Showing papers in "Clinical Transplantation in 2005"

Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004

Abstract: As of December 31, 2004, more than 23,000 pancreas transplant had been reported to the IPTR, >17,000 in the US and almost 6000 from outside the US. An analysis of US pancreas transplants performed between 1988 and 2003 showed a progressive improvement in outcome, with pancreas transplant graft survival rates (GSRs) going from 75% at 1 yr for 1988/1989 to 85% for 2002/2003 simultaneous pancreas-kidney (SPK) cases, from 55 to 78% for pancreas after kidney (PAK) cases, and from 45 to 77% for pancreas transplants alone (PTA) cases. The improvements were due both to decreases in technical failure (TF) rates (from 12 to 6% in SPK, 13-8% in PAK, and 24-7% in PTA) and immunological failure rates (going from 7 to 2% for SPK, from 28 to 7% for PAK, and from 38 to 8% for PTA cases). These results are even more impressive under the aspect that during the same time the rate of potential risk factors increased and the duct management techniques changed from bladder to enteric drainage. The improvement in outcome allowed also an increase in the number of solitary pancreas transplants from initially 12% to now 35%. Contemporary primary deceased donor pancreas transplant outcomes were calculated separately for 2000-2004 US and non-US cases. The US patient survival rates at 1 yr were >95% in each recipient category, with 1 yr primary pancreas GSRs of 85% for SPK, 78% for PAK, and 76% for PTA (p or =80% in all three recipient categories. The results were comparable (> or =83% 1-year GSR) for patients (approximately 10%) treated with Sirolimus (SIR) under various protocols. In regard to non-US pancreas transplants, even for 2000-2004 the overwhelming majority continued to be in the SPK category (91%), with 1-year patient, kidney and pancreas survival rates of 94, 92, and 87%. Solitary transplants are still very rarely done outside the US. Non-US PAK GSR at 1 yr was 85%, non-US PTA GSR at 1 yr was 76%. In summary, with the new advancements in immunosuppression and changes in surgical techniques the outcomes in patient survival and pancreas transplant graft function continue to improve even with an increasing proportion of high risk patients in all three categories.

Liver transplantation in the United States.

Abstract: Based on the data reported to the OPTN/UNOS Liver Transplant Registry between 1987-2005, we found: 1. The number of deceased-donor liver transplantations increased slowly each year, with most of the increase being in adult recipients. The number of LD transplants, on the other hand, decreased sharply after 2002, following 3 years of rapid increase from 1998-2001 in both pediatric and adult recipients. 2. The number of DD liver recipients with non-cholestatic liver diseases increased very quickly during the past 18 years. Malignant disease as a cause of end-stage liver disease increased after implementation of MELD in 2002. Among LD liver recipients, non-cholestatic disease increased sharply from 1998-2001, but decreased from 2002. Malignant diseases as a cause for LD transplants decreased after 2002. 3. Among pediatric recipients, LD transplants provided better 5-year graft survival rates than transplants from deceased donors; in contrast, LD transplants in adults had poorer graft survival rates than those from deceased donors. 4. The use of marginal donors, including older donors, HCV (+) donors, donation after cardiac death donors, and diabetic donors, increased in the past 18 years. HCV(+) livers transplanted into HCV(+) cirrhosis recipients had similar graft survival when compared with HCV(-) donor livers, whereas when they were transplanted into non-HCV cirrhosis patients, they had poorer graft survival (60% vs. 70% at 5 years, respectively). When livers from diabetic donors were transplanted into diabetic recipients, they had much poorer graft survival than transplants from non-diabetic donors (54% vs. 77% at 5 years, respectively). 5. Split and partial liver transplants had poorer 5-year graft survival rates (58% and 57%, respectively) than whole liver transplants (62%), but the difference was mainly due to poorer outcomes during the first posttransplant year. 6. PELD allocation has resulted in improved one- and 3-year graft survival rates among pediatric liver recipients. Among adults MELD-based allocation has resulted in better one-year survival rates. When comparing the different original diseases, only HCC patients showed better one- and 3-year graft survival rates after MELD. 7. Within one year after transplantation, primary non-function and infection were the major causes of graft failure. These decreased after 1996, but recurrent hepatitis has increased as a cause of graft failure. After one year, chronic rejection and infection had decreased, while hepatitis recurrence still increased. 8. Cardiovascular deaths and deaths from multiorgan failure that occurred within the first year after transplantation have increased since 1996, while deaths due to infections have decreased. After the first year, deaths from graft failure increased, while CVD and infections decreased.

Urinary tract infections after renal transplantation: a retrospective review at two US transplant centers

Abstract: Urinary tract infections (UTIs) are the most common infectious complication following renal transplantation. Previous studies uniformly report that renal transplant recipients develop UTIs more often than the general population, but widely differ on how frequently UTIs occur after transplantation. These studies also disagree on the risk factors associated with developing post-transplant UTIs, as well as the effect that UTIs may have on graft outcomes and patient mortality. We performed a retrospective cohort study including all the adult patients who received a renal transplant at two US transplant centers from January 1996 to December 2002 (500 patients). Two hundred and thirteen (43%) patients developed one or more post-transplant UTIs over a mean follow-up period of 42 months. Significant risk factors for post-transplant UTIs were advanced age, female gender, reflux kidney disease, use of azathioprine and cadaveric donor. UTIs did not increase risk for renal graft loss, but were associated with increased mortality (3.5 odds ratio, 95% confidence interval 1.68-7.23). We conclude UTIs may be associated with an increased mortality risk in renal transplant recipients. Prevention of UTIs in high-risk renal transplant patients or those with recurrent UTIs may possibly decrease post-transplant mortality.

