Ciprofloxacin prophylaxis in kidney transplant recipients reduces BK virus infection at 3 months but not at 1 year.

BACKGROUND: BK polyomavirus (BKV) infection remains a significant cause of nephropathy and graft loss. Fluoroquinolones inhibit BKV replication in vitro, and small studies suggest in vivo benefit. A strategy of fluoroquinolone prophylaxis directed specifically against BKV has not been formally tested against a control group in kidney transplant recipients. METHODS: We retrospectively compared the impact of a change in antibiotic prophylaxis practice from no BKV prophylaxis (Group 1, n=106, July-December 2009) to BKV prophylaxis with ciprofloxacin 250 mg twice daily for 30 days (Group 2, n=130, January-June 2010) on the rate of BKV infection during the first 12 months after kidney transplantation. RESULTS: Baseline demographics, transplant characteristics, induction immunosuppression, and 1-year incidence of acute rejection were similar between groups. Group 1 had fewer patients on maintenance corticosteroids (65.1% vs. 83.2%, P=0.002). At 3 months, Group 1 had a significantly higher risk of developing BK viremia (0.161 vs. 0.065, P=0.0378) and viruria (0.303 vs. 0.146, P=0.0067) compared with Group 2, but this difference disappeared at 12 months for both viremia (0.297 vs. 0.261, P=0.6061) and viruria (0.437 vs. 0.389, P=0.5363). Adjusting for the difference in steroid use did not change the results. There was a trend toward higher incidence of biopsy-proven BKV nephropathy in Group 1 (4.7% vs. 0.8%, P=0.057). CONCLUSION: Thirty-day ciprofloxacin prophylaxis in kidney transplant recipients is associated with a lower rate of BKV infection at 3 months but not at 12 months. The long-term effectiveness and optimal duration of fluoroquinolone prophylaxis against BKV infection remain unknown.

Critical care of the end-stage liver disease patient awaiting liver transplantation.

Patients with end-stage liver disease awaiting liver transplantation frequently require intensive care admission and management due to either complications of liver failure or to intercurrent illness, particularly infection. Mortality in such patients is high and the development of an illness necessitating intensive care unit management can influence transplant candidacy. Specialized support frequently requires hemodynamic support, mechanical ventilation, and renal support. In this review, areas of management of particular importance to patients with end-stage liver disease in the intensive care unit are discussed. These areas are hepatic encephalopathy, infectious diseases, cardiovascular support, mechanical ventilation, renal support and combined transplantation, and decisions regarding delisting. Current knowledge specific to these patients, when available, is discussed, current practice is described, and areas of uncertainty in the evidence are discussed.

A prospective, randomized, multicenter study evaluating early corticosteroid withdrawal with Thymoglobulin in living-donor kidney transplantation.

BACKGROUND: This study compared the safety and efficacy of early corticosteroid withdrawal (ECSWD) with rabbit anti-thymocyte globulin (rATG) induction to chronic corticosteroid therapy (CCST) without antibody induction in primary, living-donor renal transplant recipients. METHODS: Eligible subjects were randomized 2:1 to receive either an ECSWD (n = 103) or CCST (n = 48) regimen, with all subjects receiving tacrolimus and mycophenolate mofetil (MMF). RESULTS: Results are reported as ECSWD vs. CCST. No significant differences were observed in the primary composite endpoint of freedom from biopsy-proven acute rejection (BPAR), graft loss, and death at six months (85.4% vs. 85.4%) or 12 months (84.4% vs. 74.4%). At 12 months, no difference was observed in BPAR (13.9% vs. 19.4%); however, ECSWD was associated with lower total cholesterol (159.7 +/- 39.2 vs. 196.5 +/- 56.7 mg/dL, p = 0.012), and trends toward significance were noted in serum triglycerides (151.9 +/- 92.0 vs. 181.4 +/- 78.8 mg/dL, p = 0.073) and weight gain (+3.6 +/- 9.4 vs. +6.4 +/- 9.3 kg, p = 0.069). No differences were observed in serious adverse events or infectious complications, with the exception of a higher incidence of leukopenia with ECSWD. CONCLUSIONS: rATG with tacrolimus and MMF therapy may allow early elimination of corticosteroids, is associated with trends toward lower lipid levels, less weight gain, and a safety profile comparable to CCST therapy.

Long-term renal function and cardiovascular disease risk in obese kidney donors.

