephric living donors has yet to be validated. This is especially important in older living donors, who often have senescence-related depression of GFR.We compared urinary creatinine clearance, four-variable Modification of Diet in Renal Disease estimating equation (eGFR), and the recently reported CKD-EPI GFR estimating equation with true GFR measured by the urinary iothalamate clearance (iGFR) in 64 subjects after kidney donation.Creatinine clearance overestimated iGFR. Both creatinine-based estimating equations were poorly correlated with and underestimated iGFR. More than half of kidney donors had eGFR <60 ml/min per 1.73 m(2) after donation, a level that categorized them as having stage 3 chronic kidney disease by our current laboratory reporting, whereas only 25% had iGFR <60 ml/min per 1.73 m(2). This misclassification disproportionately affected older donors age > or =55 years, of whom 80% had eGFR <60 ml/min per 1.73 m(2). Neither significant albuminuria nor hypertension was observed.The current practice of reporting eGFR after donation commonly leads to a misclassification of chronic kidney disease, particularly in older donors. To ensure long-term well-being of living kidney donors, more precise estimates of GFR are required, particularly among older potential donors.
View details for DOI 10.2215/CJN.05280709
View details for Web of Science ID 000275325000017
View details for PubMedID 20110343
Gene Arrays May Predict Stable Clinical Kidney Tolerance and Support Safe Immunosuppression Withdrawal
WILEY-BLACKWELL PUBLISHING, INC. 2010: 1-1
View details for Web of Science ID 000273654600002
Factors Associated With Progression of Interstitial Fibrosis in Renal Transplant Patients Receiving Tacrolimus and Mycophenolate Mofetil
2009; 88 (7): 897-903
We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed.Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study.At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)-ci + ct more than or equal to 2-increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies.A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.
View details for DOI 10.1097/TP.0b013e3181b723f4
View details for Web of Science ID 000270842500009
View details for PubMedID 19935461
Asynchronous, Out-of-Sequence, Transcontinental Chain Kidney Transplantation: A Novel Concept
AMERICAN JOURNAL OF TRANSPLANTATION
2009; 9 (9): 2180-2185
The organ donor shortage has been the most important hindrance in getting listed patients transplanted. Living kidney donors who are incompatible with their intended recipients are an untapped resource for expanding the donor pool through participation in transplant exchanges. Chain transplantation takes this concept further, with the potential to benefit even more recipients. We describe the first asynchronous, out of sequence transplant chain that was initiated by transcontinental shipment of an altruistic donor kidney 1 week after that recipient's incompatible donor had already donated his kidney to the next recipient in the chain. The altruistic donor kidney was transported from New York to Los Angeles and functioned immediately after transplantation. Our modified-sequence asynchronous transplant chain (MATCH) enabled eight recipients, at four different institutions, to benefit from the generosity of one altruistic donor and warrants further exploration as a promising step toward addressing the organ donor shortage.
View details for DOI 10.1111/j.1600-6143.2009.02730.x
View details for Web of Science ID 000269180500027
View details for PubMedID 19563335
Calcineurin-Inhibitor-Free Immunosuppression Based on the JAK Inhibitor CP-690,550: A Pilot Study in De Novo Kidney Allograft Recipients
AMERICAN JOURNAL OF TRANSPLANTATION
2009; 9 (8): 1936-1945
This randomized, pilot study compared the Janus kinase inhibitor CP-690,550 (15 mg BID [CP15] and 30 mg BID [CP30], n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients received an IL-2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP-690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6-month biopsy-proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6-month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by =77% in CP-690,550-treated patients. In the CP-690,550 arms, there were modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months. These data suggest that coadministration of CP-690,550 30 mg BID with MMF is associated with overimmunosuppression. At 15 mg BID, the efficacy/safety profile was comparable to the tacrolimus control group, excepting a higher rate of viral infection. Further dose-ranging evaluation of CP-690,550 is warranted.
View details for DOI 10.1111/j.1600-6143.2009.02720.x
View details for Web of Science ID 000268050200032
View details for PubMedID 19660021
Glomerular Function, Structure, and Number in Renal Allografts from Older Deceased Donors
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2009; 20 (1): 181-188
The 5-yr survival rate of renal allografts is significantly lower for grafts from older deceased donors than from younger deceased donors. For evaluation of the potential contribution of renal senescence in this shortened graft survival, glomerular function and structure were analyzed in allografts from deceased donors older than 55 yr ("aging") or younger than 40 yr ("youthful"). Aging donors had a significantly higher prevalence of sclerotic glomeruli (P < 0.002), and their nonsclerotic glomeruli tended to be larger, had a larger filtration surface area (P = 0.02), and had a higher single-nephron ultrafiltration coefficient (K(f); P = 0.07), suggesting a compensatory response to functional loss of glomeruli. After serum creatinine reached a stable nadir in the transplant recipients, GFR and its hemodynamic determinants were evaluated and the whole allograft K(f) was computed. Compared with the allografts from youthful donors, allografts from aging donors exhibited a 32% lower GFR, which was exclusively attributable to a 45% reduction in allograft K(f) (both P < 0.001). In addition, the number of functioning glomeruli per allograft was profoundly lower in grafts from aging donors than from youthful donors (3.6 +/- 2.1 x 10(5) versus 8.5 +/- 3.4 x 10(5); P < 0.01), and this could not be explained by the relatively modest 17% prevalence of global glomerulosclerosis in the aging group. The marked reduction in overall glomerular number in many aging donors may lead to a "remnant kidney" phenomenon, potentially explaining the shorter mean survival of these allografts.
