Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group.

BACKGROUND: Numerous studies have demonstrated that renal allograft survival is reduced in African-Americans (AAs). This posthoc racial subgroup analysis (AAs vs. non-AAs) tested whether mycophenolate mofetil (MMF) might have favorable implications for the treatment of AA renal allograft recipients. METHODS: Patients received a triple therapy regimen of corticosteroids, cyclosporine, and azathioprine (AZA) 1-2 mg/kg/day, MMF 2 g/day (MMF 2 g), or MMF 3 g/day (MMF 3 g). RESULTS: AAs in the AZA group had the highest biopsy-proven rejection/treatment failure (BPR/TF) rate (57.5% vs. 43.5% for non-AAs). AAs in the MMF 3 g group showed a significant reduction in BPR/TF (57.5% vs. 24.2%, P=0.0008). BPRs were more frequent for AAs in either the AZA (47.5%) or MMF 2 g group (31.8%) than in the MMF 3 g group (12.1%), whereas rejections were reduced for non-AAs receiving either MMF dosage (AZA, 35.5%; MMF 2 g, 15.7%; MMF 3 g, 18.8%). AAs in the AZA group experienced BPR/TF earlier than AAs in the MMF 3 g group (median onset at 64 days vs. > 183 days, P=0.0012). But AAs in the MMF 3 g experienced BPR/TF the latest among the six subgroups of treatment and race. AAs had more severe rejection episodes and higher serum creatinine levels at 6 months after transplant, regardless of treatment group. CONCLUSIONS: Dose-dependent prevention of acute rejection in AAs is best afforded by a dosage of MMF at 3 g/day, whereas 2 g/day provides a superior benefit/risk ratio for non-AAs. MMF at 3 g/day thus provides an improvement over conventional immunosuppressive strategies in reducing the frequency of acute rejections in this immunologically high-risk group.

Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group.

BACKGROUND: Results of a multicenter, randomized, clinical trial demonstrated that tacrolimus was more effective than cyclosporine in preventing acute rejection in cadaveric renal transplant patients. As African-Americans comprised approximately 25% of the study population, their outcome was analyzed relative to the experience of Caucasian patients. METHODS: Of the 205 patients randomized to tacrolimus, 56 (27.3%) were African-American and 114 (55.6%) were Caucasian. Of the 207 patients randomized to cyclosporine, 48 (23.2%) were African-American and 123 (59.4%) were Caucasian. The efficacy variables were 1-year patient survival, graft survival, and incidence of acute rejection. RESULTS: The incidence of acute rejection was significantly lower in African-American and Caucasian patients treated with tacrolimus than with cyclosporine. Additionally, no African-American patient who was treated with tacrolimus experienced moderate or severe acute rejection, as determined by blinded independent review. The incidence of nephrotoxicity, cardiovascular and gastrointestinal events, malignancies, and opportunistic infections was similar between treatments and race groups. However, there was an increased incidence of posttransplant diabetes mellitus in tacrolimus-treated patients, particularly in African-Americans, and tacrolimus was associated with significantly lower lipid levels in both Caucasians and African-Americans. African-American patients required a 37% mean higher dose of tacrolimus than Caucasian patients to achieve comparable blood concentrations. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in both African-American and Caucasian patients. However, tacrolimus was associated with an increased risk of posttransplant diabetes mellitus, particularly in African-Americans, which was reversible in some patients.

Cyclosporine increases the oxidizability of low-density lipoproteins in renal transplant recipients.

Blood specimens from twenty-six renal transplant recipients treated with cyclosporine (CsA) were collected at weekly intervals, two months after transplantation. Specimens were grouped according to their CsA concentrations. Group I consisted of ten specimens with CsA concentration of >400 ng/ml; group II consisted of ten specimens with CsA concentrations ranging from 120-300 ng/ml; and group III consisted of six specimens with CsA concentrations of < 100 ng/ml. In addition, specimens from five renal transplant patients who, instead of CsA, received the immunosuppressant FK506 (group IV), and from six healty individuals were included. Plasma low-density lipoproteins (LDL) were isolated and their susceptibility to oxidation was studied by continuously monitoring the formation of conjugated dienes during copper ion-mediated oxidation. Patients with higher blood concentrations of CsA (groups I and II) had significantly higher oxidizability of LDL, as indicated by the shorter time required to start the oxidation (lag phase). The oxidizability of samples with low concentration of CsA (group III) was not significantly different from that of FK506-treated patients or healthy individuals. There was a negative correlation (r = -0702, P < 0.01) between oxidizability (lag phase) and CsA concentration in LDL. No correlation between blood CsA and plasma cholesterol or triglyceride concentration was evident during a three-month period postoperatively. Similarly, no correlation between the degree of oxidizability and plasma cholesterol or triglycerides was found at the time of the experiment. These findings suggest a prooxidant effect of CsA to plasma LDL, and may indicate that CsA is an important risk factor in the accelerated atherosclerosis of renal transplant recipients.

