Ronald M. Ferguson

The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation

Abstract: Background:  Mycophenolate mofetil (MMF) has proven to be a very effective drug for the prevention of acute rejection following renal transplantation when dosed as prescribed at 2 or 3 g/d. However, circumstances arise in clinical transplantation where the dose must be lowered, either to avoid drug toxicity or because of concurrent infection. The impact on the incidence of acute rejection and graft survival when the MMF dose must be lowered has not previously been investigated.

Impact of acute rejection and early allograft function on renal allograft survival

Both acute rejection and the function of a renal allograft early after transplantation correlate with long-term graft survival. In this study we assessed the relationship between these two factors in 843 adult recipients of first cadaveric renal grafts, transplanted at a single institution and followed for a minimum of 3.5 years. Patients were divided into four groups according to (1) history of acute rejection (AR) during the first 6 months after transplantation, and (2) concentration of serum creatinine at 6 months after transplantation (SCr(6mo) < or > or = 2 mg/dl). Death censored allograft survival was not significantly different among patients without AR and with low SCr(6mo) (group 1, n=376), patients without AR but with an elevated SCr(6mo) (group 2, n=117), and patients with AR but low SCr(6mo) (group 3, n=185). In contrast, graft survival was significantly worse in patients with AR and an elevated SCr(6mo) (group 4, n=165) compared with patients in the other three groups (Cox, P<0.0001). The elevated SCr(6mo) in group 4 patients was not necessarily the consequence of AR, as 32% of patients in group 4 had a SCr at 10 days after transplantation (SCr(10d)), before they had AR, that was equal to or higher than the SCr(6mo). Based on this observation we investigated the implications of the SCr(10d) concentration for graft prognosis. The SCr(10d) correlated weakly with graft survival (Cox, P=0.05). However, an elevated SCr(10d) correlated with other potential risk factors for graft survival including: Older donors (P<0.0001), male recipients (P<0.0001), and heavier recipients (P<0.0001, all by multivariate regression); and posttransplant factors such as, increasing numbers of AR (P<0.0001), higher posttransplant blood pressure (P<0.0001), and lower doses of cyclosporine (P<0.0001, all by multivariate regression). In conclusion, graft dysfunction predicts poor graft survival only when associated with AR. Similarly, AR predicts a poor renal allograft survival only when associated with graft dysfunction. The SCr(10d) is an indicator of risk factors from both the donor and recipient, and an elevated SCr(10d) predicts a higher risk of acquiring additional risk factors early after transplantation.

Immunosuppression with Belatacept‐Based, Corticosteroid‐Avoiding Regimens in De Novo Kidney Transplant Recipients

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1‐year, randomized, controlled, open‐label, exploratory study assessed two belatacept‐based regimens compared to a tacrolimus (TAC)‐based, steroid‐avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept‐mycophenolate mofetil (MMF), belatacept‐sirolimus (SRL), or TAC‐MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty‐nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept‐MMF, belatacept‐SRL and TAC‐MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two‐thirds of patients in the belatacept groups remained on CNI‐ and steroid‐free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC‐MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC‐based regimen.

Medication compliance following renal transplantation.

BACKGROUND There appears to be general consensus that a relationship exists between noncompliance and clinical outcomes in health care, including renal transplantation. This study investigated variables associated with medication noncompliance after renal transplantation. METHODS A mail survey containing objective and subjective variables was sent to individuals who met eligibility criteria. Medication compliance was measured by two items: 1) Frequency of forgetting to take medications and 2) Frequency of not taking medications exactly as prescribed. Descriptive and multivariate analyses were utilized to examine the data. RESULTS Individuals who were older and those who perceived less pain were less likely to forget medications. The belief that health outcomes were controlled by chance and feeling bothered by part of the transplant experience were associated with greater likelihood of forgetting medications. Individuals who perceived a higher level of social functioning and those who believed that health outcomes were controlled by powerful others were more likely to take medications exactly as prescribed. An internal locus of control for health outcomes and feeling bothered by part of the transplant experience were associated with less likelihood of taking medication exactly as prescribed. CONCLUSIONS The finding of this study suggest that compliance with medications after renal transplant is associated with subjective, not objective variables. Positive feelings regarding their physicians and the transplant experience increased compliance. Combining consistent measurement of compliance, examination of its relationship to clinical outcomes, and appreciation for the patient perspective should result in increased levels of compliance and better clinical outcomes.