View details for DOI 10.1681/ASN.2008030306
View details for Web of Science ID 000262677200025
View details for PubMedID 18815243
Accounting for Donor Charges in Kidney Donor Chains.
WILEY-BLACKWELL. 2009: 435-436
View details for Web of Science ID 000265068800857
Gene Arrays May Predict Stable Clinical Tolerance and Support Safe Immunosuppression Withdrawal.
WILEY-BLACKWELL. 2009: 280-280
View details for Web of Science ID 000265068800306
Glomerular function and number in ECD transplants
WILEY-BLACKWELL. 2008: 602-602
View details for Web of Science ID 000255763202411
Islet cell survival during isolation improved through protein kinase C epsilon activation
2008; 40 (2): 375-378
Strategies inhibiting cell death signaling pathways may enhance the availability of islet transplantation for patients with type 1 diabetes mellitus. The epsilon isoform of protein kinase C (PKC epsilon) has been shown to have an anti-apoptotic effect in many cell types. The present study investigated whether activation of PKC epsilon may improve the yield of functional islet cells for transplantation. Islet cells were isolated from wild-type BALB/c mice preconditioned with either a PKC epsilon activator (psi epsilon RACK) or a TAT carrier control peptide and further treated with the same agents during isolation and in vitro for either 0, 1, 16, or 40 hours. Islet cells were assessed at each time point for viability, apoptosis, and function. psi epsilon RACK-treated islets showed significantly decreased islet cell death up to 40 hours after isolation compared with TAT-treated control islets. Beta-cell function in response to high glucose challenge remained unchanged.
View details for DOI 10.1016/j.transproceed.2008.01.014
View details for Web of Science ID 000254695600014
View details for PubMedID 18374073
Tolerance and chimerism after renal and hematopoietic-cell transplantation.
New England journal of medicine
2008; 358 (4): 362-368
We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.
View details for DOI 10.1056/NEJMoa074191
View details for PubMedID 18216356
Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: A randomized study
AMERICAN JOURNAL OF TRANSPLANTATION
2007; 7 (11): 2538-2545
We conducted a randomized, multicenter study to determine whether treatment of subclinical rejection with increased corticosteroids resulted in beneficial outcomes in renal transplant patients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and prednisone. One hundred and twenty-one patients were randomized to biopsies at 0,1,2,3 and 6 months (Biopsy arm), and 119 to biopsies at 0 and 6 months only (Control arm). The primary endpoint of the study was the prevalence of the sum of the interstitial and tubular scores (ci + ct)> 2 (Banff) at 6 months. Secondary endpoints included clinical and subclinical rejection and renal function. At 6 months, 34.8% of the Biopsy and 20.5% of the Control arm patients had a ci + ct score >or= 2 (p = 0.07). Between months 0 and 6, clinical rejection episodes were 12 in 10 Biopsy arm patients and 8 in 8 Control arm patients (p = 0.44). Overall prevalence of subclinical rejection in the Biopsy arm was 4.6%. Creatinine clearance at 6 months was 72.9 +/- 21.7 in the Biopsy and 68.90 mL/min +/- 18.35 mL/min in the Control arm patients (p = 0.18). In conclusion, we found no benefit to the procurement of early protocol biopsies in renal transplant patients receiving TAC, MMF and prednisone, at least in the short term. This is likely due to their low prevalence of subclinical rejection.
View details for DOI 10.1111/j.1600-6143.2007.01979.x
View details for Web of Science ID 000250077600014
View details for PubMedID 17908280
Once-daily tacrolimus extended release formulation: Experience at 2 years postconversion from a Prograf-based regimen in stable liver transplant recipients
2007; 83 (12): 1639-1642
Compliance with complex immunosuppressant drug therapies in transplant recipients might be improved with regimens that require less frequent dosing. A once-daily extended release (XL) formulation of tacrolimus has been developed that allows a 1:1 conversion from the twice-a-day tacrolimus (TAC) formulation and has a good exposure to trough concentration correlation. In an open-label, multicenter study, stable liver transplant recipients (n=69) were converted from twice-a-day TAC to XL once-daily in the morning, and were maintained for at least 2 years postconversion using the same therapeutic monitoring and patient care techniques employed with TAC. Two years after conversion, the incidence of biopsy-confirmed acute rejection was 5.8% (4 of 69); patient and graft survival was 98.6% (68 of 69). The safety profile of XL was consistent with that previously reported for TAC. Liver transplant recipients can be converted from twice-a-day TAC to once-daily XL and maintained for at least 2 years postconversion with neither unique efficacy nor safety concerns.
View details for DOI 10.1097/01.tp.0000265445.09987.f1
View details for Web of Science ID 000247578200019
View details for PubMedID 17589349
Transjugular intrahepatic portosystemic shunt creation in a polycystic liver facilitated by hybrid cross-sectional/angiographic imaging
JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
2006; 17 (4): 711-715
Polycystic liver disease (PCLD) has long been considered to represent a contraindication to transjugular intrahepatic portosystemic shunt (TIPS) creation, primarily because of the risk of hemorrhage. Three-dimensional (3D) navigation within the enlarged and potentially disorienting parenchyma can now be performed during the procedure with the development of C-arm cone-beam computed tomography, which relies on the same equipment already used for angiography. Such a hybrid 3D reconstruction-enabled angiography system was used for safe image guidance of a TIPS procedure in a patient with PCLD. This technology has the potential to expedite any image-guided procedure that requires 3D navigation.