BACKGROUND AND OBJECTIVES: Increasing demand for live-donor kidneys has encouraged the use of obese donors despite the absence of long-term outcome data and evidence that obesity can adversely affect renal function. We wished to determine whether obesity increased the risk for renal dysfunction and other medical comorbidities in donors several years after donation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Ninety-eight patients who donated a kidney 5 to 40 years previously were stratified according to body mass index (BMI) at donation and evaluated for renal dysfunction and risk factors for cardiovascular disease. Patients who were from the 2005 through 2006 National Health and Nutrition Examination Survey database; did not have renal disease; and were matched for age, gender, race, and BMI served as two-kidney control subjects. RESULTS: Renal function in obese (BMI > or =30) and nonobese (BMI <30) donors was similar, and both donor groups had reduced renal function compared with BMI-matched two-kidney control subjects. Obesity was associated with more hypertension and dyslipidemias in both donors and two-kidney control subjects; however, there were no significant differences between the two groups within each BMI category. CONCLUSIONS: These results indicate that obese donors are not at higher risk for long-term reduced renal function compared with nonobese donors and that the increased incidence of hypertension and other cardiovascular disease risk factors in obese donors is due to their obesity and is not further exacerbated by nephrectomy. These findings support the current practice of using otherwise healthy overweight and obese donors but emphasize the need for more intensive preoperative education and postoperative health care maintenance in this donor group.

Improvement in 3-month patient-reported gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients.

BACKGROUND: The benefit of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in terms of gastrointestinal symptom burden has been evaluated previously using patient-reported outcomes. However, data are lacking concerning the sustained effect of conversion over time, and the potential impact of concomitant calcineurin inhibitor. METHODS: In this 3-month, prospective, multicenter, longitudinal, open-label trial, MMF-treated renal transplant patients with gastrointestinal symptoms receiving cyclosporine or tacrolimus were converted to equimolar doses of EC-MPS. Change in gastrointestinal symptom burden was evaluated using a validated Gastrointestinal Symptom Rating Scale (GSRS). RESULTS: A significant improvement in GSRS score was observed from baseline (2.61, 95% CI 2.54-2.68) to month 1 (1.87, 95% CI 1.81-1.93) after conversion to EC-MPS and was sustained to month 3 (1.81, 95% CI 1.74-188; both P<0.0001 versus baseline). The mean change in overall GSRS score from baseline to month 1 was -0.74 overall (cyclosporine: -0.73 and tacrolimus: -0.74; all P<0.0001 versus baseline), with a slight further improvement (-0.79) at month 3 (cyclosporine: -0.82 and tacrolimus: -0.78; all P<0.0001 versus baseline). A significant improvement in GSRS subscale scores was also observed in the total population regardless of calcineurin inhibitor at month 1, sustained to month 3 (all P<0.0001 versus baseline). The improvement in GSRS score postconversion was similar in African-American and non-African-American patients, and in diabetic and nondiabetic patients. CONCLUSIONS: This exploratory study in 728 patients demonstrates that following conversion from MMF to EC-MPS, regardless of concomitant calcineurin inhibitor, GSRS is improved and sustained over 3 months.

Increased rejection in living unrelated versus living related kidney transplants does not affect short-term function and survival.

BACKGROUND: At our institution, increased kidney donation from unrelated donors accounts for a steady rise in live donor kidney transplantation rates. We compared outcomes of living related (LRT) versus living unrelated kidney transplants (LURT) and analyzed the effect of early rejection upon graft survival. METHODS: A retrospective analysis on 428 adult living donor kidney transplants was performed. Graft function and survival were compared between LRT and LURT and risk factors for 1-year rejection were defined by multivariate analysis. RESULTS: Between 1/1/97 and 12/31/01, 308 LRT and 120 LURT were performed at the University of California San Francisco. Donor age and number of mismatches were significantly higher in the LURT group. Patient and graft survival were similar in both groups. After a median follow-up of 26 months, graft survival was 94.8% (LRT) versus 93.3% (LURT). Five-year serum creatinine levels were comparable in both populations. One-year rejection was higher in the LURT group (30% vs. 18.5%; P<0.01). Rejection was influenced by the number of human leukocyte antigen mismatches. Other independent risk factors for early rejection were poor initial graft function, donor age greater than 55 years, and recipient body mass index greater than 30. Patients with poor initial graft function and early rejection had a statistically greater incidence of subtherapeutic tacrolimus trough levels on postoperative day 7. CONCLUSIONS: Despite a higher incidence of early rejection, LURT show similar function and survival compared with LRT. In high-risk patients receiving living unrelated renal transplants, consideration should be given to intensify initial immunosuppression to prevent early rejection episodes.

Comparison of outcomes after delayed graft function: sirolimus-based versus other calcineurin-inhibitor sparing induction immunosuppression regimens.

