David Landsberg

A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

BACKGROUND The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. METHODS Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. RESULTS The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). CONCLUSIONS MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients.

BACKGROUND Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids. METHODS Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts. RESULTS At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149+/-58 micromol/L, compared with 158+/-102 micromol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density. CONCLUSIONS On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.

The Living Anonymous Kidney Donor: Lunatic or Saint?

Studies indicate that 11% to 54% of individuals surveyed would consider donating a kidney, while alive, to a stranger. The idea of ‘living anonymous donors’ (LADs) as a donor source, however, has not been embraced by the medical community. Reservations focus on the belief that LADs might be psychologically unstable and thus unsuitable donors. Our goal was to inform policy development by exploring the psycho‐social make up and motivations of the LAD. Ninety‐three unsolicited individuals contacted our center expressing interest in living anonymous donation. Of these, 43 participated in our study, completing two extensive inventories of psychopathology and personality disorder and taking part in the Comprehensive Psycho‐Social Interview (CPSI). From the Personality Assessment Inventory (PAI), the revised NEO Personality Inventory (NEO PI‐R), and the CPSI, coders assessed psychological health, psycho‐social suitability, commitment, and motivations. Twenty‐one participants passed the stringent criteria to be considered potential LADs. Content analysis of motivations showed that potential LADs were more likely than non‐LADs (those who did not pass the criteria) to have a spiritual belief system and to be altruistic. Non‐LADs were more likely than potential LADs to use donation to make a statement against their families. The authors conclude with a preliminary outline of eight policy recommendations.

Nephrectomy After Transplant Failure: Current Practice and Outcomes

The role of transplant nephrectomy after transplant failure is uncertain. We report the use and consequences of transplant nephrectomy among 19 107 transplant failure patients between 1995 and 2003 in the United States. Among 3707 patients with early transplant failure (graft survival <12 m), nephrectomy was performed in 56%, and was associated with an increased risk of death (HR 1.13, 95% CI 1.01–1.26). In contrast, among 15 400 patients with late transplant failure (graft survival ≥12 m), nephrectomy was performed in 27%, and was associated with a decreased risk of death (HR 0.89, 95% CI 0.83–0.95). In early transplant failure patients, nephrectomy was associated with a lower risk of repeat transplant failure (HR 0.72, 95% CI 0.56–0.94), while among late transplant failure patients; nephrectomy was associated with a higher risk of repeat transplant failure (HR 1.20, 95% CI 1.02–1.41). Definitive conclusions are not possible from this observational study. The role of nephrectomy in the management of dialysis treated transplant failure patients, and the implications of nephrectomy for repeat transplantation should be further studied in prospective studies.

Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients: a report of the Canadian Neoral Renal Study Group.

BACKGROUND There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events. METHODS The long-term safety and tolerability of conventional cyclosporine (CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up. RESULTS No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine > or = 20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035). CONCLUSIONS Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

Cardiovascular Events and Investigation in Patients Who Are Awaiting Cadaveric Kidney Transplantation

The optimal strategy for cardiovascular (CV) disease surveillance in kidney transplant candidates is uncertain. In this observational study of 604 wait-listed patients in British Columbia, the risk for CV event in diabetic and nondiabetic candidates was 12.7 and 4.5% per year, respectively. CV event rates were relatively constant during the first 3 yr of wait-listing (5.3 to 6.6 per 100 patient-years; 95% confidence interval [CI], 3.7 to 9.3) but rose dramatically during the peritransplantation period (39.6/100 patient-years; 95% CI, 20.6 to 76.1) and remained high throughout the first posttransplantation year (4.0 per 100 patient-years; 95% CI, 2.2 to 7.5). The results of noninvasive cardiac investigations before wait-listing were not predictive of the time to CV event after wait-listing. The practice of surveillance cardiac investigation in wait-listed patients on the basis of ongoing clinical assessment of cardiac risk resulted in fewer investigations (n = 171) than with the recommended practice of periodic screening on the basis of waiting time alone (n = 530) and was not associated with an increased frequency of CV events (CV event rate in patients with and without the recommended frequency of investigation was 9.9 [95% CI, 7.1 to 13.7] and 6.7 [95% CI, 5.2 to 8.7] per 100 patient-years). It is concluded that transplant candidates are at high risk for CV events particularly during the perioperative period. Initial cardiac investigations have limited value in guiding the timing of patient reevaluation after wait-listing. Periodic surveillance cardiac investigation after wait-listing may be unnecessary and requires further study.