View details for DOI 10.1097/01.RVI.0000208984.17697.58
View details for Web of Science ID 000236836700015
View details for PubMedID 16614155
Circulating growth hormone binding protein levels and mononuclear cell growth hormone receptor expression in uremia
JOURNAL OF RENAL NUTRITION
2006; 16 (2): 141-149
Resistance to growth hormone (GH) in end-stage renal disease (ESRD) causes growth retardation and muscle wasting. In humans, circulating GH binding protein (GHBP), the extracellular domain of the GH receptor that is shed into the circulation and is believed to reflect tissue GH receptor levels, is reduced in uremia and suggests that cellular GH receptor levels are correspondingly reduced. If true, this could be a cause of GH resistance. We set out to establish whether serum GHBP levels reflect cellular GH receptor levels and whether changes in serum GHBP levels are related to nutritional or inflammatory status.GH receptor protein expression in peripheral blood mononuclear cells (PBMC) from 21 ESRD and 14 normal subjects were analyzed by fluorochrome flow cytometry.The GH receptor density and percent total PBMCs expressing the GH receptor were similar in the 2 groups, and there was no difference in percent GH receptor positive T or B cells or monocytes. In contrast, serum GHBP levels were 80% lower in ESRD. GHBP levels did not correlate with serum albumin, body mass index, or muscle mass but seemed to be partly related to the log serum C-reactive protein levels.Serum GHBP levels are markedly reduced in ESRD; this seems to occur independent of nutritional status and may in part be caused by inflammation. Because GH receptor expression on PBMC of ESRD and control subjects was similar, our findings argue against a reduction in GH receptor as a cause of GH resistance and the use of serum GHBP levels as a reliable marker of specific tissue GH receptor levels.
View details for DOI 10.1053/j.jrn.2006.01.007
View details for Web of Science ID 000236735600007
View details for PubMedID 16567271
Validation of a screening protocol for identifying low-risk candidates with type 1 diabetes mellitus for kidney with or without pancreas transplantation
2006; 20 (2): 139-146
Certain clinical risk factors are associated with significant coronary artery disease in kidney transplant candidates with diabetes mellitus. We sought to validate the use of a clinical algorithm in predicting post-transplantation mortality in patients with type 1 diabetes. We also examined the prevalence of significant coronary lesions in high-risk transplant candidates.All patients with type 1 diabetes evaluated between 1991 and 2001 for kidney with/without pancreas transplantation were classified as high-risk based on the presence of any of the following risk factors: age >or=45 yr, smoking history >or=5 pack years, diabetes duration >or=25 yr or any ST-T segment abnormalities on electrocardiogram. Remaining patients were considered low risk. All high-risk candidates were advised to undergo coronary angiography. The primary outcome of interest was all-cause mortality post-transplantation.Eighty-four high-risk and 42 low-risk patients were identified. Significant coronary artery stenosis was detected in 31 high-risk candidates. Mean arterial pressure was a significant predictor of coronary stenosis (odds ratio 1.68; 95% confidence interval 1.14-2.46), adjusted for age, sex and duration of diabetes. In 75 candidates who underwent transplantation with median follow-up of 47 months, the use of clinical risk factors predicted all eight deaths. No deaths occurred in low-risk patients. A significant mortality difference was noted between the two risk groups (p = 0.03).This clinical algorithm can identify patients with type 1 diabetes at risk for mortality after kidney with/without pancreas transplant. Patients without clinical risk factors can safely undergo transplantation without further cardiac evaluation.
View details for DOI 10.1111/j.1399-0012.2005.00461.x
View details for Web of Science ID 000237095200001
View details for PubMedID 16640517
Treatment of hepatic venous outflow obstruction after piggyback liver transplantation
2005; 236 (1): 352-359
To evaluate retrospectively the endovascular management of hepatic venous outflow obstruction after piggyback orthotopic liver transplantation.The study was performed with the approval and under the guidelines of the institutional review board and complied with the Health Insurance Portability and Accountability Act. Informed consent from patients was not required by the institutional review board for this retrospective study. From 1995 to 2003, 13 patients (eight male, five female), including 12 adults and one adolescent (age range, 14-67 years; median age, 52 years), underwent endovascular treatment of hepatic venous outflow obstruction after piggyback orthotopic liver transplantation. Patients gave informed consent for all procedures. Eleven patients received whole livers, and two received living-related donor right liver lobes. Four underwent repeat piggyback orthotopic liver transplantation prior to intervention. Primary stent placement was performed in 12 patients. One patient refused primary stent placement and chose venoplasty alone, but required a stent 5 months later. Short balloon-expandable stents (mean diameter, 14.6 mm +/- 1.1 [standard deviation]) were used to minimize jailing of branch vessels and to resist recoil. Pre- and post-procedural pressure gradients were measured. Follow-up included venography, cross-sectional imaging, and laboratory tests. The Wilcoxon signed rank test or the sign test was performed to compare pre- and post-procedural pressure gradients, body weights, and laboratory values.Technical success (pressure gradient < or = 3 mm Hg) was achieved in 13 of 13 patients, and clinical success, in 12 of 13. Mean pre- and post-procedural pressure gradients were 13.0 mm Hg +/- 1.4 and 0.8 mm Hg +/- 0.3. Mean interval from transplantation to intervention was 348 days +/- 159. Mean follow-up was 678 days (range, 16-2880 days). Technical success did not result in clinical improvement in one patient. Biopsy demonstrated severe hepatic necrosis, likely from prolonged venous congestion, and the patient required repeat transplantation. Only one patient required reintervention for stent migration, and no other complications occurred. No significant restenosis was encountered after stent placement.Hepatic venous outflow obstruction is an uncommon but potentially fatal complication of piggyback orthotopic liver transplantation. Endovascular treatment with balloon-expandable stents is effective, safe, and apparently durable.
