Cyclosporine versus Tacrolimus Treated Liver Transplant Recipients with Chronic Hepatitis C: Outcomes Analysis of the UNOS/OPTN Database

Recurrent hepatitis C virus (HCV) remains a problematic cause of morbidity and mortality for liver transplant patients. Immunosuppression including calcineurin‐inhibitors has been implicated in the acceleration of recurrent HCV. Recent studies suggest that outcomes may be better with cyclosporine (CSA‐ME) compared to tacrolimus (TAC), but the data are inconclusive. We retrospectively analyzed data received from the United Network for Organ Sharing on 8809 chronic HCV liver transplant recipients receiving either cyclosporine microemulsion (CSA‐ME) or tacrolimus (TAC) as maintenance immunosuppression prior to discharge. We analyzed patient death, graft failure, failure due recurrent disease and acute cellular rejection (ACR) for CSA‐ME versus TAC treated patients. Three‐year unadjusted patient and graft survival rates were 76.8% and 71.5%, respectively, in the CSA‐ME group versus 79.9% and 75.0% in the TAC group. Propensity score‐adjusted results suggest CSA‐ME treated patients are at increased risk of patient death and graft failure [Hazards ratio (HR) = 1.17; 95% CI = 1.01–1.36 and HR = 1.19; 95% CI = 1.04–1.35, respectively] and biopsy‐confirmed AR (HR = 2.03; 95% CI = 1.54–2.67) compared to TAC treated patients. These results provide evidence to reconsider the targeted administration of CSA‐ME to HCV‐infected liver transplant recipients.     

Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes

Induction and maintenance immunosuppression protocols with or without long-term steroid therapy in kidney transplant recipients are variable and are transplant center-specific. The aim of this prospective randomized pilot study was to compare 5-year outcomes in kidney recipients maintained on 4 different calcineurin inhibitor (CNI)-based immunosuppression protocols without long-term steroid therapy. Two hundred consenting patients who received kidney transplants between June 2000 and October 2004 were enrolled in 4 immunosuppression protocol groups, with 50 patients in each group: cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/sirolimus (SRL), tacrolimus (TAC)/MMF, and TAC/SRL. Induction therapy was done with basiliximab and methylprednisolone. Steroids were withdrawn on post-transplant day 2, and long-term steroid therapy was not used. Demographic characteristics among the four groups were comparable; approximately 50% of the recipients were African American and > or =80% of the kidneys transplanted were from deceased donors. Clinical acute rejection (CAR) was confirmed by biopsy and treated with intravenous pulse steroid therapy. Steroid-unresponsive CAR was treated with Thymoglobulin. Surveillance biopsies were performed at 1, 6, 12, 24, 36, 48, and 60 months to evaluate subclinical acute rejection (SCAR), chronic allograft injury (CAI), and other pathological changes per the Banff 2005 schema. The primary end point was CAR, and secondary end points were 5-year patient and graft survival rates, renal function, SCAR, CAI, and adverse events. In the first year post-transplant, the incidence of CAR was 18% in the CSA/MMF group, 8% in the CSA/SRL group, 14% in the TAC/MMF group, and 4% in the TAC/SRL group (CSA/MMF vs. TAC/SRL; p=0.05). The incidence of SCAR was 22% in the CSA/MMF group, 8% in the CSA/SRL group, 16% in the TAC/MMF group, and 6% in the TAC/SRL group (CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.05). After the first year, the incidences of CAR and SCAR decreased and were comparable in all 4 groups. At 5 years post-transplant, cumulative CAI due to interstitial fibrosis/tubular atrophy (IF/TA), hypertension (HTN), and chronic calcineurin inhibitor (CNI) toxicity was observed in 54%, 48%, and 8% of the CSA/MMF group vs. 16%, 36%, and 12% of the CSA/SRL group vs. 38%, 24% and 6% of the TAC/MMF group vs. 14%, 25% and 12% of the TAC/SLR group (IF/TA: CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.04, HTN: CSA/MMF vs. TAC/MMF and TAC/SRL; p=0.05, CNI toxicity: TAC/SRL and CSA/SRL vs. TAC/MMF; p=0.05). Five-year patient and graft survival rates were 82% and 60% in the CSA/MMF group, 82% and 60% in the CSA/SRL group, 84% and 62% in the TAC/MMF group, and 82% and 64% in the TAC/SRL group (p=0.9). Serum creatinine levels and creatinine clearances at 5 years were comparable among the groups. Our data show that the rates of CAR and SCAR in the first year post-transplant were significantly lower in the CSA/SRL and TAC/SRL groups and that cumulative CAI rates due to IF/TA and HTN at 5 years were significantly lower in the TAC/MMF, TAC/SRL, and CSA/SRL groups than in the CSA/MMF group. Despite significant differences in the incidences of CAR and SCAR and prevalence of different types of CAI at 5 years, renal function and patient and graft survival rates at 5 years were comparable among kidney recipients maintained on 4 different immunosuppression protocols without long-term steroid therapy.     