Renal transplantation in older people

Renal transplantation in people 60 years old or more is controversial due to the morbidity associated with immunosuppression and the scarcity of renal allografts. We have reviewed the outcome of 1222 consecutive renal transplants done at a single institution with a uniform immunosuppressive protocol over 10 years. 5-year graft survival was the same in the under sixties as in the sixties and over. Patient survival was worse in the older group (p = 0.0001), but there were significantly fewer immunological graft losses: 11% vs 31% (p = 0.0009; relative risk [RR] = 0.36 [95% confidence interval 0.19-0.66]). A majority of the deaths in both groups were secondary to cardiovascular disease, not due to complications of immunosuppression. We conclude that renal transplantation in people 60 and over has results equivalent to a younger population. Age 60 and over should not be a major factor in considering if a patient is eligible for renal transplantation.

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

Background. FTY720, a novel immunomodulator, displays potent immunosuppressive activity in a variety of preclinical transplant models. This study examined the safety, pharmacodynamics, and pharmacokinetics of multiple doses of FTY720 in stable renal transplant patients. Methods. This randomized, multicenter, double-blind, placebo-controlled, phase I study included adults who had been maintained on a regimen of cyclosporine A (CsA) microemulsion and prednisone (or its equivalent) for at least 1 year after renal transplantation. Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. After completion of study drug administration, the patients were monitored until day 56 by serial laboratory tests, clinical examinations, and recording of adverse events. The study includes 76 treatment courses (61 FTY720 and 15 placebo), with 65 patients enrolled once and 11 reenrolled. Results. FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85%, which reversed within 3 days after discontinuation of study medication. Compared with placebo-treated patients, FTY720 subjects did not show a major increase in adverse events or a change in renal function. Pharmacokinetic measurements revealed that FTY720 displayed linear relations of doses and concentrations over a wide range, but had no effect on CsA exposure. Conclusions. At doses up to 5.0 mg/day for 28 days, stable renal transplant patients treated with FTY720 in combination with CsA and prednisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxicities, except possibly bradycardia.

Cytomegalovirus as a risk factor in renal transplantation.

A prospective study of 276 patients that were greater than 12 years old and received transplants between October 1,1977 and September 30, 1979 has been undertaken. Any patient with clinical findings compatible with overt cytomegalovirus (CMV) disease was placed on a “CMV disease diagnostic protocol.” All diagnosed cases of CMV occurring before November 15, 1979 have been analyzed. Eighty patients (29%) had overt CMV disease. Seventy-two (90%) of them contracted CMV within the first 3 months post-transplant. The incidence of overt CMV varied with donor type. Eight percent (4 of 49), 17% (8 of 48), 20% (5 of 25), 40% (46 of 115) and 43% (15 of 35) of HLA-identical (ID) siblings, non-ID siblings, child donor, cadaveric donor, and parental donor, respectively, contracted CMV disease. Overt clinical CMV disease influenced the graft function and patient survival rates significantly (P < 0.01). Several risk factors have been considered as possible indicators of CMV disease. These include age, sex, diabetic status, time of onset of CMV, donor and recipient CMV complement-fixing (CF) and indirect fluorescence (IF) titers. The same variables were analyzed to determine whether they might also predict the severity of the disease. Donor CF is the single most important risk factor. Recipient serology alone was not found to be a significant risk factor but 15 of 27 (56%) persons who had a negative titer and received a kidney from a donor with a positive CF titer contracted overt CMV. Nine of those 15 (60%) had moderate, severe, or lethal illness.

Aspergillosis in 25 renal transplant patients. Epidemiology, clinical presentation, diagnosis, and management.