View details for DOI 10.1148/radiol.2361040327
View details for Web of Science ID 000229905300046
View details for PubMedID 15955856
Conversion from cyclosporine microemulsion to tacrolimus-based immunoprophylaxis improves cholesterol profile in heart transplant recipients with treated but persistent dyslipidemia: The Canadian multicentre randomized trial of tacrolimus vs cyclosporine microemulsion
JOURNAL OF HEART AND LUNG TRANSPLANTATION
2005; 24 (7): 798-809
Tacrolimus improves lipid profile in renal and liver transplant recipients. The impact of conversion from cyclosporine microemulsion (Neoral) to tacrolimus (Prograf) in a large randomized study of stable heart transplant recipients with treated but persistent mild dyslipidemia is reported.One hundred twenty-nine long-term (>or=12 months) cyclosporine microemulsion-treated heart transplant recipients with low-density lipoprotein cholesterol >2.5 mmol/liter and/or a total cholesterol/high-density lipoprotein cholesterol ratio >4 were recruited for the study. Complete lipid profile was assessed before (baseline) and after 6 months of treatment with either cyclosporine microemulsion maintenance (n=64) or tacrolimus conversion (n=65).At 6 months, tacrolimus-converted patients exhibited a greater decrease in total cholesterol (from 5.51 +/- 0.16 to 4.88 +/- 1.22 mmol/liter [tacrolimus], vs 5.61 +/- 1.36 to 5.38 +/- 0.87 mmol/liter [cyclosporine]; p = 0.0078). This decrease in cholesterol was caused largely by a decrease in low-density lipoprotein cholesterol (-0.41 +/- 0.54 [tacrolimus] vs -0.13 +/- 0.55 [cyclosporine]; p=0.0018). There were no changes in high-density lipoprotein cholesterol and triglyceride levels, but apolipoprotein B therapy was reduced in tacrolimus-converted vs cyclosporine-maintained patients (p=0.0003). By 6 months, 23.7% of tacrolimus- vs 6.7% of cyclosporine-treated patients met the target lipid levels for high-risk patients (p=0.0094). Conversion from cyclosporine to tacrolimus resulted in decreases in blood urea nitrogen, creatinine, and uric acid without any changes in glucose, HbA(1C), and insulin levels.Conversion from cyclosporine microemulsion- to tacrolimus-based immunoprophylaxis resulted in decreased cholesterol, apolipoprotein B, urea, creatinine, and uric acid without any clinically evident perturbation of glucose metabolism in stable heart transplant recipients with treated but persistent mild dyslipidemia.
View details for DOI 10.1016/j.healun.2004.05.023
View details for Web of Science ID 000230423400002
View details for PubMedID 15982605
Conversion of stable liver transplant recipients from a twice-daily prograf-based regimen to a once-daily modified release tacrolimus-based regimen
2005; 37 (2): 1211-1213
Modified release (MR) tacrolimus is an extended release formulation administered once daily. The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable liver transplant recipients converted from Prograf twice a day to MR tacrolimus once daily.This was an open-label, multicenter study with a single sequence, four-period crossover design. Eligible patients were 18 to 65 years of age, >6 months posttransplant with stable renal and hepatic function and receiving stable doses of Prograf twice a day for >2 weeks prior to enrollment. Patients received Prograf twice a day on days 1 to 14 and 29 to 42. Patients were converted to the same milligram-for-milligram daily dose of MR once daily on days 15 to 28 and 43 to 56. Twenty-four-hour PK profiles were obtained on days 14, 28, 42, and 56. Laboratory and safety parameters were also evaluated.Of 70 patients, 62 completed all four PK profiles. The AUC0-24 of tacrolimus was comparable for Prograf twice a day (days 14 and 42) and MR tacrolimus once daily (days 28 and 56). The 90% confidence intervals for MR tacrolimus versus Prograf at steady state (days 28 and 56 vs days 14 and 42) was 0.85 to 0.92 for AUC0-24. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 14, r = .93; Day 42, r = .89) and for MR tacrolimus (day 28, r = .93; day 56, r = .92). Renal and liver function remained stable. One patient experienced acute rejection.The steady-state tacrolimus exposure of MR tacrolimus once daily is equivalent to Prograf twice a day after a milligram-for-milligram conversion in stable liver transplant recipients.