The use of intravenous tacrolimus and mycophenolate mofetil as induction and maintenance immunosuppression in simultaneous pancreas--kidney recipients with previous transplants

Clinical trials using quadruple immunosuppression that include the combination of tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas-kidney (SPK) transplantation. In attempting to obtain a low rejection rate without antibody induction therapy, we proceeded with the combination of TAC intravenous (i.v.), MMF, and steroids as induction therapy and as primary immunosuppression for recipients with previous transplants. In this study, we analyzed 10 patients who received previous transplants, treated with low-dose TAC i.v. as induction therapy. Group A consisted of 6 patients with previous transplants that underwent SPK and group B consisted of four recipients with previous SPK that underwent cadaveric kidney transplants. For group A, the previous transplants were: living related kidney (LRK) followed by islet cell (IC) transplant (n=2), LRK transplant (n=1), cadaver kidney (CAD) and IC transplant (n=1), SPK (n=1), and three previous CAD kidney transplants (n=1). In group A, all six kidneys were lost due to recurrent diabetic nephropathy, IC possibly to rejection, and the pancreas due to thrombosis. In group B with previous SPK transplants, three recipients lost their kidney to chronic rejection and one to long-term use of a nephrotoxic antibiotic. Currently, in all group A and B patients, the kidney and the pancreas are functioning, although 1 patient in group A developed type 2 diabetes (normal fasting C-peptide). Two patients in group A developed three rejection episodes that responded to steroid treatment. The results indicate the TAC i.v. in combination with oral TAC, MMF, and steroids offer effective induction therapy in patients with previous transplants.     

Ethnic differences in clinical response to corticosteroid treatment of acute renal allograft rejection

BACKGROUND: Limited in vitro data suggest that African-Americans exhibit greater resistance to corticosteroids than do non-African-American transplant recipients. However, ethnic differences in clinical response to corticosteroids for treatment of acute rejection have not been investigated previously. The purpose of this study was to evaluate the clinical response to corticosteroid treatment for acute rejection in both African-American and non-African-American renal allograft recipients. METHODS: We retrospectively reviewed the medical records of 497 consecutive renal allograft recipients to identify patients who had received corticosteroids as initial treatment of acute rejection. One hundred and twenty patients who received corticosteroids for treatment of acute rejection were evaluated in this analysis. The study population was divided into two groups: the African-American group (n=73) and non-African-American group (n=47). All acute rejection episodes were documented by biopsy and were classified as mild-moderate histologically. Corticosteroid therapy consisted of either methylprednisolone, 500 mg intravenously for 3 days, or oral prednisone, 2 mg/kg/day rapidly tapered over 3 weeks. RESULTS: Twenty-six percent (26%) of African-Americans were considered corticosteroid treatment failures compared to an 8.0% failure rate among non-African-Americans (P<0.05). One-year graft survival was 78% in African-American versus 96% in non-African-American (P<0.05). Among African-American and non-African-American recipients, 1-year patient survival rates were 97% and 100, respectively (P=NS). CONCLUSIONS: African-American patients exhibit higher failure rates with corticosteroid treatment of acute rejection. Alternative anti-rejection therapies may need to be considered for this "high-risk" patient population to improve long-term graft survival.     