Living anonymous kidney donation: What does the public think?

Background. Health professionals are increasingly turning to living organ donation to augment cadaveric donation. Although living donation is currently performed with donors who are either genetically or emotionally related to the recipient, a 1997 British Columbia Transplant Society survey indicated that 32% of BC residents would be willing to donate a kidney, while alive, to a stranger (unpublished data). The goal of this study is to tap the public pulse about the living anonymous donor (LAD) by replicating and expanding the 1997 findings. Methods. Five hundred BC residents completed a telephone survey including demographic information, questions about their organ donation behaviors and attitudes, and their willingness to donate a kidney, while alive, to particular individuals (child, spouse, parent, relative, friend, and stranger). To improve the methodological rigor of the 1997 study, an informed condition was added in the current study where participants learned about living donation before being asked about their willingness to donate. Results. There were no differences among the 1997 results and the two conditions in the 2000 survey. Twenty-eight percent of participants in the uninformed condition and 29% of participants in the informed condition indicated that they would be willing to be LADs. LADs were more likely than self-reported non-donors to have registered as cadaveric donors and to endorse attitudes that were congruent with wanting to donate to a stranger. Conclusions. This study replicates the 1997 findings and increases confidence that a significant minority of British Columbians support living anonymous donation and that some would consider becoming LADs themselves.

Living Donor Age and Kidney Allograft Half-Life: Implications for Living Donor Paired Exchange Programs

BACKGROUND AND OBJECTIVES Living donor paired exchange programs assume that kidneys from living donors are of comparable quality and anticipated longevity. This study determined actual allograft t(1/2) within different recipient age groups (10-year increments) as a function of donor age (5-year increments), and juxtaposed these results against the probabilities of deceased donor transplantation, and exclusion from transplantation (death or removal from the wait-list). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from the US Renal Data System (transplant dates 1988-2003 with follow-up through September 2007) were used to determine allograft t(1/2), whereas data from patients on the United Network for Organ Sharing waiting list between 2003 and 2005 (with follow-up through February 2010) were used to determine wait-list outcomes. RESULTS With the exception of recipients aged 18-39 years, who had the best outcomes with donors aged 18-39 years, living donor age between 18 and 64 years had minimal effect on allograft t(1/2) (difference of 1-2 years with no graded association). The probability of deceased donor transplantation after 3 years of wait-listing ranged from 21% to 66% by blood type and level of sensitization, whereas the probability of being excluded from transplantation ranged from 6% to 27% by age, race, and primary renal disease. CONCLUSIONS With the exception of recipients aged 18-39 years, living donor age between 18 and 64 years has minimal effect on allograft survival.

Lack of long-term benefits of steroid withdrawal in renal transplant recipients

Glucocorticoids used in renal transplantation have been associated with numerous adverse effects. Most studies that showed short-term benefits of steroid withdrawal made comparisons for patients administered prednisone, 10 to 17.5 mg/d, versus no prednisone. Few have studied long-term benefits of steroid withdrawal. We performed a retrospective review and identified 58 patients administered cyclosporine, azathioprine, and prednisone who underwent complete steroid withdrawal. Post-steroid withdrawal follow-up was 7.6 +/- 1.9 years. Nine patients restarted prednisone therapy, 3 patients lost their grafts (2 of those restarted on prednisone therapy), and 2 patients died with functioning grafts. When prednisone dosage was tapered from 10 mg/d to 10 mg every other day, clinically significant improvements were seen in weight, systolic and diastolic blood pressure, blood pressure medications, glycosylated hemoglobin level, and diabetic medications. No further benefits were seen in these parameters and total cholesterol level on complete steroid withdrawal from prednisone, 10 mg every other day. Most of the earlier benefits were not sustained on long-term follow-up, and the increase in these parameters was similar to that of a similar matched control group (that underwent transplantation during the same period) maintained on prednisone, 5 mg/d. Major differences were decreases in creatinine clearances and hemoglobin levels, which were greater in the steroid-withdrawal group (7.4 +/- 1.9 mL/min and 1.2 +/- 0.2 g/dL, respectively) compared with the control group (2.6 +/- 1.5 mL/min and 0.5 +/- 0.2 g/dL, respectively). In conclusion, most of the metabolic benefits were seen with steroid dosage taper from prednisone, 10 mg/d to 10 mg every other day, with no further benefits with steroid withdrawal. Most of these benefits were not sustained on long-term follow-up, questioning the utility of steroid withdrawal.