View details for DOI 10.1016/j.transproceed.2004.11.086
View details for Web of Science ID 000228568900224
View details for PubMedID 15848672
A prospective 3-yr evaluation of tacrolimus-based immunosuppressive therapy in immunological high risk renal allograft recipients
2005; 19 (1): 26-32
There have been no published data on use of the the newer immunosuppressants tacrolimus and mycophenolate mofetil (MMF) in high immunological risk renal transplantation. We therefore undertook a prospective study to systematically assess outcomes using these agents as part of an aggressive immunosuppressive regimen.Fifty-nine high-risk renal allograft recipients were enrolled at 10 Canadian sites and given a regimen of: a biological induction agent, tacrolimus, MMF, and corticosteroids. Patients included 10 (17%) who had lost a previous graft to rejection <1 yr, 31 (53%) with a current panel reactive antibody (PRA) >30%, 47 (80%) with a historic PRA >50%, four (7%) who had a positive historical T-cell crossmatch with the current donor, and six (10%) with a current positive B-cell crossmatch. The mean peak PRA was 76 +/- 33%.The estimated 3-yr Kaplan-Meier patient and graft survival estimates were 89% and 75%, respectively. There were nine graft losses other than deaths with a functioning graft, of which six were preceded by delayed graft function (p = 0.01, chi2). Sixteen (27%) recipients experienced at least one episode of biopsy-confirmed acute rejection. Infections included cytomegalovirus in 16 patients, eight of whom had tissue-invasive disease. Only one malignancy occurred.The immunosuppressive strategy investigated is effective and displays a satisfactory safety profile in high immunological risk renal allograft recipients.
View details for DOI 10.1111/j.1399-0012.2005.00275.x
View details for Web of Science ID 000226347700005
View details for PubMedID 15659130
Preoperative renal volumes as a predictor of graft function in living donor transplantation
AMERICAN JOURNAL OF KIDNEY DISEASES
2004; 44 (5): 877-885
Nephron underdosing and donor kidney-recipient body size mismatch can lead to poor allograft function. The purpose of this study is to examine the relationship between donor kidney volume and posttransplantation graft function by using magnetic resonance imaging (MRI) to obtain renal volumes. Previous investigators used donor body surface area as a surrogate for kidney size or measured renal volume by using ultrasonography; both these techniques are inaccurate measures of renal volume. Intraoperative weights are more accurate, but provide information only after the transplantation is underway. More recently, MRI has been used preoperatively to screen living donors; these novel MRI techniques also provide information regarding renal size.We performed a retrospective analysis of 54 patients who underwent living donor transplantation at our institution from 2000 to 2002. All living donors underwent preoperative renovascular imaging using MRI, and renal volumes were obtained for each donor. A transplant kidney volume-recipient body weight (Vol/Wt) ratio was determined for each donor-recipient pair, and patients were divided into tertiles corresponding to 3 groups: high (>2.7), medium (2 to 2.7), and low (<2) "nephron dose" ratios.Glomerular filtration rate (GFR) correlated with Vol/Wt ratio at 6 and 12 months (r = 0.46; P = 0.0005 and r = 0.41; P = 0.003). At 6 months, mean GFRs in the low, medium, and high groups were 52.4 +/- 2.8 (SEM), 64.5 +/- 6.2, and 82.0 +/- 4.4 mL/min, respectively (P < 0.0005). At 12 months, GFRs in the low, medium, and high groups were 51.6 +/- 3.6, 63.3 +/- 3.8, and 83.9 +/- 5.4 mL/min, respectively (P < 0.0001).Transplantation of donor-recipient pairs with a Vol/Wt ratio less than 2 cm 3 /kg was associated with significantly worse graft function. Donor kidney volumes measured by means of preoperative MRI can be used to calculate Vol/Wt ratios before transplantation and identify patients at risk for a low GFR posttransplantation.
View details for DOI 10.1053/j.ajkd.2004.07.012
View details for Web of Science ID 000225044100015
View details for PubMedID 15492954
Effect of steroid avoidance on early graft function after kidney transplantation
WILEY-BLACKWELL. 2004: 354-354
View details for Web of Science ID 000221322500721
Pre-operative MRI kidney volumes as a predictor of graft function in living donor kidney transplantation.
AMER SOC NEPHROLOGY. 2003: 11A-11A
View details for Web of Science ID 000186219100048
Synergistic effects of RAD and Neoral in inhibition of host-vs.-graft and graft-vs.-host immune responses in rat small-bowel transplantation
2003; 23 (5): 476-482
The combined effects of RAD and Neoral were tested in a rat orthotopic small-bowel transplantation model. Seven groups (n = 6) were involved in this study, and each one was included in three rejection models for the evaluation of host-vs.-graft disease (HVG) (LBN-F1 to LEW), graft-vs.-host disease (GVH) (LEW to LBN-F1), and combined HVG and GVH immune responses (BN to LEW). Both drugs were administered orally throughout the study. Low doses of RAD (1.0-2.5 mg/kg/day) combined with Neoral (2.0-5.0 mg/kg/day) produced strong synergistic effects in the prolongation of small-bowel graft survival in HVG (combination index, CI = 0.095, 0.1212), GVH (CI = 0.027, 0.020), and combined HVG and GVH immune responses (CI = 0.070, 0.301). The combination therapy of RAD and Neoral produces a strong synergistic effect toward the inhibition of HVG, GVH, and combined HVG and GVH immune responses in a rat small-bowel transplantation model.