An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group.

This was a multicenter, open-label, concentration-ranging trial of FK506 and cyclosporine in 120 patients undergoing primary cadaveric kidney transplant. Patients were randomized to a cyclosporine-based regimen or to one of three FK506-based regimens designed to achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, and 0.4 mg/kg/day. Patients were evaluated at 42 days after transplant for the occurrence of the first episode of acute rejection or toxicity, necessitating a dosage reduction. There was no significant difference among the three FK506-based regimens and the cyclosporine-based regimen for rejection or toxicity at 42 days. However, the incidence of acute rejection was significantly lower (14% for FK506 and 32% for cyclosporine; P=0.048) for the aggregate of all FK506-treated patients versus cyclosporine. The incidence of neurotoxic and gastrointestinal events was higher among FK506-treated patients during the first month after transplant. A significant trend was observed for increasing toxicity with increasing maximum trough FK506 concentrations (P=0.01) and for decreasing rates of rejection with increasing minimum trough FK506 concentrations (P=0.021). FK506 was effective in preventing early rejection in kidney transplant recipients. The target range of whole blood levels that optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The corresponding recommended initial dose of FK506 for kidney transplant recipients seems to be 0.2 mg/kg/day.

One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group.

Patients undergoing primary cadaveric kidney transplantation were followed for 1 year as part of a phase II, multicenter, open-label concentration-ranging trial of FK506 and cyclosporine. One hundred twenty patients were randomly assigned to a cyclosporine-based regimen or one of three FK506-based regimens designed to achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, or 0.4 mg(kg/day, respectively. Patients with toxicity to FK506 had their target concentration reduced by lowering the dose of FK506. Ninety-two patients completed a 1-year follow-up to determine patient and graft survival and long-term safety. At 1-year, the patient survival rate was 98% for FK506 and 92% for cyclosporine, and the graft survival rate was 93% and 89% in the FK506 and cyclosporine groups, respectively. The incidence of acute rejection was significantly lower (14% FK506, 32% cyclosporine, P=0.048) at day 42 after transplantation. However, the incidence of rejection episodes requiring treatment at 1 year was similar in both groups (33% for FK506 and 32% for cyclosporine). Nephrotoxicity occurred with a similar frequency with FK506 and cyclosporine, but the incidence of neurotoxic events and the incidence of new insulin use were higher among FK506-treated patients. The target range of whole blood levels that optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The corresponding recommended initial dose of FK506 for kidney transplant recipients is 0.2 mg/kg/day. These results indicate that the efficacy and safety of FK506 were comparable to that for cyclosporine for primary immunosuppression in patients undergoing cadaveric kidney transplantation.

Gene expression analysis in human renal allograft biopsy samples using high-density oligoarray technology.

BACKGROUND: High-density oligoarray technology is a novel method for screening the expression of thousands of genes in a small tissue sample. Oligoarray analysis of genes expressed during human renal allograft rejection has not been reported previously. METHODS: Seven human renal allograft biopsies with histologic evidence of acute cellular rejection and three renal allograft biopsies without evidence of rejection (control) were analyzed for the expression of 6800 human genes using high-density oligoarrays (GeneChip, Affymetrix, Santa Clara, CA). Quantitative expression of gene transcripts was determined and a comparison analysis between acute rejection and control biopsy samples was performed. Up-regulation of a specific gene transcript during acute rejection was considered to be significant if transcript abundance increased fourfold or more relative to control biopsy samples. RESULTS: Comparison analysis revealed that between 32 and 219 gene transcripts are up-regulated (>fourfold) during acute rejection. Of these transcripts, only four (human monokine induced by interferon-gamma, T-cell receptor active beta-chain protein, interleukin-2 stimulated phosphoprotein, and RING4 (a transporter involved in antigen presentation)) were consistently up-regulated in each acute rejection sample relative to at least two of three control biopsy samples. Six other genes were up-regulated in six of seven acute rejection samples. These were interferon-stimulated growth factor-3, complement factor 3, nicotinamide N-methyltransferase, macrophage inflammatory protein-3beta, myeloid differentiation protein, and CD18. Only two gene transcripts were down-regulated in five of seven acute rejection samples. Significant up-regulation of cytotoxic T-cell effector molecules, previously reported as markers of acute renal rejection in humans, was not detected. CONCLUSIONS: High-density oligoarray technology is useful for screening gene expression in transplanted tissues undergoing acute rejection. Because this method does not rely on a priori knowledge of which genes are involved in acute rejection, it is likely to yield novel insights into the mechanisms and diagnosis of rejection.