Guidelines for the treatment and management of new-onset diabetes after transplantation

Abstract: Although graft and patient survival after solid organ transplantation have improved markedly in recent years, transplant recipients continue to experience an increased prevalence of cardiovascular disease (CVD) compared with the general population. A number of factors are known to impact on the increased risk of CVD in this population, including hypertension, dyslipidemia and diabetes mellitus. Of these factors, new-onset diabetes after transplantation has been identified as one of the most important, being associated with reduced graft function and patient survival, and increased risk of graft loss. In 2003, International Consensus Guidelines on New-onset Diabetes after Transplantation were published, which aimed to establish a precise definition and diagnosis of the condition and recommend management strategies to reduce its occurrence and impact. These updated 2004 guidelines, developed in consultation with the International Diabetes Federation (IDF), extend the recommendations of the previous guidelines and encompass new-onset diabetes after kidney, liver and heart transplantation. It is hoped that adoption of these management approaches pre- and post-transplant will reduce individuals' risk of developing new-onset diabetes after transplantation as well as ameliorating the long-term impact of this serious complication.

The OPTN/UNOS renal transplant registry.

Abstract: This chapter summarizes analyses of 66,843 kidney-only transplants reported to the OPTN/UNOS Renal Transplant Registry between January 1999-December 2003. The 5- and projected 10-year graft survival rates for 28,260 recipients of living donor (LD) kidneys were 80.5% and 67.0%, respectively, based on a computed halflife of 17.8 years for those grafts that survived one year. Comparable results for 33,118 recipients of standard criteria deceased donor (SCD) and 5,943 recipients of expanded criteria deceased donor (ECD) kidneys were 68.8% and 50.9%, and 51.8% and 32.9%, respectively. The half-lives for SCD and ECD were 10.8 and 6.8 years, respectively. ECD kidneys (from donors aged 60+ or 51-59 with other risk factors) were preferentially transplanted to older patients (median age 58) even though there was no formal requirement to allocate these kidneys to older patients. The oldest recipients of deceased donor (DD) kidneys, 991 aged 71-75 and 254 over age 75 had 5-year graft survival rates of 48.9% and 40.7%, respectively and 40% of graft losses in these groups were due to death with a functioning graft. Among 469 LD kidney recipients over age 70, graft survival rates were 70% or higher with 40% of grafts lost due death with function. About 13% of DD and 5% of LD kidneys were transplanted to broadly sensitized patients during this period. One-fourth and one-fifth of broadly sensitized patients who were transplanted received an HLA-matched DD or LD kidney, respectively. Overall, the proportion of transplants to unsensitized patients has increased in recent years to more than 50% of DD and nearly 70% of LD kidneys. There was no apparent correlation between the sensitivity of crossmatch tests and graft survival of first or repeat DD transplants; however, use of the more sensitive flow cytometry and AHG enhanced crossmatches significantly reduced the incidence of early rejections. Mean cold ischemia times have declined by about 7 hours between 1991- 2003, but the reduction in average cold time has not produced any notable reduction in the incidence of delayed graft function for recipients of SCD or ECD kidneys. Histocompatibility laboratories that waited for donor spleen or lymph node cells to perform final crossmatches added an average of 3 hours of cold ischemia for the kidneys they tested compared with laboratories that performed the tests with peripheral blood lymphocytes. There was no net increase in delayed graft function (DGF) with SCD kidneys tested at labs using spleen or nodes but the incidence of DGF among ECD kidneys was 25% when the lab used PBLs and 35% when the lab used spleen or nodes.

Enteric-coated Mycophenolate Sodium Delivers Bioequivalent MPA Exposure Compared With Mycophenolate Mofetil

Abstract: Mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), is routinely used as an adjunct immunosuppressant therapy in renal transplantation. Although highly effective, MMF therapy is associated with significant gastrointestinal adverse effects. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering MPA. The enteric coat dissolves at pH > 5 allowing for MPA delivery in the small intestine. A single-center, open-label, randomized, three-way crossover study of 24 stable Caucasian renal transplant patients receiving cyclosporine-based immunosuppression, compared the relative bioavailability of two EC-MPS doses (640 and 720 mg) with MMF (1000 mg). Both EC-MPS doses delivered bioequivalent mean MPA exposure (AUC(0-infinity)) compared with 1000 mg MMF: 60.7 microg h/mL for 640 mg EC-MPS, 66.5 microg h/mL for 720 mg EC-MPS, and 63.7 microg h/mL for 1000 mg MMF. Median t(max) was significantly delayed for both EC-MPS doses compared with MMF (2.0 h vs. 0.75 h, respectively; p < 0.01), consistent with a functional enteric coating of EC-MPS. Furthermore, both EC-MPS doses were bioequivalent to 1000 mg MMF for AUC and C(max) for mycophenolic acid glucuronide. All three treatments were well tolerated. The EC-MPS 720 mg dose most closely approximated the MPA exposure of 1000 mg MMF and was selected for subsequent phase III studies.

Family discussions about organ donation: how the media influences opinions about donation decisions.

Abstract: In this study, 78 family pair dyads (spouses, parent-child pairs, or siblings) were brought into an interaction laboratory set up like a living room. After being briefed on the study, family members discussed a series of eight questions about their thoughts and opinions about organ donation. Thematic analysis of the thousands of pages of transcripts revealed that family members believe that they receive important information about organ donation through the media. Unfortunately, the most influential information came from sensationalistic, negative media portrayals. The myths that seem to be the most actively referenced by the media include premature declaration of death, the transference of personality traits from donor to recipient, a US black market for organs, corruption in the medical community, and corruption in the organ allocation system (which allows celebrities to get transplants first). Although these are not the only myths that the generally public holds to be true, the media is a powerful source of support for these particular myths. Therefore, such myths must be countered effectively if greater consent for organ donation is to be attained.

Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation.