View details for DOI 10.1002/micr.10167
View details for Web of Science ID 000186223500016
View details for PubMedID 14558006
- Low-dose tacrolimus, trough-monitored mycophenolate mofetil, and planned steroid withdrawal for cadaveric kidney transplantation: A single center experience TRANSPLANTATION PROCEEDINGS 2002; 34 (5): 1694-1695
- Chest wall and liver resection for chondrosarcoma ANNALS OF THORACIC SURGERY 2002; 74 (2): 598-598
In vivo higher glucuronidation of mycophenolic acid in male than in female recipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil
THERAPEUTIC DRUG MONITORING
2001; 23 (5): 520-525
Mycophenolate mofetil (MMF), an immunosuppressant drug used in organ transplantation to prevent rejection, is being used increasingly in association with cyclosporine and tacrolimus. Mycophenolic acid (MPA) is primarily metabolized in the liver to its 7-O-glucuronide (MPAG) derivative. The concentrations of MPAG in serum are many times the concentrations of MPA. Although MPAG has not shown immunosuppressant activity, it was postulated that it could displace MPA from its binding sites on albumin and hence increase the biologic effects of MPA. This effect could be important for patients with acute renal failure; under this condition, MPAG was shown to accumulate. The goal of this study was to document the MPAG/MPA concentration ratio in 100 renal transplant patients under a mixed immunosuppressive therapy. Further, the study addressed the question of whether MPAG can displace MPA in vivo from bound albumin in a representative renal transplant patient population under immunosuppressive therapy. Levels of MPAG and MPA were measured by high-performance liquid chromatography. The distribution of the ratios was not parametric as it tailed toward elevated values. After a square root transformation of the data, parametric analysis was possible. The average MPAG/MPA ratio was 15.0 +/- 2.2 for men versus 7.7 +/- 0.9 for women. Men treated with MMF and tacrolimus showed a lower ratio than patients treated with MMF and cyclosporine, confirming that tacrolimus inhibits glucuronidation of MPA. Further, it was determined that at physiologic concentrations, MPAG does not increase the amount of free MPA. Because MPAG can favor the elimination of MPA, it can be concluded that gender differences and cotreatment with tacrolimus must be taken into consideration when MMF is being administered.
View details for Web of Science ID 000171210300004
View details for PubMedID 11591897
- Tacrolimus, MMF, steroid, and ALG immunotherapy for high immunological risk renal transplant recipients ELSEVIER SCIENCE INC. 2001: 1044-1045
- Canadian multicentre trial of tacrolimus/azathioprine/steroids versus tacrolimus/mycophenolate mofetil/steroids versus neoral/mycophenolate mofetil/steroids in renal transplantation ELSEVIER SCIENCE INC. 2001: 1266-1267
Effect of intraoperative blood transfusion on patient outcome in hepatic transplantation
ARCHIVES OF SURGERY
1999; 134 (1): 25-29
To evaluate the effect of intraoperative transfusion of red blood cells (RBCs) on patient and graft survival.A retrospective study.A tertiary care referral center.Between January 1, 1992, and December 31, 1994, medical records from 225 adult patients who underwent primary liver transplantations were analyzed.Overall patient survival was 90% at 1 year and 86% at 3 years, while graft survival was 89% at 1 year and 85% at 3 years. The following factors were associated with patient and graft survival: age, sex, medical condition at the time of transplantation, and intraoperative transfusion of RBCs. When these factors were subjected to a multivariate analysis, all were independently associated with survival. Fifty-four recipients (24%) underwent transplantation without intraoperative transfusion of RBCs, while 171 recipients (76%) received at least 1 U of RBCs intraoperatively. Recipients who did not receive transfusion of RBCs had higher patient and graft survival rates than patients who did receive RBCs. By multivariate analysis, transplantation without intraoperative transfusion of RBCs no longer remained statistically significant, and only sex and the patient's medical condition were independently associated with patient and graft survival. Patient and graft survival decreased if 5 or more U were transfused, but transfusion of 5 or more U was not independently associated with survival by multivariate analysis.Increased transfusion requirement for RBCs was independently associated with patient and graft survival. While transplantation without transfusion of intraoperative RBCs was associated with superior patient and graft survival, these effects were overridden by patient sex and medical condition at the time of transplantation.
View details for Web of Science ID 000078053500006
View details for PubMedID 9927126
Regression of hypertrichosis and gingival hypertrophy in renal transplant recipients following replacement of cyclosporin by tracrolimus.
ANNALES DE CHIRURGIE
1999; 53 (8): 687-689
Gingival Hyperplasia (GH) and hypertrichosis (HT) are two sides effects associated with the usage of cyclosporine (CyA) but not with tacrolimus (FK 506). The aim of this study is to evaluate the efficacy and security of the conversion from CsA to FK 506 to treat those two complications. From August 1996 to May 1997, 15 patients (9 males, 6 females) aged from 23 to 63 years old (38 +/- 14, mean +/- SD) were switched from CsA to FK 506, 12 for GH, 2 for HT and one for combined presentation. FK 506 was first initiated at a dose of 0.15 mg/kg/day and then adjusted to a level target of 8 ng/ml. The conversion was done on an out patient basis at average 35 (5-83) months after transplantation. Patients were followed prospectively for 12 months. There was a significant reduction in GH in all patients within 3 months. Five out 13 patients had a complete resolution of GH within three months of conversion, 9/12 within 6 months and all by 12 months. HT resolved completely within 6 months. No rejection episode occurred and the serum creatinin remain stable over one year post conversion. Conversion from CsA to FK 506 is thus a safe and valid option to treat CsA induced GH and HT.