Everolimus plus dosage reduction of cyclosporine in cardiac transplant recipients with chronic kidney disease: a two-year follow-up study

The calcineurin inhibitor cyclosporine (CSA) displays nephrotoxic side effects. We switched 95 maintenance heart transplant recipients with chronic kidney disease (CKD) stages 3-4 from CSA to everolimus (EVL). The CSA dosage was reduced by 50%. Kidney function, lipid metabolism, and cardiac function investigated during a 2-year follow-up were compared with heart transplant recipients with CKD stages 2-3 who continued to receive CSA (CSA group; n = 84). Whereas 64/95 patients received reduced CSA plus EVL during the entire follow-up period (EVL continued subgroup, ECN), 31 discontinued EVL (EVL discontinued subgroup, EDS) after 4.3 months (median) because of various clinically relevant adverse events. Glomerular filtration rates (estimated using the modification of diet in renal disease formula) increased by 4.0 mL/min/1.73 m² in the ECN subgroup but decreased by 2.4 mL/min/1.73 m² and 9.0 mL/min/1.73 m² in the EDS subgroup and the CSA group, respectively (P < .001). Triglyceride and total cholesterol concentrations increased significantly among the ECN group, but remained constant in the EDS subgroup and the CSA group. Statin use was increased by 15% in the ECN group (P < .01). Mortality and cardiac rejection rates did not differ significantly among the 3 groups. In summary, EVL combined with low-dose CSA had modest beneficial effects on kidney function in heart transplant recipients with CKD stages 3-4. A significant percentage of patients had to stop EVL because of various adverse events.     

Immediate conversion from tacrolimus to cyclosporine in the treatment of posttransplantation diabetes mellitus

Posttransplantation diabetes (PTDM) is a frequent complication of tacrolimus (TAC)-based immunosuppressive therapy after kidney transplantation. We investigated whether immediate conversion from TAC to Cyclosporine (CSA) could reverse or at least improve new-onset PTDM. Between February 2002 and February 2004, 28 adult kidney transplant recipients maintained on TAC were diagnosed with new-onset PTDM. Eight adult patients with new-onset PTDM were enrolled in the study and converted from TAC to CSA, the remaining 20 patients served as controls and were continued on the TAC-based immunosuppression. The conversion to CSA was performed immediately after establishing the diagnosis of PTDM at an average of 11 months posttransplantation. We did not document any episodes of acute rejection or worsening renal function after conversion. After conversion to CSA, among the 3 patients started on insulin, 1 has come completely off antidiabetic medications, whereas 1 required decreased doses of insulin, and the third has been converted to oral medications. Of the 5 patients originally on oral medications, 3 completely discontinued therapy, whereas the other 2 were well controlled on single-drug therapy at reduced doses. After a mean follow-up of 17 months, in the control group 9 of the 16 patients started on oral antidiabetics ultimately required insulin treatment and no patient could stop antidiabetic or insulin therapy. These findings indicate that conversion from TAC to CSA is a simple, safe, and efficacious way to reverse or at least improve PTDM.     

Cyclosporine-associated nephropathy in patients with heart and bone marrow transplants

The morphology of kidneys from heart (n = 55) and bone marrow (n = 112) transplant recipients treated either with cyclosporine (CSA) or conventional immunosuppression was investigated at autopsy. The major findings were: In the bone marrow transplant recipients glomerular collapse, tubular atrophy, interstitial fibrosis, striped form, CSA-associated arteriolopathy and thrombi in glomeruli and/or arterioles were more often found in the CSA group as compared to conventional immunosuppression. In the heart transplant recipients glomerular collapse and obsolescence, tubular atrophy and intimal fibrosis in arteries were more frequent in the CSA group. Vascular interstitial toxicity known to be associated with CSA treatment from renal transplant patients was found in 54% (25% severe) of the bone marrow and 19.5% (9.7% severe) of the the heart transplant recipients. The prevalence of vascular interstitial toxicity in bone marrow versus heart transplant recipients is possibly due to higher CSA dosage and pretreatment with cytostatic drugs and irradiation. Analyses of the lesions from early stages to the full picture of vascular interstitial toxicity suggests that CSA causes a form of thrombotic microangiopathy with focal glomerular and/or arteriolar thrombosis followed by typical CSA-associated arteriolopathy which results in interstitial fibrosis with tubular atrophy.     

A prospective randomized trial comparing the efficacy of tacrolimus versus cyclosporine in black recipients of primary cadaveric renal transplants.