Abstract: Objective: Tacrolimus is an immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp, encoded by MDR1) play an important role in the absorption and metabolism of tacrolimus. The objective of this study was to evaluate whether or not CYP3A5*1/*3 or MDR1 C3435T polymorphisms are associated with the tacrolimus concentration per dose. Methods: CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis in 118 Chinese renal transplant patients receiving tacrolimus. Whole blood trough tacrolimus concentration was measured by enzyme-linked immunosorbent assay and dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 wk, 1 month, and 3 months after transplantation. Results: The dose-adjusted concentration of CYP3A5*1/*1 and *1/*3 patients was significantly lower than *3/*3 patients (32.8 ± 17.7 and 41.6 ± 15.8 vs. 102.3 ± 51.2 at 1 wk; 33.1 ± 7.5 and 46.4 ± 12.9 vs. 103 ± 47.5 at 1 month; 35.3 ± 20.9 and 59.0 ± 20.6 vs. 150 ± 85.3 at 3 months after transplantation respectively). At 1 wk, 46% of the CYP3A5*1 allele carriers had a tacrolimus concentration lower than 5 ng/mL and 77% lower than 8 ng/mL, whereas 20% of the *3/*3 patients had a concentration higher than 20 ng/mL. There was a mild difference between *1/*1 homozygotes and *1/*3 heterozygotes at 1 and 3 months after transplantation. No difference was found among the MDR1 genotypes. Conclusion: CYP3A5*1/*3 polymorphisms are associated with tacrolimus pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods could be employed prospectively to help initial dose selection and to individualize immunosuppressive therapy.

Impact of mycophenolate mofetil (MMF)‐related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients

Abstract: Mycophenolate mofetil (MMF), a mycophenolic acid prodrug, is a highly effective adjunct immunosuppressive agent in transplant therapy. Although MMF is generally well tolerated, optimal therapy may be limited by adverse effects, in particular gastrointestinal (GI) toxicity, which has been reported to occur in up to 45% of MMF-treated patients. MMF dose changes resulting from these adverse events may lead to sub-therapeutic dosing and impaired clinical outcomes. This retrospective study analyzed clinical records from 772 renal transplant patients from 10 US transplant centers who were initiated on MMF. The analysis revealed that 49.7% (n = 382) of patients experienced at least one GI complication within the first 6 months post-transplant, with 66.8% (n = 255) of these having multiple GI complications. Of the patients with GI complications, 39.0% experienced MMF dose adjustments or discontinuation of MMF therapy. Patients with GI complications who experienced MMF dose adjustments/discontinuation had a significantly increased incidence of acute rejections compared with patients without GI complications (30.2% vs. 19.4%; p = 0.005). Mean treatment costs were higher in patients with GI complications than in those with no GI complications, particularly in those who experienced MMF dose adjustments/discontinuation (p = 0.0001). The mean incremental cost for patients experiencing GI complications was US$3700 per patient during the 6 months post-transplant (p < 0.001), which was mainly attributable to hospitalization costs. In summary, GI complications and MMF dose adjustments/discontinuations are associated with a significant negative impact on transplant outcomes and markedly increase short-term treatment costs.

The natural history of renal function following orthotopic heart transplant.

Abstract: Background: The outcome of solid organ transplantation has dramatically improved after the introduction of the calcineurin inhibitor cyclosporine. With the increasing longevity of heart transplant recipients, the long-term effects of cyclosporine on renal function have become more evident. The natural history of kidney function following orthotopic heart transplant is not well defined and long-term follow up studies are scant. Methods: We conducted an observational study on patients who received a heart transplant at Saint Louis University Hospital between January 1, 1983 and December 31, 1988. Patients were followed up for 15 yr or until death whichever occurred first. In order to assess the effect of heart transplantation and cyclosporine exposure on long-term renal function we restricted the statistical analysis to patients who survived the first year post-transplantation. Results: A total of 68 patients received orthotopic heart transplants at Saint Louis University Hospital between 1983 and 1988. Forty-eight (71%) patients survived for more than 1 yr. All patients were treated with cyclosporine based triple immunosuppressive regimen, with gradual cyclosporine dose reduction over time. The mean duration of follow-up was 8 yr. The estimated GFR at 5 and 10 yr post-transplant were significantly lower than estimated GFR at baseline and 1 yr post-transplant. There was no significant difference between estimated GFR at 15 yr and estimated GFR at baseline or 1 yr post-transplant. The cumulative incidence of chronic renal failure (GFR ≤ 29 mL/min/1.73 m2) at 5, 10 and 15 yr was 4.2, 10.4 and 12.5%, respectively (p < 0.05). The cumulative incidence of severe chronic renal failure (GFR ≤ 15 mL/min/1.73 m2) at 5, 10 and 15 yr was 2.1, 8.3 and 8.3%, respectively. The mortality rate was 8, 37, and 52% at 5, 10, and 15 yr, respectively. The 10 and 15 yr survivors had an estimated GFR at 1 yr post-transplant that was significantly higher than the non-survivors. Age, pre-transplantation estimated GFR, pre-transplantation diabetes and pre-transplantation hypertension are risk factors associated with ≥10 mL/min/1.73 m2 decrement in estimated GFR. Conclusion: Heart transplant survivors beyond the first year post-transplant have a significant decrease in renal function and significant mortality observed over time. Age, pre-transplant GFR, pre-transplant diabetes and pre-transplant hypertension are important risk factors for decrement in renal function.

Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients.