The evaluation of candidates for renal transplantation. The current practice of U.S. transplant centers.

The criteria for acceptance of candidates for renal transplantation varies throughout the United States. The Patient Care and Education Committee of the American Society of Transplant Physicians conducted a survey of all U.S. centers that participate in the United Network for Organ Sharing (UNOS) concerning their evaluation of adult candidates for kidney transplantation. The response to each question was examined according to the specialty of the individual who filled out the questionnaire, as well as the type of transplant center (university or private) and the size of the center. The response rate to the survey was 81% (147/182). We found the following: (1) university-based and larger centers accepted more medically complicated patients; (2) 83% noted that attendance to dialysis was an important indicator of compliance after transplantation; (3) 79% did not require preoperative blood transfusions for cadaver kidney recipients; (4) 66% set no specific upper age limit for transplantation; (5) 56% excluded patients with chronic active hepatitis in the setting of hepatitis B antigenemia; (6) 50% had no specific policy for evaluating hepatitis C antibody-positive patients, while 54% excluded the use of hepatitis C antibody-positive donors, and (7) 15% obtained coronary angiography on all diabetic patients. U.S. transplant centers have a heterogeneous approach to the evaluation of patients for renal transplantation, particularly in the areas of viral hepatitis, cardiovascular disease, and noncompliance. University-based centers and centers that perform a larger number of transplants accept more medically complicated patients.

Pentoxifylline does not prevent the cytokine-induced first dose reaction following OKT3--a randomized, double-blind placebo-controlled study.

The use of OKT3 as an immunosuppressive agent is accompanied by increased cytokine production and constellation of side effects collectively termed cytokine release syndrome (CRS). Pentoxifylline (PTF) inhibits synthesis of some cytokines, and has been shown to attenuate CRS when administered before OKT3. In this double-blinded, placebo-controlled study, 46 renal allograft recipients were randomized to receive either PTF (800 mg q 8 hr for at least 24 h) p.o. or placebo, along with methylprednisolone (7 mg/kg), diphenhydramine, and acetaminophen, prior to beginning OKT3 as therapy for acute rejection. Patients were observed, and symptoms scored semiquantitatively. Despite the presence of therapeutic PTF levels (721 +/- 726 ng/ml), the frequency and severity of side effects (fever, chills, headache, neurocortical symptoms, dyspnea, nausea, vomiting, diarrhea) did not differ between treatment groups. Likewise PTF did not affect renal function or immunologic response to OKT3, with similar graft and patient survival in both groups. Plasma levels of TNF alpha, IFN gamma, IL-6, and IL-8 increased as predicted following OKT3 administration, without significant differences between PTF and placebo groups. In this controlled, multicenter trial, pretreatment with oral PTF was ineffective in attenuating OKT3-related CRS in renal allograft recipients.

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Epitope specificity of HLA class I alloantibodies. I. Frequency analysis of antibodies to private versus public specificities in potential transplant recipients.

Sera obtained sequentially from 419 patients awaiting solid organ transplantation were screened and analyzed for HLA class I epitope specificity. Antibodies detected in each serum were defined as "private" if reactivity could only be demonstrated against a single specificity within one of the eight major CREGs, or as "public" if reactivity in a serum could be demonstrated against two or more specificities within a single CREG. A total of 139 sera contained % PRA > 0, in which 147 specific antibodies were identified. Of the 103 positive sera, 93 (90%) contained antipublic antibodies, with or without additional antiprivate antibodies, whereas just 10 (10%) sera contained only apparent antiprivate antibodies. The success rate in defining antibody specificities was low at PRA values of 1%-20% due to weak reactivity and high false-positive rates. Specificity analysis with high test sensitivity and specificity was achieved with PRA values between 40% and 80%. At PRA values > 80%, test sensitivity remained high but specificity declined. We conclude that most anti-HLA antibodies are directed against high frequency public epitope clusters (CREGs), and highly sensitized patients develop antibodies in a fairly predictable fashion, a feature that significantly improved the success rate of specificity analysis. Since high frequency antipublic antibodies are common sequelae of CREG mismatches, further definition of HLA class I public epitopes eventually may be important in donor-recipient matching.