BACKGROUND: Sirolimus (SRL) may increase the incidence of or prolong delayed graft function (DGF) after cadaveric renal transplantation. This study compares transplant outcomes of SRL-based induction immunosuppression (IS) with other calcineurin-inhibitor (CNI) sparing regimens in the DGF setting. METHODS: Adult cadaveric renal-transplant recipients who received transplants between January 1, 1997 and June 30, 2001 and experienced DGF (n=132) were divided into three groups by induction IS: A, depleting antibody (n=41); B, SRL (n=49); and C, neither (n=42). All recipients also received steroids and mycophenolate mofetil with delayed initiation of CNIs when good renal function returned. Patient survival, graft survival, and time to rejection within 1 year of transplantation were assessed by Kaplan-Meier analysis. One-year graft function was compared using Kruskal-Wallis and Fisher's exact tests. RESULTS: The SRL group had longer DGF duration (P=0.01). The three groups had comparable patient (P=0.27) and graft survival (P=0.69), but the depleting antibody group experienced less rejection (P=0.004). There were no clinically significant differences in 1-year graft function. CONCLUSIONS: In our analysis of a large and modern cohort of adult cadaveric transplant recipients with DGF, induction immunosuppression with a depleting antibody preparation reduced rejection, whereas SRL prolonged DGF duration. All three CNI-sparing induction IS regimens resulted in comparable patient survival, graft survival, and graft function.

Early graft function after living donor kidney transplantation predicts rejection but not outcomes.

Poor early graft function (EGF) after deceased donor kidney transplantation (DDKT) has been intensely studied. Much less is known about poor EGF after living donor kidney transplantation (LDKT). Data were collected on 469 LDKTs performed between 1/1/97 and 12/31/01 to determine risk factors for and outcomes associated with poor EGF, defined as either delayed or slow graft function (DGF or SGF). The incidence of DGF and SGF were 4.7% and 10.7%, respectively. Diabetic etiology (OR 2.22; p = 0.021) and warm ischemia time (WIT) (OR 1.05 per min increment; p = 0.0025) emerged as independently associated with poor EGF. Neither functional graft survival nor 1-year graft function differed among the EGF groups. However, DGF and SGF strongly predisposed to acute rejection (AR), which compromised functional graft survival (p = 0.0007) and 1-year graft function. Therefore, we conclude that diabetic etiology of renal disease and WIT are the dominant risk factors for poor EGF after LDKT. Poor EGF did not directly compromise functional graft survival but strongly predisposed to AR. We suggest that immunosuppression should be intensified in the poor EGF setting to maximize LDKT longevity, as AR does impair functional graft survival.

Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients.

African-American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end-points of dose-adjusted PK parameters AUC0-12 and Cmax of MPA using log-transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back-transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose-adjusted AUC0-12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race-by-gender effects (p-values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA.

Effects of exercise training on coronary heart disease risk factors in renal transplant recipients.

BACKGROUND: Multiple risk-factor interventions that include lifestyle changes have been proved to be effective in reducing risk profile in persons at high risk for developing coronary heart disease (CHD). There have not been similar studies involving transplant recipients. The purpose of this study is to examine effects of exercise training on cardiovascular risk profile during the first year after renal transplantation. We used traditional CHD risk factors and the Framingham CHD prediction methods. METHODS: Ninety-six transplant recipients were randomly assigned to 2 groups at 1 month posttransplantation: the exercise training (EX group; n = 51) and usual care groups (UC group; n = 45). Testing was performed at baseline and 12 months posttransplantation and included maximal exercise testing and evaluation of CHD risk factors and risk-factor categories, determined by means of the Framingham equations. RESULTS: Overall 10-year CHD risk score did not change in either group. All patients showed increases in total cholesterol (TC) level, high-density lipoprotein fraction of cholesterol (HDL-C), and body mass index over time. No differences were observed between groups, except for a trend toward greater improvement in HDL cholesterol levels in the EX group (P = 0.07). Significantly more patients in the EX group moved out of the high-risk category in TC-HDL ratio. All patients remained in the high-risk category for physical fitness. There was a significant negative correlation of CHD risk and maximal exercise capacity (r = -0.406; P < 0.001). CONCLUSION: Exercise training alone does not reduce CHD risk during the first year after transplantation. Research to determine the effects of multiple risk interventions during a longer period in transplant recipients is warranted.

Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients have historically been excluded from consideration for transplantation out of concern for the effects of immunosuppression on the progression of HIV disease. Improvements in HIV-related morbidity and mortality with the use of highly active antiretroviral therapy (HAART) have prompted a reevaluation of transplantation as a treatment option for HIV-infected patients with end-stage kidney and liver disease. METHODS: Eligible patients met standard transplant criteria. They had undetectable plasma HIV-1 RNA levels (viral load) for 3 months (kidney) or were predicted to achieve viral load suppression posttransplantation if unable to tolerate HAART (liver); a CD4+ T-cell count of more than 200 cells/microL (kidney) or more than 100 cells/microL (liver) for 6 months; and no history of opportunistic infections and neoplasm. Standard immunosuppression included prednisone, mycophenolate mofetil (CellCept, Roche Pharmaceuticals, Basel, Switzerland), and cyclosporine (Neoral, Novartis, East Hanover, NJ). RESULTS: Fourteen patients received transplants (10 kidney transplants, mean follow-up 480 days; four liver transplants, mean follow-up 380 days). All of the kidney transplant recipients (100%) are alive and with functioning grafts, and three of four liver transplant patients (75%) are alive and well with functioning grafts (all liver transplant patients with normal liver function tests). The one death occurred 445 days posttransplantation in a liver recipient coinfected with hepatitis C virus, who died as the result of its rapid reoccurrence. Rejection occurred in 5 of 10 kidney transplant recipients but did not occur in any of the four liver transplant recipients. HIV viral loads have remained undetectable in all patients maintained with HAART. CD4 counts have remained stable in patients not treated for rejection. Patients receiving protease inhibitors require 25% of the dose of cyclosporine compared with patients receiving nonnucleoside reverse transcriptase inhibitors. CONCLUSIONS: There has been no evidence of significant HIV progression and no adverse effect of HIV on allograft function. Rejection is a concern in kidney transplant recipients, as is the possible poor outcome in hepatitis C virus-coinfected liver transplant recipients. Preliminary data are encouraging and indicate that transplantation should be a treatment option for individuals with well-controlled HIV disease.

Exercise capacity and muscle structure in kidney recipient and twin donor.

Exercise capacity and muscle function are known to be abnormal in patients with renal disease. We present a case study in which we studied a kidney transplant recipient who received a kidney from his identical twin. Testing included maximal exercise testing with measurement of oxygen uptake (VO2max), isokinetic muscle function testing, body composition analysis using dual energy X-ray absorptiometry (DEXA) imaging and quality of life using The Medical Outcomes Short Form (SF-36) questionnaire. Muscle biopsies were also analysed for fibre composition and size and ultrastructure. We found that the twin recipient had lower values for VO2max, muscle strength, muscle mass and quality of life scales (physical domains) compared with the twin donor. Muscle fibre composition was identical in the twins, however, muscle fibres size was reduced in the twin donor in Type I, and Type IIA fibre types. The twin recipient also showed lower fibre density (volume percentage) and greater intrafibrillar space than the donor. The twins were both sedentary, thus we conclude that the low exercise capacity and abnormalities observed in the recipient are characteristics of renal failure, and not the result of physical deconditioning, nor was it related to prednisone therapy, which may negatively affect muscle function.

Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation.

Sirolimus, lacking known nephrotoxicity, appeared to be an ideal immunosuppressive agent in the setting of delayed graft function (DGF) after renal transplantation. Coincident with our use of sirolimus however, we noticed prolongation of DGF. To investigate possible causes of prolonged DGF, extensive donor, recipient, transplant, and post-transplant data were collected on 132 consecutive cases of DGF at the University of California, San Francisco between 1/1/97 and 6/30/01. Cox proportional hazards analysis of time to graft function was used in univariate and multivariate models to identify factors that prolong DGF. Sirolimus had a large and highly significant effect on time to graft function (hazard ratio 0.48, p = 0.0007). The hazard ratio indicates that a recipient on sirolimus is half as likely to resolve DGF or twice as likely to remain on dialysis as a recipient without sirolimus. Two other factors had less potent but still significant association with DGF duration: recipient sensitization (hazard ratio 0.66, p = 0.037), and Novartis score (hazard ratio 0.93 per 1.0 increase; p = 0.034). Sirolimus retained its profound negative association with time to graft function in all multivariate models. Because sirolimus appears to prolong DGF, it may not be the optimal immunosuppressive choice in the DGF setting.

Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation.