Abstract: Sirolimus is a potent immunosuppressive agent used with increasing frequency in solid organ transplantation (SOT). However, it has been associated with rare but devastating pulmonary toxicity. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 64-yr-old heart transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among SOT recipients in an effort to better understand the pathophysiology, risk factors, and outcomes of this rare but serious complication. A total of 64 cases have been reported since January 2000 including the present case. These consisted of 52 kidney, four lung, three liver, three heart, one heart-lung and one islet cell transplants. In most cases, patients presented with a constellation of symptoms consisting of fever, dyspnea, fatigue, cough, and occasionally hemoptysis. Although the risk factors for this association have not been clearly established, high dose, late exposure to the drug and male gender have been noticed among most. In almost all of the reported cases, sirolimus was added later in the course of immunosuppressive therapy, usually in an effort to attenuate the nephrotoxic effects of a previous regimen containing a calcineurin inhibitor. There were three deaths (4.8%) among 62 patients with known status at follow up; all deaths were among heart transplant recipients. Most patients (95%) resolved their clinical and radiographic findings with discontinuation or dose-reduction of the drug. Sirolimus-induced pulmonary toxicity is a rare but serious entity that should be considered in the differential diagnosis of a transplant recipient presenting with respiratory compromise. Dose-reduction or discontinuation of the drug can be life saving.

Early onset post-transplant lymphoproliferative disease is associated with allograft localization.

Abstract: Post-transplant lymphoproliferative disease (PTLD) is a major complication after solid organ transplantation. We analyzed incidence, patient characteristics, clinical presentation, and prognostic factors for treatment outcome and survival of PTLD patients transplanted at our center. Records from adult kidney and lung transplant recipients, transplanted between January 1985 and December 2002 with a histologically confirmed diagnosis of PTLD, were retrieved. Histology was reviewed and prognostic factors for treatment outcome were evaluated by multivariable analysis. Of 1354 kidney and 206 lung transplants, PTLD was diagnosed in 40 transplant recipients (2.6%). Lung transplant recipients had a significantly higher incidence of PTLD (8.3%) than kidney transplant recipients (1.7%). Sites of presentation were highly heterogeneous. Notably, PTLD localized in the allograft occurred significantly earlier after transplantation than PTLD localized outside the allograft (p = 0.001). This was true for lung (p = 0.006) as well as for kidney transplant recipients (p = 0.03). In multivariable Cox regression, performance status (p = 0.01) and advanced stage (p = 0.04) were factors negatively predictive for response to first-line treatment. Only performance status remained as negative predictive factor for survival (p = 0.002) and freedom from tumor progression (p = 0.01). In conclusion, the allograft is significantly more often involved as primary site of PTLD presentation during the first post-transplant year. This may have clinical consequences and give new insights in pathogenesis of PTLD. Performance status and stage are important risk factors for outcome of PTLD.

Objective measures of health-related quality of life over 24 months post-liver transplantation.

Abstract: Many studies have reported improved health-related quality of life (HRQoL) from pre- to immediate post-orthotopic liver transplantation (OLT). However, few studies have evaluated longitudinal changes over the first 2 yr post-OLT and none have simultaneously examined objective measures of health-related fitness. A total of 50 OLT recipients (32 males,18 females; 51.4 +/- 11.8 yr) completed testing at 2, 6, 12, and 24 months post-OLT. Testing included assessment of exercise capacity (peak VO2), quadriceps muscle strength, body composition, physical activity participation, and self-reported functioning (SF-36). Repeated measures of analysis of variance (ANOVA) with post hoc contrasts was performed to determine differences over time and a second ANOVA assessed differences over time between genders. All patients increased peak VO2, quadriceps muscle strength, and percent body fat (p < 0.0001) from 2 to 24 months. Men and women differed in their changes of peak VO2 and percent body fat (p < 0.05). At 24 months, only 50% of the patients reported participating in regular physical activity. All SF-36 physical measures except general health, improved from 2 to 24 months (p < 0.0001). Measures of health-related fitness and QoL improve over the first 2 yr post-OLT with the greatest gains occurring in the first 6 months and all measures remain lower than recommended for cardiovascular and overall health. A randomized clinical trial of lifestyle modifications such as diet and exercise intervention is warranted to determine the impact of such modifications on HRQoL and fitness post-OLT.

Refractory acute kidney transplant rejection with CD20 graft infiltrates and successful therapy with rituximab.

Abstract: Acute rejection is an expected event after transplantation and has been associated with poor long-term kidney transplant outcome. The presence of B cells in the kidney graft with acute rejection is thought to be an omnious sign, as it has been associated with poor graft outcome. There is no definitive treatment for acute rejection with B cells in the graft. Rituximab, a humanized monoclonal antibody against CD20, has been used in the treatment of B cell lymphoma. We present the case of a 49-yr-old Caucasian male with early acute kidney allograft rejection that was refractory to high doses of steroids and rabbit anti-thymocyte globulin (thymoglobulin). Repeat renal biopsy revealed T cell and B cells in the kidney graft and responded to the combination of rituximab and muromonab (a mouse monoclonal antibody to CD3 receptor). Over 9 months post-transplant, the patient remains rejection free with a serum creatinine of 1.7 mg/dL.

Outcomes of pancreas transplants for patients with type 2 diabetes mellitus.

Abstract: Background: The objective of this study was to examine how effectively pancreas transplants provide long-term glucose control in patients with type 2 diabetes mellitus (DM). We used guidelines from the American Diabetes Association (ADA) and the World Health Organization (WHO) to appropriately classify recipients with type 2 DM (vs. type 1 DM). Results: From 1994 through 2002, a total of 17 patients with type 2 DM underwent a pancreas transplant at our center. Mean recipient age was 52.5 yr. The mean age at diabetes onset was 35.7 yr; mean duration, 16.8 yr. Most recipients had one or more secondary complications related to their diabetes: retinopathy (94%), neuropathy (76%), or nephropathy (65%). At the time of their transplant, three (18%) were on oral hypoglycemic agents alone and 14 (82%) were on insulin therapy. Of the 17 transplants, seven (41%) were a simultaneous pancreas-kidney transplant (SPK); four (24%), pancreas after kidney transplant (PAK); and six (35%), pancreas transplant alone (PTA). One recipient died during the perioperative period because of aspiration. The other 16 recipients became euglycemic post-transplant and had a functional graft at 1 yr post-transplant (patient and graft survival rates, 94%). Now, with a mean follow-up of 4.3 yr post-transplant, the patient survival rate is 71%. The four additional deaths were because of sepsis (n = 2), suicide (n = 1), and unknown cause (n = 1). All four of these recipients were insulin-independent at the time of death, although one was on an oral hypoglycemic agent. Of the 12 recipients currently alive, 11 remain euglycemic without requiring insulin therapy or oral hypoglycemic agents; one began insulin therapy 1.2 yr post-transplant (current daily dose, 60 units). Conclusion: These findings suggest that pancreas transplants can provide excellent glucose control in recipients with type 2 DM. All 16 (94%) of our recipients whose transplant was technically successful were rendered euglycemic. Long-term results were comparable with those seen in transplant recipients with type 1 DM.

Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury

Abstract: Background: Interventions that minimize hepatic ischemia/reperfusion injury (IRI) can expand the donor organ pool. Thymoglobulin (TG) induction therapy has been shown to ameliorate delayed graft function and possibly decrease IRI in cadaver renal transplants recipients. This controlled randomized trial was designated to assess the ability of TG to protect against IRI in liver transplant recipients. Patients and methods: Twenty-two cadaveric liver transplant recipients were randomized to receive either TG (1.5 mg/kg/dose) during the anhepatic period and QOD ×2 doses or no TG. No differences in recipients’ demographics were present and donor characteristics were similar in terms of age, cause of death, and cold ischemia time. Maintenance immunosupression consisted of Tacrolimus (or Cyclosporine) and steroids for both groups. Donor biopsies were obtained during organ procurement, cold storage and 1 h after re-vascularization. Post-operative liver function tests were monitored. Early graft function, length of stay, patient and graft survival rates, incidence of primary non-function and rate of rejection were assessed. Results: Patient and graft survival at 3 months was 100%. There was no incidence of primary graft non-function and no need for re-transplantation. The incidence of acute rejection was similar between the two groups. Patients in the TG group had significant decreases in alanine aminotransferase test at day 1 compared to the control group (p = 0.02). There were also near significant decreases of total bilirubin at day 5 and shorter length of hospitalization. Liver biopsy (at procurement, when cold, and post-reperfusion) of TG group demonstrated a trend for increased central ballooning. Conclusion: The TG allowed for more compromised liver grafts to be transplanted with less clinical evidence of IRI and improved function. Further studies on the degree of apoptosis in the liver biopsy post-reperfusion are underway.

Hypertension, antihypertensive agents and outcomes following renal transplantation

Abstract: Hypertension is common following renal transplantation and adversely affects graft and patient survival. However, strategies for antihypertensive drug therapy and target blood pressure have not been clearly defined. Aim: To assess the influence of achieved blood pressure and antihypertension drug therapy on graft and patient survival with the aim of identifying targets and event rates for future intervention studies. Methods: We undertook a longitudinal follow up study of 634 renal transplant patients. Patients were surveyed in December 1994 and followed up after 102 months. Blood pressure (BP) was determined from the mean of three clinic readings and antihypertensive drug therapy recorded. Results: Complete follow up data were available for analysis on 622 patients (57.2% male; mean age: 45.2 ± 13.0 yr. There were 158 (25.4%) deaths and 115 (18.5%) death-censored graft failures. Lower systolic and diastolic blood pressure were associated with better graft survival in the Kaplan–Meier analysis. Univariate analysis showed serum creatinine (HR 1.012, p < 0.001), duration of renal replacement therapy (HR 0.946, p = 0.012), age (HR 0.979, p = 0.014) and pulse pressure (HR 1.017, p = 0.044) to be predictors of graft survival with serum creatinine and duration of renal replacement therapy as the only significant factors in the multivariate analysis. Lower systolic and pulse pressure were associated with better patient survival in the Kaplan–Meier analysis. Age (HR) 1.062, p < 0.0001), serum creatinine (HR 1.002, p = 0.021), diabetes (HR 3.371, p < 0.0001), and pulse pressure (HR 1.013, p = 0.036) were significant predictors of patient survival in the univariate and multivariate analysis. Patient survival was reduced with increasing number of antihypertensives (p < 0.05), as was graft survival (p < 0.05). Reduced patient and graft survival were seen in patients prescribed calcium channel antagonists (p < 0.01). There was no increased patient mortality in those patients on beta-blockers or angiotensin converting enzyme (ACE) inhibitors. Conclusion: Hypertension is a risk factor, which remains despite the use of anti-hypertensives, for reduced patient and graft survival. The risk was not significant when blood pressure was entered together with serum creatinine in the multivariate analysis. Beta-blockers may have a beneficial effect on cardiovascular mortality, and ACE inhibitors a beneficial effect on both patient and graft survival. There is a pressing need for interventional studies to assess the impact of blood pressure targets on patient and graft survival and the effect of individual agents on these outcomes.

Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation.

Abstract: Cystic fibrosis (CF) related diabetes mellitus (DM) occurs in 15% of adult pancreatic insufficient CF patients. Lung transplantation is a treatment option for end-stage CF. We hypothesized that the prevalence of DM increases after lung transplantation. The study population included adult patients undergoing lung transplantation from March 1988 to March 2002 for end-stage CF at the University of Toronto. Demographic data, exocrine pancreatic function, presence of DM before and after transplant, as well as timing of its development after transplant were collected. Eighty-six patients met the study criteria; 77 of 86 (89.5%) of patients were pancreatic insufficient and were further analyzed. Median follow-up post-transplant was 3.3 yr (interquartile range: 1.2-7.2). Their mean age was 29.7 +/- 8.1 yr and 46 of 77 (59.7%) were male. The prevalence of DM increased from 22 of 77 (28.6%) before transplant to 38 of 77 (49.4%) after transplant (p = 0.008). The median time of DM development after transplant was 80 d (range: 13-4352). Sixteen of 55 (29.1%) of pancreatic insufficient patients who were non-diabetic prior to transplant, developed DM after transplant. DM is common in CF patients undergoing lung transplantation and the prevalence increases after transplant.