BACKGROUND: We performed a prospective randomized trial to compare the efficacy and safety of tacrolimus (FK506) versus cyclosporine (CSA) in black primary cadaveric renal transplant (CRT) recipients. METHODS: Between December 1994 and February 1997, 35 black primary CRT recipients were enrolled in this trial. All patients received 7 days of induction therapy with OKT3. Fourteen patients received FK506 and prednisone only. Twenty-one patients received CSA, azathioprine, and prednisone. The two groups were comparable in terms of age, gender, plasma renin activity, human leukocyte antigen mismatches, and cause of renal failure. RESULTS: Patient and graft survival were 12 of 14 (86%) for the FK506 group and 20 of 21 (95%) for the CSA group (P = 0.71). Three patients died owing to cardiac events with functioning grafts. Acute rejection was 2 of 14 (14%) for the FK506 and 8 of 21 (38%) for the CSA group (P = 0.25). Two other patients on CSA were converted to FK506 as rescue for OKT3-resistant rejection. Mean serum cholesterol at 1 year was 198 +/- 45 mg/dL for the FK506 group and 244 +/- 49 mg/dL for the CSA group (P = 0.03). Mean serum creatinine at 1 year was 1.39 +/- 0.38 mg/dL for the FK506 group and 1.94 +/- 0.64 mg/dL for the CSA group (P = 0.02). CONCLUSION: Patient and graft survival were similar in both groups at 1 year posttransplant. Although statistically not significant, the incidence of acute rejection was lower in the FK506 group. Furthermore, FK506-treated patients had significantly lower serum creatinine and cholesterol levels at 1 year posttransplant.     

Clinical outcome of heart transplant recipients receiving tacrolimus with or without mycophenolate mofetil

Tacrolimus (TAC) is a calcineurin inhibitor that is used for cardiac allograft rejection. Efficacy and safety data of a combined TAC/mycophenolate mofetil (MMF) therapy in comparison with a TAC/cortisone therapy in heart recipients are lacking. We analysed the clinical outcome of 41 patients who received TAC in combination with MMF (TMF group) and of 41 patients who received TAC in combination with cortisone (TCO group). Outcomes were serum creatinine levels, cardiac rejections, cytomegalovirus infections, graft vasculopathy, malignancy rates and two-yr survival. Baseline characteristics were comparable in the two study groups. During follow-up, serum creatinine levels decreased slightly in the TMF group (p=0.039) but not in the TCO group. Compared with the TMF group, more clinically proven cardiac rejections which needed a cortisone bolus and more severe rejections that needed lymphoablative therapy with OKT occurred in the TCO group (p=0.001 and 0.04, respectively). In contrast, significantly more cytomegalovirus (CMV) infections occurred in the TMF group compared with the TCO group (p=0.01). The number of patients with graft vasculopathy as well as malignancy rates and overall survival did not differ significantly between the two study groups. The introduction of MMF was associated with an improvement of renal function and a more efficient immunosuppressive therapy. However, this treatment strategy also had led to a higher CMV infection rate compared with cortisone. Consequently, no general recommendation can be given at present whether TAC should be combined with MMF or with cortisone in heart transplant recipients.     

Long-term results of liver transplantation in older patients 60 years of age and older

BACKGROUND: Advances in perioperative care and immunosuppression have enabled clinicians to broaden the indications for organ transplantation. Advanced age is no longer considered a contraindication to transplantation at most centers. Although short-term studies of elderly liver transplant recipients have demonstrated that the incidence of complications and overall patient survival are similar to those of younger adults, transplant center-specific, long-term data are not available. METHODS: From August of 1984 to September of 1997, 91 patients 60 years of age or older received primary liver transplants at the University of Wisconsin, Madison. This group of patients was compared with a group of younger adults (n=387) ranging in age from 18 to 59 years who received primary liver transplants during the same period. The most common indications for transplantation in both groups were Laennec's cirrhosis, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis. There was no difference in the preoperative severity of illness between the groups. Results. The length of hospitalization was the same for both groups, and there were no significant differences in the incidence of rejection, infection (surgical or opportunistic), repeat operation, readmission, or repeat transplantation between the groups. The only significant difference identified between the groups was long-term survival. Five-year patient survival was 52% in the older group and 75% in the younger group (P<0.05). Ten-year patient survival was 35% in the older group and 60% in the younger group (P<0.05). The most common cause of late mortality in elderly liver recipients was malignancy (35.0%), whereas most of the young adult deaths were the result of infectious complications (24.2%). CONCLUSION: Although older recipients at this center did as well as younger recipients in the early years after liver transplantation, long-term survival results were not as encouraging.     