BACKGROUND: Gengraf capsule, an AB-rated generic cyclosporine for Neoral, has been shown to be bioequivalent in previous studies. The purpose of this pharmacokinetic study performed in stable renal transplant recipients was to evaluate interchangeability of Gengraf and Neoral. METHODS: Using an open-label, three-period design, 50 renal transplant recipients taking stable doses of Neoral completed a multicenter study. Subjects continued their Neoral regimen during period I (days 1-14). Subjects then switched from Neoral on a milligram-for-milligram basis to Gengraf during period II (days 15-28), followed by conversion to the same milligram-for-milligram dosing regimen of Neoral during period III (days 29-35). Twelve-hour pharmacokinetic evaluations (maximum observed blood concentration [C(max) ], concentration before dosing [C(trough) ], time to maximum observed concentration [T(max) ], and area under the blood concentration-vs.-time curve [AUC]) occurred on days 1, 14, 15, 28, and 29. Additional predose samples (C (trough)) were evaluated on days 7, 21, and 35. Laboratory and safety parameters were also evaluated. RESULTS: The pharmacokinetics of Gengraf (C(max), T(max), C(trough), and AUC) were indistinguishable from the Neoral values in stable renal allograft recipients. The bioequivalent capsules were interchangeable with respect to C(max), C(trough), and AUC at steady state and also on conversion from one capsule formulation to the other. The 90% confidence intervals (CI) for the Gengraf versus Neoral comparison at steady state (day 28 vs. day 14) were 0.95 to 1.03 for AUC and 0.92 to 1.04 for C(max). Trough concentrations remained consistent throughout the study, with no need for dosage adjustment in any of the subjects. Gengraf is well tolerated, with an excellent safety profile, comparable to the safety profile of Neoral. CONCLUSIONS The pharmacokinetics of Gengraf are equivalent and indistinguishable from those of Neoral. Gengraf is well tolerated and interchangeable with Neoral in stable renal transplant recipients.

A randomized trial of exercise training after renal transplantation.

BACKGROUND: Significant health benefits result from regular physical activity, many which are important for transplant recipients. Although exercise capacity improves initially after transplant, it is not normalized, and only two studies have reported the effects of exercise training in this population. We report a randomized clinical trial of exercise after renal transplantation (RTX). METHODS: One hundred sixty-seven patients were randomized at 1 month after RTX into two groups: exercise intervention (EX) and usual care (UC), with repeat testing at 6 and 12 months. Ninety-five patients completed the following testing at both testing times: symptom-limited treadmill testing with measurement of peak oxygen uptake (peak Vo2); isokinetic muscle testing for muscle strength; and dual-energy X-ray absorptiometry scans for body composition. The SF-36 Health Status Questionnaire assessed self-reported functioning. The exercise intervention consisted of individually prescribed programs to be conducted at home with regular phone follow-up to enhance adherence. Repeated measures analysis of variance was performed to determine differences between the groups for the three testing times. RESULTS: At 1 year 67% of the EX group were exercising regularly compared with 36% of the UC group (P=0.01). Compared with the UC group, the EX group had significantly greater gains in peak Vo2 (P=0.016), percent age-predicted Vo2 (P=0.03), and muscle strength (P=0.05), and a trend toward higher self-reported physical functioning (P=0.06). There were no differences between the groups in changes in body composition. At 1 year, peak Vo2 was significantly correlated with age, percent fat, muscle strength, hematocrit, and self-reported physical functioning. CONCLUSIONS: Exercise training after RTX results in higher levels of measured and self-reported physical functioning; however, exercise alone does not affect body composition.

Successful long-term outcomes using pediatric en bloc kidneys for transplantation.

GOAL: The objective of our study was to determine whether acceptable long-term graft survival and function can be achieved using pediatric en bloc renal transplants by employing specific immunologic and selection strategies. MATERIALS AND METHODS: A retrospective analysis of pediatric en bloc kidney transplants at a single institution was performed. A Kaplan-Meier analysis was used to evaluate graft survival. FINDINGS: Fifty-seven adult recipients with at least a 1-year follow-up period were successfully transplanted using pediatric en bloc kidneys between 1993 and 1998. Complete data regarding immunosuppression were available for 53 patients. All patients had a cyclosporine (CsA)- or tacrolimus (TAC)-based regimen with either azathioprine (Aza) or mycophenolate mofetil (MMF) and corticosteroids. All but two received induction with OKT3. One-, 3-, 4-, 5- and 7-year graft survival was calculated to be 88%, 86%, 83%, 68% and 68%, respectively. The mean serum creatinine value at 3 years was 1.0+/-0.4 mg/dL. Thirteen patients (23%) had biopsy-proven rejection. Ten of 19 (53%) patients treated with CsA/Aza had rejection, whereas 2/15 (13%) on CsA/MMF and 1/19 (5%) of patients on TAC/MMF had rejection. Nine patients (16%) had surgical complications. CONCLUSION: Excellent long-term results can be achieved in pediatric en bloc kidney transplantation using OKT3, TAC and MMF in carefully selected adult recipients.