Causes of early acute graft failure after liver transplantation: analysis of a 17-year single-centre experience

Abstract: Despite satisfactory overall results reported, early post-operative period after liver transplantation (LT) still represents a critical time with persistently high rate of graft loss. We retrospectively reviewed our experience of 17 yr in LT, analysing the impact on grafts and patient survivals of the acute complications affecting the graft in the early period following LT. To evaluate the changes that occurred over the years in case of early acute graft failure (EAGF), the study population was divided into three equal groups of 223 patients corresponding to three different periods. Ninety (13.5%) experienced an EAGF. Causes of EAGF were hepatic artery thrombosis (HAT) in 32 cases (4.8%), primary graft non-function in 29 cases (4.3%), caval stenosis in 19 (2.8%), early irreversible acute rejection in 6 (0.9%) and portal vein thrombosis in 4 (0.6%). The use of elderly donors and the introduction of the piggyback technique proved to be associated with a higher incidence of HAT and caval stenosis, respectively. Female recipients of male donors were independently associated with Primary graft non-function. Of 90 patients with EAGF, 20 (22.2%) died within the first month after LT, 34 (37.8%) underwent retransplantation (ReLT) and 36 (40%) received conservative treatment. Conservative treatments increased from 3.6% in the first group to 47.0 and 66.8% in the second and third one (p = 0.000). One-year graft and patient survival of patients with EAGF significantly improved over the three eras analysed. The incidence of EAGF remains consistent. Nevertheless, a better understanding of the clinical situations and changes in treatment strategies have led to significant improvements in terms of graft and patient survival rates, now close to the survival rate of EAGF-free patients.

A survey of dental care protocols among US organ transplant centers.

Abstract: Untreated dental disease represents a potential risk for infection in transplant patients, but the vast transplantation literature has few references to this complication. There is also little information with regard to dental care protocols for patients before and after organ transplantation. To obtain more definitive documentation about the policies that deal with dental care and experience with dental infections, we conducted a survey of US transplant centers. The instrument consisted of eight questions that addressed pre-transplant dental evaluation procedures, incidence of pre- and post-transplant dental infections, and recommendations for antibiotic prophylaxis with dental treatment after transplantation. Questionnaires were sent to 768 medical and/or surgical directors at all US transplant centers. Responses were received from 294 recipients (38%). Among the respondents, 80% routinely requested a pre-transplant dental evaluation, but 49% of these were only for specific organs. The occurrence of a dental infection prior to transplantation that resulted in a postponement or cancellation was reported by 38% of the respondents. Post-transplantation sepsis from a suspected dental source was acknowledged in 27% of the surveys. Prophylaxis with antibiotics prior to dental care was recommended by 83%; 77% indicated that it be used for all dental procedures, whether invasive or not. Most respondents (96%) recommended the 1997 American Heart Association endocarditis prevention regimen. A survey of organ transplant centers has provided some information with regard to pre-transplantation dental screening, dental infections, and the use of prophylactic antibiotics. Additional studies are needed in order to accrue more definitive data that will assist with the development of standardized and appropriate pre- and post-transplant dental care protocols.

Therapeutic drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy, and safety data

Abstract: The aims of the current study were to determine whether therapeutic drug monitoring (TDM) might benefit kidney transplant recipients receiving everolimus, and to establish dosage recommendations when everolimus is used in combination with cyclosporine and corticosteroids. The analysis was based on data from 779 patients enrolled in two 12-month trials. Everolimus trough concentrations >/=3 ng/mL were associated with a reduced incidence in biopsy-proven acute rejection (BPAR) in the first month (p = 0.0001) and the first 6 months (p = 0.0001), and reduced graft loss compared with lower concentrations (4% vs. 20%, respectively). By contrast, cyclosporine in the standard concentration range had no impact on BPAR within the same timeframes. Most patients receiving everolimus 1.5 or 3 mg/d achieved trough concentrations above the therapeutic threshold of 3 ng/mL, regardless of reductions in cyclosporine dose. TDM simulation showed that just two dose adjustments would achieve median everolimus trough values >/=3 ng/mL in 95% of patients during the first 6 months. This investigation indicates that improved efficacy is likely when TDM is considered as an integral component of the immunosuppressive strategy of everolimus.

Influence of cumulative number of marginal donor criteria on primary organ dysfunction in liver recipients.

Abstract: Background: The aim of this cohort study was to assess the cumulative effect of marginal donor criteria on initial graft function and patient survival after liver transplantation. Methods: We included 734 consecutive patients who underwent orthotopic liver transplantation at the Vienna General Hospital between January 1993 and December 2003. We employed the local registry of the Department of Transplant Surgery, where variables of all patients are routinely and prospectively recorded. Primary outcome was initial graft function, secondary outcome was patient survival. Results: Cumulative number of marginal donor criteria was significantly and linearly associated with an increased rate of primary dysfunction (PDF; p = 0.005). In patients with more than three cumulative marginal donor criteria the rate of PDF was 36%. Patient survival was not influenced by the cumulative number of donor criteria (log-rank test, p = 0.81). Independent marginal donor criteria to predict PDF were cold ischemia time >10 h [odds ratio (OR) 0.56; 95% CI 0.32–0.98] and donor peak serum sodium >155 mEq/L (OR 0.44; 95% CI 0.26–0.77), as assessed in a multivariate regression model. Conclusions: The use of marginal liver donors with more than three marginal donor criteria shows deleterious effects on initial graft function. Noteworthy, patient survival was not associated with marginal donor criteria, which may be explained by early and successful retransplantation of liver recipients with primary non-function.

Mycophenolate mofetil vs. azathioprine is associated with decreased acute rejection, late acute rejection, and risk for cardiovascular death in renal transplant recipients with pre-transplant diabetes.