View details for Web of Science ID 000083530400001
- Mycophenolate mofetil's effect on accelerated heart allograft rejection and rejection markers in the rat TRANSPLANTATION PROCEEDINGS 1998; 30 (4): 1049-1050
- Conversion from neoral (cyclosporine) to tacrolimus of kidney transplant recipients for gingival hyperplasia or hypertrichosis TRANSPLANTATION PROCEEDINGS 1998; 30 (4): 1247-1248
Experience with the piggyback technique without caval occlusion in adult orthotopic liver transplantation
1998; 65 (1): 77-82
To assess the feasibility and outcome of a piggyback technique without caval occlusion or veno-venous bypass (VB), we retrospectively reviewed 131 consecutive adult orthotopic liver transplantation (OLT) performed in 129 patients between May 1993 and February 1995. Six were second transplants, and six were combined liver-kidney transplants. The piggyback technique was attempted in all cases.We were able to perform the piggyback technique in 98 OLTs (75%). The remaining 33 OLTs (25%) were converted to the standard technique; of these, 20 (15%) required VB. The reasons for conversion to the standard technique were: anatomical (22 transplants), severe portal hypertension requiring VB (8 transplants), tumor (1 transplant), and other reasons (2 transplants). Six retransplantations were performed (four piggyback, two standard).There was no significant difference in age, United Network for Organ Sharing status, Child's classification, and diagnosis between the patients in whom piggyback was possible or not. The actuarial patient and graft survival at 1 year were similar between the piggyback group and the group of patients converted to standard technique (87/85% vs. 86/86%, respectively). No death was related to either technique. With piggyback, the average operative time was 8.6+/-1.9 hr, median amount of blood transfused intraoperatively was 2 U (33% did not require transfusion), and median intensive care unit and hospital stays were 3 and 11 days, respectively. With the piggyback technique, the mean preoperative and maximum postoperative serum creatinine levels were 1.4+/-1.0 and 1.8+/-1.5 mg/dl.The piggyback technique without caval occlusion is possible in the majority of patients. It is safe and has reduced the use of VB to 15% of our adult OLTs. The piggyback technique avoids retrocaval dissection, facilitates retransplantation, and is associated with a short anhepatic phase, low blood product usage, and short intensive care unit stay.
View details for Web of Science ID 000071516900014
View details for PubMedID 9448148
Tacrolimus (FK506) and sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat
1997; 64 (12): 1853-1856
Combined use of tacrolimus (FK506) with sirolimus (rapamycin [RAPA]) was examined in a model of vascularized heart allograft in the rat. For prevention of acute rejection, three different combinations of low doses of FK506 and RAPA from day 1 up to day 14 after transplantation produced significantly longer cardiac allograft survival than each agent alone (P<0.05). Identical results were observed in a model of reversal of ongoing acute rejection, where two combinations of low doses of FK506 and RAPA from day 4 up to day 18 after surgery also demonstrated significantly longer graft survival than each immunosuppressant alone (P<0.05). All the low-dose-treated groups in these two models presented significantly longer heart graft survival than naive controls (P<0.05), confirming that both agents are potent immunosuppressants in the models chosen. These results also indicate that, in contrast with in vitro studies, the combined use of FK506 and RAPA in vivo did not produce antagonism, but rather had synergistic effect in prolonging the allograft survival as compared with each agent alone. It appears likely that the abundance of FKBP-12 available for binding in vivo prevents inhibitive competition of the two agents for their receptor.
View details for Web of Science ID 000071404400039
View details for PubMedID 9422432
Left hepaticogastrostomy for biliary obstruction: Long-term results
1997; 204 (3): 780-786
To evaluate the long-term results of peripheral biliary diversion by means of anastomoses of the left lobe of the liver to the stomach.Transhepatic perforation of the left lobe of the liver into the lesser curvature of the stomach was performed in 35 patients with a presumed diagnosis of malignant obstructive jaundice. Jaundice was found to be caused by a malignant stricture in 32 patients and a benign stricture in three. Perforation was performed under fluoroscopic, endoscopic, and laparoscopic guidance in 33 patients and without laparoscopy in the other two. The hepaticogastric anastomosis was secured with a gastrostomy tube; patency of the tract was maintained with placement of a metallic stent. Kaplan-Meier analysis was used to evaluate survival, anastomosis patency rate, and jaundice recurrence.Technical success was achieved in all patients. Two (6%) patients had anastomotic obstruction. The actuarial survival rate was 91%, 80%, 59%, and 26% at 1, 3, 6, and 12 months. The mean patency was 234 days +/- 252. The jaundice-free rate among surviving patients was 100%, 96%, 93%, and 80% at 1, 3, 6, and 12 months. The reintervention rate was 14%. Late cholangitis occurred in seven (20%) patients.This peripheral diversion procedure appears to be safe and shows good long-term patency.
View details for Web of Science ID A1997XR60200031
View details for PubMedID 9280259
- Induction of long-term small bowel graft survival by low-dose immunosuppression in tolerized recipient rats ELSEVIER SCIENCE INC. 1997: 697-698
Intra-hepatic glutathione and oxidative stress in liver transplantation in the pig.