Assessment of the frequency and costs of posttransplantation hospitalizations in patients receiving tacrolimus versus cyclosporine.

We assessed the frequency and costs of hospitalizations in patients receiving tacrolimus (FK506) compared with patients receiving cyclosporine A for immunosuppression during 1 year after kidney transplantation. Four hundred twelve cadaveric kidney transplant recipients were randomized onto a phase III, prospective, multicenter, clinical trial. Hospital billing data were collected for 1 year posttransplantation. Total inpatient costs were calculated from billed charges and standardized to 1995 US dollars. Medical resource utilization rates and inpatient costs were compared between treatment groups using unpaired Student's t-tests. Complete billing data (transplantation and all posttransplantation hospitalizations) were available for 65% (268 of 412) of the study patients. Among tacrolimus and cyclosporine patients with complete billing data, the rates of allograft rejection were 32% and 47%, respectively (P=0.009), and the rates of rehospitalization during the year after transplantation were 53% and 63%, respectively (P=0.080). The mean per-episode rehospitalization costs were significantly lower among tacrolimus-treated patients compared with cyclosporine-treated patients ($7,495 v $11,497; P=0.031), and the mean total rehospitalization costs were significantly lower in the tacrolimus group compared with the cyclosporine group ($8,550 v $14,869; P=0.029). In addition, the total 1-year hospitalization costs (including transplantation and posttransplantation hospitalizations) were significantly lower in the tacrolimus group compared with the cyclosporine group ($53,435 v $61,191; P=0.046). Compared with cyclosporine-based immunosuppression, tacrolimus-based immunosuppression for kidney transplant recipients was associated with a significantly lower rate of rejection, which was associated with significantly lower per-episode rehospitalization costs, lower total 1-year rehospitalization costs, and lower total 1-year hospitalization costs.

Conclusions: the maintenance of allograft acceptance.

This article summarizes all of the findings of the authors in this issue who examined various laboratory procedures used to implement and monitor transplantation treatment strategies. Histocompatibility matching, crossmatching, monitoring immunosuppression and rejection, and immunologic monitoring of allograft rejection and acceptance are reviewed.

Race and sex differences in the identification of candidates for renal transplantation.

The availability of renal transplantation to individuals with end-stage renal disease (ESRD) is an issue of considerable concern. The role of age, race, sex, socioeconomic status, illness severity, and comorbidity in determining access to this therapy remains unclear. We examined the influence of these factors on transplant candidacy in 8,315 patients receiving dialysis treatment for ESRD in North Carolina, South Carolina, and Georgia. We found important race-sex differences in the likelihood of being identified as a transplant candidate. These differences persisted after adjustment for other patient characteristics, including illness severity and certain comorbid conditions. Characteristics found to be positively associated with candidacy included age less than 30 years (P less than 0.00001), living with a spouse and children (P = 0.004), and employment status (P = 0.006). Characteristics and comorbid conditions that were negatively associated with candidacy included 8 years or less of formal education (P = 0.001), cancer (P = 0.0006), visual impairment (P = 0.006), congestive heart failure (P = 0.008), and peripheral vascular disease (P = 0.01). Compared with white males, after adjustment for these factors, the likelihood (95% confidence interval) of being identified as a transplant candidate was: white females, 0.88 (0.65 to 1.18); black males, 0.77 (0.59 to 0.99); and black females, 0.66 (0.51 to 0.87). We conclude that although socioeconomic and medical factors are strongly associated with transplant candidacy, these associations do not adequately explain the observed race-sex differences in transplant candidacy status.

Hypertension after renal transplantation.

Hypertension is a frequent complication after organ transplantation in both children and adults and is a significant risk factor for the development of cardiovascular disease and graft dysfunction. There are multiple mechanisms responsible for the development of posttransplant hypertension. In the precyclosporine era, chronic rejection was the most common cause. The introduction of cyclosporine A has increased the prevalence of hypertension in solid organ transplant recipients. Cyclosporine increases renal vascular resistance by causing vasoconstriction of the afferent arteriole. From a pathophysiologic point of view, a calcium channel blocker should be used as the initial therapy in patients with cyclosporine-associated hypertension. Hypertension needs to be treated aggressively in all transplant recipients in an attempt to minimize allograft and cardiovascular damage.