Abstract: Outcomes specifically in mycophenolate mofetil (MMF)-treated diabetic renal transplant patients have not been previously reported This study compared acute rejection (AR), late acute rejection (LAR), patient survival [and specifically death from cardiovascular (CV), infectious and malignant causes], incidence of post-transplant malignancies, and graft loss in MMF- or azathioprine (AZA)-treated renal transplant patients with pre-transplant diabetes Outcomes were compared between MMF- (n = 14 144) and AZA- (n = 3001) treated diabetic patients using the Scientific Registry of Transplant Recipients data on all US adult renal transplants performed between 1995 and 2002 Statistical analyses included Kaplan-Meier survival analysis, Cox multivariable regression and chi-square tests MMF patients had less AR compared with AZA-treated patients (235% vs 283%, p < 0001) and less risk for LAR over 4 yr [hazard ratio (HR): 064, 95% CI 044, 092; p = 002] While time to any-cause death did not differ between the groups, MMF treatment was associated with a 20% decreased risk of CV death (HR: 080, 95% CI 067, 097; p = 0020) compared with AZA treatment MMF patients also had a lower incidence of malignancies than AZA patients (22% vs 37%, p < 0001) These results suggest treatment with MMF compared with treatment with AZA in diabetic transplant patients is associated with less AR, less risk of LAR, a decreased risk of CV death, and a lower incidence of malignancies

Reproducibility of the Banff classification in subclinical kidney transplant rejection

Abstract: The Banff classification for kidney allograft pathology has proved to be reproducible, but its inter and intraobserver agreement can vary substantially among centres. The aim of this study was to evaluate Banff reproducibility of surveillance renal allograft biopsies among renal pathologists from different transplant centres. This study included 32 renal transplant patients with stable graft function. Biopsies were performed 2 and 12 months post-transplant. Histology was interpreted according to the Banff schema by three renal pathologists, and inter and intraobserver agreement were measured. The best reproducibility was obtained for the presence or absence of acute rejection (AR), with kappa values ranging from moderate (kappa = 0.47; p = 0.006) to good (kappa = 0.72; p = 0.0001). However, the agreement for 'suspicious for AR' category was poor between all observers. For scoring and grading interstitial inflammation and intimal arteritis the agreement were poor and moderate, respectively. Reproducibility for the presence or absence of chronic allograft nephropathy (CAN) was heterogeneous, ranging from poor (kappa = 0.13; p = NS) to moderate (kappa = 0.56; p = 0.007). Scoring chronic changes such as fibrous intimal thickening gave a reasonable interobserver agreement. Intraobserver reproducibility was good for presence or absence of AR, but was poor for the diagnosis of CAN. In conclusion, histologic analysis of stable renal allografts based on Banff criteria showed a good agreement for the diagnosis of AR and a reasonable kappa for CAN, but reproducibility for scoring and grading showed a substantial interobserver variation.

Establishing pediatric immune response zones using the Cylex ImmuKnow assay.

Abstract: For all transplant patients, the transplant physician must balance the risk of rejection caused by under-immunosuppression against the risk of drug toxicity, secondary infections and post-transplant lymphoproliferative disorder with over-immunosuppression. A Food and Drug Administration (FDA)-approved in vitro assay, the Cylex® ImmuKnowTM assay, provides a global assessment of cellular immune function to help monitor the immune status of immunosuppressed patients. This assay uses the plant lectin phytohemagglutinin to stimulate lymphocytes; an ATP assay is then used to measure the degree of activation of CD4+ T cells. However, the normal values for this assay were developed with healthy adult patients. In this study, we determined the normal ranges for the ImmuKnowTM assay in healthy children and compared those values to levels obtained in healthy adults and in stable pediatric renal transplant patients. We found that healthy children 12 yr of age and older showed immune function levels indistinguishable from adults, while healthy children under 12 had significantly lower immune function levels than adults. For adults, the ImmuKnowTM assay zones (in ng/mL ATP) of strong, moderate and low immune function correspond to >525, 225 to 525, and 395, 175–395 and <175 ng/mL. The median value for normal adults is 415, whereas it is only 295 for children <12 yr of age and this value decreases to 165 in stable renal transplant patients <12 yr of age (compared with 258 for stable adult renal transplant patients). Thus, this study provides critical information necessary to utilize the ImmuKnowTM assay with pediatric patients. In adults, the degree of immune function as assessed by the ImmuKnowTM assay helps to predict patients at risk for infection or rejection. If further studies in pediatric patients document the same and is true for children, then the ImmuKnowTM assay will provide a useful adjunct tool to prevent over- or under-immunosuppression as newly developed drugs are utilized or drug treatment is altered because of drug side effects, toxicity, concurrent illnesses or rejection.

Lung transplantation in the United States: 1990-2005.

Abstract: The number of lung transplants reported to the OPTN/UNOS Registry has been increasing during the past 15 years. The increase is mainly due to a steady increase in transplants in the 50-64 age group. There is also a trend toward increasing lung transplants for older patients (> 65 yr) since 2001. Among whites, COPD, IPF, CF, alpha1-ATD, and PPH were the top 5 original diseases leading to lung transplantation; while for blacks, sarcoidosis, COPD, and IPF were the major original diseases. Recipients with IPF had significantly lower graft survival rates than COPD patients. One-year graft survival rates increased from 70% in the early 1990s to more than 80% in the most recent 3-year period, but the increase in long-term graft survival has been very limited. The negative effect of previous transplantation on graft survival was only significant within the first post transplant year; in contrast, the negative effect of HLA mismatches is more apparent on long-term graft survival. Acute rejection within the first year had a significant deleterious effect on long-term graft survival.

Laparoscopic donor nephrectomy vs. open live donor nephrectomy: a quality of life and functional study.