ANNALES DE CHIRURGIE
1997; 51 (8): 839-844
To determine the loss of endogenous GSH from livers cold-stored and reperfused, using a model of liver transplantation in the pig.Four female Yorkshire pigs weighing 19 to 40 kg received a liver allograft. Donor livers were cold-stored in the UW solution. Mean cold ischemic time was 6.5 hours. Malondialdehyde (MDA) levels were used as an index of oxidative stress. MDA plasma levels were measured following recipient laparotomy (H0), immediately (H1), and 90 minutes after liver reperfusion (H2). MDA and GSH levels in liver were measured following donor laparotomy (T0), at the end of cold ischemic period (T1), and at 90 minutes following liver reperfusion (T2).Three animals survived. MDA liver levels decreased of 44% between T0 and T1, then increased to 92% at T2. In contrast, in plasma, graft reperfusion was associated with an increase of MDA to 140% of the baseline values which reached 188% at H2. Intrahepatic GSH levels decreased of 49% at T1, then to 72% at T2.our study suggests that in liver transplantation: (1) Hepatic GSH is depleted to 49% during cold-storage, and an additional 23% is lost after reperfusion; (2) GSH contained in the UW solution does not prevent the loss of hepatocellular glutathione during preservation and reperfusion; (3) after short periods of cold ichemia, endogenous hepatic GSH may protect against oxydative stress in the transplanted liver.
View details for Web of Science ID A1997YF47800002
View details for PubMedID 9734091
Primary liver transplantation without transfusion of red blood cells
MOSBY-ELSEVIER. 1996: 698-704
This study examines factors associated with the performance of orthotopic liver transplantation (OLT) without red blood cell (RBC) transfusion.Between January 1992 and December 1994, 306 primary OLTs were performed with recipients divided into two groups: group 1 patients (61 recipients, 20% of total) underwent transplantation without packed RBCs, and group 2 patients (245 recipients, 80% of cases) received a transfusion of at least 1 unit of RBCs during operation.Recipients in group 1 compared with group 2 had less advanced liver disease (20% hospitalized and 48% Child's class C versus 58% hospitalized and 73% Child's class C, p < 0.01) and lower frequency of right upper quadrant surgery (13% versus 25%, p < 0.05). Group 1 recipients also had significantly higher preoperative hematocrits (38% versus 33%, p < 0.01), lower prothrombin times (15.4 versus 16.7 seconds, p < 0.001) and partial thromboplastin times (36.9 versus 42.2 seconds, p < 0.01), a greater proportion of patients transplanted by piggyback technique (87% versus 59%, p < 0.001), and shorter operative times (7.9 hours versus 9.2 hours, p < 0.001). Moreover, a greater percentage of patients underwent OLT without RBC transfusion in each successive year: 9% in 1992, 21% in 1993, and 31% in 1994 (p < 0.001). Logistic regression analysis showed the following factors to be independent predictors of OLT without RBC transfusion. Preoperative Hct, United Network of Organ Sharing status, piggyback technique, operative time, and year of transplantation.OLT can be performed without transfusion of RBCs in recipients with less advanced liver disease, and surgical technique, along with increased experience by the transplant team, are important factors.
View details for Web of Science ID A1996VP42300036
View details for PubMedID 8862380
CYCLOSPORINE AND THE REVERSIBILITY OF CHRONIC VASCULAR REJECTION
ELSEVIER SCIENCE INC. 1994: 2564-2566
A model of chronic vascular rejection of cardiac allografts has been developed in inbred rats using the WF.1L/Gut congenic strain as donor into LEW recipients. The hearts beat for more than 200 days without the need for exogenous immunosuppression. The histopathology is characterized by cellular rejection, vasculitis, and myointimal arterial wall thickening, and by day 60 posttransplant, there are widespread occlusive vascular changes similar to those seen in human cardiac allografts. CsA, at a dose of 15 mg/kg/d, is effective in preventing as well as reversing the vasculopathy. These data (1) confirm other studies of ours on the reliability of the experimental model using this strain combination, (2) establish the time window of days 40 to 60 whereby mechanisms of lesion regression can be studied, (3) prove the MHC class I and class II antigen incompatibility are not a necessary condition for the generation of the vascular lesions, (4) show that CsA is a useful probe for study of the vasculopathy, and (5) suggest that the model is a useful probe of the mechanism of action of CsA.
View details for Web of Science ID A1994PM60300032
View details for PubMedID 7940792
- PASSENGER LEUKOCYTE EFFECT NOT MEDIATED BY INTERSTITIAL DENDRITIC CELLS ELSEVIER SCIENCE INC. 1993: 98-98
SIMULTANEOUS LIVER AND WHOLE PANCREAS HARVESTING IN THE MULTIORGAN CADAVERIC DONOR
CANADIAN JOURNAL OF SURGERY
1990; 33 (4): 277-281
Simultaneous harvesting of the liver and whole pancreas is usually not performed because it is believed that the shared vascular supply of both organs is incompatible with safe grafting. A careful review of the vascular anatomy, however, shows that simultaneous removal of the two organs is feasible, and a technique is described by which the liver is revascularized in the recipient through the celiac axis or the common hepatic artery and the pancreas is revascularized through the superior mesenteric and splenic arteries. When the vascular supply is abnormal, reconstruction of the vascular tree of one or both organs may be needed. The results of this technique used on 10 recipients are analysed.
View details for Web of Science ID A1990DV37100008
View details for PubMedID 2383835