Mycophenolate mofetil monotherapy in liver transplant recipients: a single center experience.

The long-term use of calcineurin inhibitors (CIs) is associated with significant morbidity in liver transplant recipients. Although mycophenolate mofetil (MMF) is well tolerated, two small studies reported an unacceptable rate of acute allograft rejection in liver transplant recipients receiving MMF monotherapy. In this study, we retrospectively investigated the safety and efficacy of MMF monotherapy in liver transplant recipients. We reviewed the medical records of all patients who underwent liver transplant at our institution. Sixteen patients were identified who received MMF either as monotherapy (n = 13) or with corticosteroids (n = 3; 2 of them for other comorbid conditions), and these patients were studied to determine the efficacy and complications. Fifteen (15/16) patients were converted from a CI to MMF because of renal insufficiency. Patients were converted to MMF monotherapy after a median of 2,056 days (range, 606-5,893) after liver transplantation. The median postconversion follow-up was 668 days (range, 60-1,509). Four patients required dialysis despite conversion; of those patients not requiring dialysis, serum creatinine stabilized and showed a trend toward improvement (2.51 +/- 1.12 mg/dL to 1.85 +/- .58 mg/dL, P = .1). However, there were 3 episodes (47, 107, and 1,203 days after conversion) of severe, irreversible allograft rejection after conversion resulting in death in 2 patients and necessitating retransplantation in 1 patient. There were no patient characteristics, except perhaps African-American race, that predicted the development of rejection. In conclusion, MMF monotherapy was associated with a significant risk (19%) of unpredictable, severe, and irreversible allograft rejection even among long-term transplant survivors. Caution should be exercised before converting patients to MMF monotherapy.     

Posttransplant diabetes mellitus after kidney transplantation with different immunosuppressive agents

Posttransplant diabetes mellitus (PTDM) is a disturbing side effect of immunosuppression. The aim of this study was to evaluate the effect of different immunosuppressive agents on the development of PTDM in renal transplant recipients (KTx). The incidence of PTDM was evaluated in 538 consecutive KTx. Baseline immunosuppression was azathioprine (AZA), cyclosporine (CSA), or tacrolimus (TAC), or sirolimus in combination with calcineurin inhibitors (SIR). All patients received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. Mean follow-up after KTx was 73 +/- 53.5 months (range 6 months to 16 years). PTDM was defined as two consecutive blood glucose determinations above 126 mg/dL. Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five oral antidiabetic medications. PTDM occurred at 25.3 +/- 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of CSA, 6.5% of KTx treated with TAC and 12.5% of KTx treated with SIR. The time of onset of PTDM was significantly shorter (P =.003) among TAC (2.1 +/- 1.7 months posttransplantation) versus CSA (27.8 +/- 34 months). PTDM disappeared in 6 of 36 patients. We conclude that with current levels of immunosuppression, there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx.     

Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Tuberculosis in renal transplant recipients on various immunosuppressive regimens.

BACKGROUND: Mycophenolate mofetil (MMF) and tacrolimus (TAC) are more potent than conventional immunosuppressive drugs, i.e. azathioprine, cyclosporin and prednisolone, and may be associated with an increase in the incidence of infections in the post-transplantation (post-tx) period. The aim of this study was to determine if the use of either or both of MMF and TAC for immunosuppression in renal transplant recipients increases the prevalence or modifies the clinical presentation of tuberculosis (TB), when compared with conventional therapy. METHODS: The medical records of 443 adult patients who received a kidney transplant between 1994 and 2002 were reviewed retrospectively. Comparisons were made between patients who had conventional immunosuppressive treatments (cyclosporin, azathioprine and prednisolone) or an alternative regimen (including MMF, TAC or both). RESULTS: We found 20 patients (4.5%) to have post-tx TB. There were 13 cases of TB (age 38.9+/-10.6 years) among 328 patients who received conventional immunosuppressants (group I) (4.0%) and seven cases (age 24.2+/-7.4 years) among 115 (6.1%) who received an alternative immunosuppressive regimen (group II) (P>0.05). The patients in group II were younger than the patients in group I (P = 0.002). A significantly higher number of patients in group II developed TB within the first 6 months post-tx (P = 0.042). However, there was no significant difference between the two groups regarding clinical and radiographic presentations or outcomes. CONCLUSIONS: Immunosuppression with TAC or MMF is associated with the development of TB earlier in the post-tx period and in younger patients.     