Abstract: Background: Few studies have compared the quality of life (QoL) and functional recuperation of laproscopic donor nephrectomy (LDN) vs. open donor nephrectomy (ODN) donors. This study utilized the SF-36 health survey, single-item health-related quality of life (HRQOL) score, and a functional assessment questionnaire (‘Donor Survey’). Methods: Questionnaires were sent to 100 LDN and 50 ODN donors. These donors were patients whose procedures were performed at The University Hospital and The Christ Hospital in Cincinnati, Ohio. Results: A total of 46 (46%) LDN and 21 (42%) ODN donors returned the completed surveys. The demographics of the two groups were similar. LDN patients reported a more rapid return to 100% normal health (69 vs. 116 d; p = 0.24), part-time work (21.9 vs. 23.2 d; p = 0.09), and necessitated fewer physician office visits post-operative (2.8 vs. 4.4; p = 0.01). ODN patients reported shorter duration of oral pain medication use (13.4 vs. 7.2 d; p = 0.02). However, a greater number of ODN patients reported post-surgical chronic pain (3 vs. 6; p < 0.05) and hernia (0 vs. 2; p = 0.19). The overall QoL for both groups was comparable with the general USA population. Conclusions: The results of this study support the decisions of many kidney transplant centers to adopt LDN programs as standard of care.

Consequences of vancomycin-resistant Enterococcus in liver transplant recipients: a matched control study

Abstract: Background: Liver transplant recipients are at high risk for multi-drug resistant infections because of broad-spectrum antibiotic and immunosuppression. This study evaluates the clinical and financial impact of vancomycin resistant Enterococcus (VRE) in liver transplant recipients. Methods: Liver transplant recipients with VRE from 1995 to 2002 were identified and matched (age, gender, UNOS status, liver disease and transplant date) to controls. Demographics, clinical factors, co-infections, antibiotic use, length of stay, abdominal surgeries, biliary complications, survival and resource utilization were compared with matched controls. Results: Nineteen patients were found to have 28 VRE infections via evaluation of microbiologic culture results of all liver transplant patients in the transplant registry. Thirty-eight non-VRE patients served as matched controls. The four most common sites VRE was cultured from included blood (35%), peritoneal fluid (35%), bile (20%), and urine (12%). Median time from transplant to infection was 48 d (range of 4–348). No significant differences in demographics were observed. The VRE group had a higher incidence of prior antibiotic use than the non-VRE group (95% vs. 34%; p < 0.05). The VRE group also experienced more abdominal surgery (20/19 vs. 3/38; p = 0.029), biliary complications (9/19 vs. 9/38; p = 0.018) and a longer length of stay (42.5 vs. 21.7 d; p = .005). Survival in the VRE group was lower (52% vs. 82%; p = 0.048). Six of the 19 VRE patients were treated with linezolid for eight infection episodes, and four of six patients survived. Eight patients were treated with quinupristin/dalfopristin for nine infections, and two of eight survived. Increased cost of care was observed in the VRE group. Laboratory costs were higher in the VRE group ($6500 vs. 1750; p = 0.02) as well. Conclusion: VRE was associated with prior antibiotic use, multiple abdominal surgeries, biliary complications and resulted in decreased survival compared to non-VRE control patients. VRE patients also utilized more hospital resources. Linezolid showed a trend toward improved survival.

Outcome of hepatic artery reconstruction in liver transplantation with an iliac arterial interposition graft.

Abstract: Background: In case of anomal hepatic arterial inflow, it can be necessary to perform revascularization of the liver allograft by iliac arterial interposition graft. Methods: We analyzed retrospectively 613 liver transplants in a 16-yr period. The hepatic artery (HA) graft group (n = 101) consisted of patients with arterial inflow based on recipient infrarenal aorta using donor iliac artery graft tunneled through the transverse mesocolon. The control group (n = 512) consisted of patients who underwent liver transplantation with routine HA reconstruction. Results: Both groups are homogeneous and comparable. In case of retransplantation, arterial conduit with iliac graft was adopted more frequently instead of conventional arterial anastomosis (24.8% vs. 9%, p 50 yr old resulted the only factor independently associated with late HAT (p < 0.0001, OR = 1.05, 95% CI: 1.02–1.07). Conclusion: Iliac arterial interpositional graft is an alternative solution for arterial revascularization of liver allograft in case of retransplantation when the use of HA is not possible. In case of primary transplantation, is better not to perform arterial conduit if it is possible, for poor graft survival and high incidence of early HAT, especially in case of liver donor aged over 50 yr.

Anemia in kidney transplanted patients.

Abstract: Background: Although a known cardiovascular risk factor, anemia in the renal transplant recipients has only recently been receiving an increasing attention. Methods: In a cross-sectional study, data was obtained from 959 patients followed at a single outpatient transplant clinic. Based on the guideline of the American Society of Transplantation, anemia was defined as hemoglobin (Hb) 130 g/L in males and 120 g/L in females. Results: About one-third (34%) of the patients were anemic. The prevalence of anemia was comparable in males and females. Serum Hb concentration was significantly correlated with the estimated glomerular filtration rate (eGFR) (abbreviated modification of diet in renal disease formula) (r = 0.266, p < 0.001), serum transferrin (r = 0.268, p < 0.001) and serum albumin (r = 0.196, p < 0.001). None of the immunosuppressive medications or the use of angiotensin converting enzyme inhibitors was associated with a higher likelihood of anemia. In multivariate analysis the eGFR, serum albumin and serum transferrin, potential markers of nutritional status and/or chronic inflammation, and also iron deficiency were independently and significantly associated with anemia. Erythropoietin was administered only to 63 (19%) anemic patients. Conclusions: Post-transplant anemia is a prevalent and under-treated condition. Based on our results we suggest that, besides other factors, protein/energy malnutrition and/or chronic inflammation may be independently associated with anemia. Further studies are needed to determine whether the presence of anemia and its treatment will have an impact on long-term outcomes of this population.