Tacrolimus, cyclosporine and plasma lipoproteins in renal transplant recipients.

To compare the effect of tacrolimus (FK506) and cyclosporine (CsA) on plasma lipoproteins in renal transplant recipients receiving maintainance therapy, the following prospective study was undertaken. Blood from nineteen recipients on tacrolimus (FK group) and from twenty-one on CsA (CsA group) was collected at baseline, 3-, 6-, and 10-month intervals. Plasma lipids, lipoproteins and oxidation properties of lipoproteins were determined. Plasma total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) were substantially increased in both groups, although only the CsA group showed significant differences at all time intervals and at the baseline. High density lipoprotein cholesterol, triglycerides, and apolipoprotein A varied in both groups at time intervals from the baseline, but not significantly. The susceptibility to oxidation of LDL isolated from the FK group at all times was uninfluenced by the tacrolimus treatment, and values were comparable to those obtained from LDL isolated from healthy individuals. A significantly higher susceptibility to oxidation as indicated by the shorter time required to start the formation of conjugated dienes was observed in LDL isolated from the CsA group at 3 and at 6 months of therapy. Tacrolimus-treated patients appear to have less hyperlipidemic and have LDL less susceptible to oxidation than patients treated with CsA.

Diagnosis of pancreatic transplant dysfunction: value of gadopentetate dimeglumine-enhanced MR imaging.

Sixteen MR studies performed in four patients who had undergone combined pancreatic and renal transplantation were reviewed retrospectively to determine if dynamic gadopentetate dimeglumine-enhanced gradient-echo imaging is useful in the early diagnosis of pancreatic transplant rejection. The MR studies were performed between 3 days and 6 months after transplantation and consisted of T1- and T2-weighted spin-echo images as well as a gradient-echo image prior to administration of an IV bolus of gadopentetate dimeglumine (0.1 mmol/kg). After injection of gadopentetate dimeglumine, a static dynamic gradient-echo scan was obtained. Signal-intensity measurements were determined for each of the gradient-echo images and used to generate an enhancement curve. Because T2 values have previously been used as an objective indicator of rejection, the mean T2 of each pancreatic transplant was calculated also. The MR results were compared with clinical and laboratory data and/or percutaneous biopsy results. In six studies of normally functioning pancreatic allografts, the percent enhancement during the first minute of the enhancement curve was 98 +/- 23% (1 SD). In six episodes of acute dysfunction (rejection or infarction), the first-minute enhancement was 42 +/- 20%. In four cases of dysfunction, the finding of an abnormal enhancement curve preceded a significant drop in urinary amylase by 1-4 days. The calculated T2 value was prolonged in only two cases in which biopsy-proved pancreatic infarction had occurred. No prolongation of T2 was evident in four cases of rejection alone. These results suggest that mean T2 calculation at 1.5 T may not be a reliable indicator of pancreatic transplant rejection, but that gadopentetate dimeglumine-enhanced gradient-echo MR imaging of the pancreatic transplant may be a reliable early indicator of pancreatic transplant dysfunction.

Payment for immunosuppression after organ transplantation. American Society of Transplantation.

Dramatic improvements in organ transplantation have meant that a growing number of patients must take expensive immunosuppressive medications for the rest of their lives. Currently, Medicare covers most transplantation procedures in the United States, but ends coverage for outpatient immunosuppressive medications after 36 months. Evidence suggests that at least some patients have reduced immunosuppression and their transplants fail because they cannot afford these medication costs. In the years since the advent of effective immunosuppressive therapy, the US Congress has struggled with this issue, and in 1999 temporarily extended medication coverage for eligible patients (based on age and disability) by 8 months. However, a more permanent solution is needed. We advocate that Medicare should cover the cost of all immunosuppressive therapy for all solid organ transplant recipients who cannot afford to pay. A number of potentially cost-effective approaches could be taken, but, in any case, something must be done to ensure that transplants do not fail because recipients cannot pay for immunosuppression.

Ureteral obstruction due to calculi in the early postoperative period in renal cadaveric transplantation: a case report and discussion of ureteral obstruction in the renal transplant patient.

We report a case of obstruction secondary to multiple ureteral calculi on postoperative day 3 after cadaveric renal transplantation. Treatment consisted of ureterolithotomy with stenting of the ureteroneocystotomy and convalescence was otherwise unremarkable. Obstructive complications of the ureter after renal transplantation are reviewed.