A Prospective Randomized Trial of Steroid-Free Maintenance Regimens in Kidney Transplant Recipients—An Interim Analysis

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine-mycophenolate mofetil (n = 85); high-level tacrolimus (TAC) (8-12 ng/mL)-low-level sirolimus (SRL) (3-7 ng/mL) (n = 72); or low-level TAC (3-7 ng/mL)-high-level SRL (8-12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death-censored graft, or acute rejection-free graft survival, or in kidney function. Wound complications were more common in SRL-treated recipients (p = 0.02); we found no other differences between groups in complication rates. Our data suggest that excellent patient and graft survival and low rejection rates can be obtained using a variety of maintenance protocols without prednisone.     

Tacrolimus plus low-dose mycophenolate mofetil in renal transplant recipients: better 2-year graft and patient survival than with a higher mycophenolate mofetil dose

OBJECTIVES: Mycophenolate mofetil (MMF) has become more widely prescribed in recent years, but its adverse effects on the gastrointestinal system and bone marrow restrict its use in certain settings. The aim of this study was to compare the demographic features and clinical data for 173 renal transplant recipients who received tacrolimus (TAC) plus 1 g/d MMF (group I, n = 112) versus TAC plus 2 g/d MMF (group II, n = 61 patients) over a 2-year period. Each patient received similar TAC doses. METHODS: We compared demographic data and clinical data for each case: acute rejection (AR) episodes, chronic rejection (CR) episodes, death, graft loss, development of posttransplantation diabetes mellitus (PTDM), and posttransplantation hypertension rates. RESULTS: Demographic features were similar. There were also no significant differences between groups I and II with respect to number of AR episodes (17/112 vs 12/61, respectively), number of CR episodes (4/112 vs 1/61, respectively), PTDM, and hypertension rate (P > .05). Kaplan-Meier survival analysis revealed 2-year graft survival rates of 94% in group I versus 83% in group II. The corresponding 2-year patient survival rates were 100% in group I versus 91% in group II. The graft survival and patient survival rates in group I were significantly higher than those in group II (log-rank 0.005 and 0.001, respectively). CONCLUSIONS: The 2-year graft and patient survival rates for the renal transplant recipients in this study suggest that the combination of a full TAC dose with 1 g/d MMF is a better choice than 2 g/d MMF.     

Enhanced cyclosporine-itraconazole interaction with cola in lung transplant recipients

BACKGROUND: Invasive aspergillosis is a major cause of morbidity and mortality in lung transplant recipients (LTR), occurring in up to 15% of patients post-transplant. The 14% aspergillus incidence at the Cleveland Clinic Foundation prompted institution of universal prophylaxis with oral itraconazole (ICZ) in 1997. We report our experience with two protocols of ICZ administration in non-cystic fibrosis LTR and the interaction with cyclosporine (CSA). METHODS: Group 1 patients (n=12) were administered ICZ capsules in a fasting or fed state, with or without a histamine-2 (H-2) receptor antagonist or proton pump inhibitor. Group 2 patients (n=12) received the same protocol as group I, but in a fed state with a carbonated beverage (cola) to increase acidity in the stomach to enhance absorption of ICZ. The ICZ dose was 200 mg/d, given as one daily dose. A historical control group (n=10) did not receive chemoprophylaxis with ICZ. CSA daily doses, dose intervals, concentration, cost, and random ICZ levels were documented over a 4-month period of time and compared using generalized estimating equations. RESULTS: The daily CSA mg/kg/d dose decreased over time in all three groups, but no differences were found between the three groups. The CSA dosing interval over time was significantly prolonged in group 2 compared to group 1 or the control group (p< or =0.003). Over time, there was no difference in CSA concentration between all groups. There was no difference in cost over time between the three groups; however, the mean cost of CSA therapy was significantly lower in group 2 compared to the control group (p=0.025). Group 2 administered ICZ with cola had greater random blood concentrations of ICZ (p=0.019). CONCLUSIONS: ICZ capsules administered in a fed state with a cola resulted in greater random levels of ICZ, a decrease in cost/d of CSA, and a prolongation of CSA dosing interval. Although daily CSA dosage trended lower in group 2, it did not reach statistical significance. We believe these changes in CSA dosing over time reflect increased absorption of ICZ and recommend verifying ICZ absorption with an itraconazole level, especially when CSA intervals are not prolonged.     

Increased risk of post-transplant diabetes mellitus despite early steroid discontinuation in Hispanic kidney transplant recipients

Early steroid discontinuation (ESD) has been associated with a lower incidence of post-transplant diabetes mellitus (PTDM). We retrospectively reviewed the incidence of PTDM in relation to racial groups in kidney transplant recipients treated with ESD. Between January 2002 and September 2003, 125 consecutive primary adult kidney transplants were performed. Group A (n = 91) had steroids discontinued on postoperative day 6 and maintenance immunosuppression of Tacrolimus and mycophenolate mofetil. Group B (n = 34), received the same immunosuppression but was maintained on steroids indefinitely. Induction consisted of thymoglobulin in African-Americans; all others received Simulect. At 1 yr, patient/graft survival, serum creatinine and rate of acute rejection were similar in both groups. The incidence of PTDM was significantly lower in group A (7%) compared with group B (26%, p = 0.0209). The incidence of PTDM in group A was limited to Hispanic patients with a family history of diabetes mellitus. African-Americans and Caucasians in group A did not experience PTDM (p = 0.005 compared with African-American in group B). Our steroid free protocol nearly eliminated the incidence of PTDM in African-Americans and Caucasians, but was still associated with significant rate of PTDM in Hispanic recipients. Alternative immunosuppression may benefit this population.     

Bone mineral content per muscle cross-sectional area as an index of the functional muscle-bone unit.

Bone densitometric data often are difficult to interpret in children and adolescents because of large inter- and intraindividual variations in bone size. Here, we propose a functional approach to bone densitometry that addresses two questions: Is bone strength normally adapted to the largest physiological loads, that is, muscle force? Is muscle force adequate for body size? To implement this approach, forearm muscle cross-sectional area (CSA) and bone mineral content (BMC) of the radial diaphysis were measured in 349 healthy subjects from 6 to 19 years of age (183 girls), using peripheral quantitative computed tomography (pQCT). Reference data were established for height-dependent muscle CSA and for the variation with age in the BMC/muscle CSA ratio. These reference data were used to evaluate results from three pediatric patient groups: children who had sustained multiple fractures without adequate trauma (n = 11), children with preterminal chronic renal failure (n = 11), and renal transplant recipients (n = 15). In all three groups mean height, muscle CSA, and BMC were low for age, but muscle CSA was normal for height. In the multiple fracture group and in renal transplant recipients the BMC/muscle CSA ratio was decreased (p <. 0.05), suggesting that bone strength was not adapted adequately to muscle force. In contrast, chronic renal failure patients had a normal BMC/muscle CSA ratio, suggesting that their musculoskeletal system was adapted normally to their (decreased) body size. This functional approach to pediatric bone densitometric data should be adaptable to a variety of densitometric techniques.     

Gingival overgrowth in renal transplant recipients: a study concerning prevalence, severity, periodontal, and predisposing factors

Gingival overgrowth (GO) is the main oral manifestation in transplant recipients who use calcineurin inhibitors. In the present study, factors for GO development were investigated in Brazilian renal transplant recipients who were prescribed cyclosporine (CsA) or tacrolimus (TAC). Demographic, pharmacological, clinical, and periodontal data were obtained from 83 patients, as well as HLA expression in 51 of them. The prevalence of GO was high (47%), but its severity was low according to periodontal indices. The prevalence of GO was greater among patients who used CsA (n = 49) than those receiving used TAC (n = 34) namely, 61% versus 26.5% (P = .003). Comparisons between patients with versus without GO were performed independent of the administered immunossupressant. The group with GO showed a greater degree of gingival inflammation index. HLA-A68 had greater expression among patients without GO (P = .04). The risk factors for GO occurrence were evaluated using a multivariate analysis that identified gingival inflammation and HLA-A24 expression as risk factors. Increased age and use of TAC were identified as protective factors. GO showed a high prevalence, yet a light intensity. Patients who were younger, men, or received CsA showed a greater occurrence of GO. The risk factors identified for GO development were the presence of gingival inflammation and HLA-A24 expression.