In immunocompromised renal transplant patients, aspergillosis can be a life-threatening opportunistic infection. During an 8-year period, 25 renal transplant recipients at the University of Minnesota Hospitals developed unequivocal invasive aspergillosis that occurred in epidemic-like patterns in immunocom-promised patients throughout the hospital. The premortem diagnosis was made in only 14 of the 25 patients. Seventeen patients died, and three of the eight survivors lost their allografts. The prognosis was dependent upon the clinical pattern of illness: three clinical patterns emerged: (1) cavitary lung disease, (2) diffuse pulmonary disease, and (3) central nervous system disease. All patients in the latter two categories died. The best results were with those patients treated with both amphotericin B and excision of cavitary lung lesions. All three patients treated in this manner survived with functioning grafts. Traditionally, sputum cultures have been thought to be unreliable because Aspergillus is a common colonizer of the upper respiratory tract and a contaminant in laboratories. In this study, false positive sputum cultures were common. A positive sputum culture can be helpful, however, all patients with two positive sputum cultures proved to have invasive aspergillosis. In addition, 86% of patients with positive sputum cultures who were clinically ill proved to have invasive infection. Bronchoscopy is a useful technique to follow up a positive sputum culture or investigate negative sputum cultures with typical clinical patterns. Routine bronchoscopy, unfortunately, also yields a high incidence of false positive cultures. Since the use of covered brush bronchoscopy technique, however, no false positive transbronchial cultures have been found. Transbronchial biopsy is a useful adjunct and is proof of the presence of invasive disease when the results are positive. However, false negative results are also found. Overall, the highest diagnostic yield is obtained both with transbronchial lung biopsy and covered brush bronchoscopy culture. All eight patients with both these procedures were correctly identified as having invasive pulmonary aspergillosis.

Treatment with anti-vascular cell adhesion molecule 1 monoclonal antibody induces long-term murine cardiac allograft acceptance.

Daily in vivo treatment of murine H-2d --> H-2b cardiac allograft recipients with 400 micrograms/day i.p. of M/K-2, a mAb to the endothelial adhesion molecule VCAM-1, resulted in prolongation of graft survival. The surviving allografts showed little of the histologic changes observed in acutely rejecting control allografts. When antibody treatment was discontinued after 20 days, grafts continued to function for at least 40 more days. This was approximately 30 days after mAb was no longer detectable by ELISA in the circulation, or by immunoperoxidase staining at the graft site. The most notable feature of grafts that survived 60 days was the presence of mild interstitial fibrosis. Endothelial reactivity was minimal with the mAbs MECA-32 and M/K-2, which have been used in previous studies to visualize the extensive endothelial inflammation that develops during untreated acute rejection. There was a mild cellular infiltrate containing T cells, but few macrophages. However, infiltrating T cells appeared to be inactive in that IL-2R+ cells were immunohistologically undetectable and mRNA for IL-2, IL-4, or IFN-gamma was undetectable by polymerase chain reaction. In general, the immunologic conditions in these long-term grafts differed from those seen in normal cardiac tissue, cardiac isografts, or cardiac allografts. These data demonstrate that M/K-2 mAb can suppress cardiac allograft rejection and induce long-term graft acceptance. This graft survival appears to be associated with the development of a unique state of immunity at the graft site.

Occult herpes family viral infections are endemic in critically ill surgical patients.

ObjectiveHerpes family viruses have been recognized as pathogens for many years in immunosuppressed transplant or human immunodeficiency virus patients, but they have garnered little attention as potential pathogens in the nonimmunosuppressed critically ill. The objective of this study was to define the prevalence of and risk factors for development of herpes family virus infection in chronic critically ill surgical patients. DesignProspective epidemiologic study. SettingA 38-bed surgical intensive care unit in a major university hospital. PatientsNonimmunosuppressed intensive care unit patients in intensive care unit for ≥5 days. InterventionsNone; patients received no antiviral treatment during the study. Measurements and Main ResultsWeekly cultures for cytomegalovirus (CMV) and herpes simplex virus, viral serologies, and T-cell counts were performed. The prevalence (95% confidence interval) of positive respiratory cultures for herpes simplex or CMV was 35% (22–49%); 15% (5–25%) cultured positive for CMV, 23% (11–35%) cultured positive for herpes simplex virus, and one patient’s respiratory secretions culturing positive for both CMV and herpes simplex virus. The prevalence of CMV viremia was only 5.8% (1–10%). CMV+ patients had longer hospital admissions, intensive care unit admissions, and periods of ventilator dependence than CMV− patients, despite having comparable severity of illness scores. CMV+ patients also had significantly higher numbers of blood transfusions, prevalence of steroid exposure, and prevalence of hepatic dysfunction, and all were immunoglobulin G positive at the beginning of the study. In contrast, herpes simplex virus–positive patients had lengths of hospital admissions, lengths of intensive care unit admissions, and periods of ventilator dependence comparable with patients without viral infections (p > .05). ConclusionsThere is a significant prevalence (22–49%) of occult active herpes family viruses in chronic critically ill surgical patients. The clinical significance of these viral infections is unknown, although CMV+ patients have significantly higher morbidity rates than CMV− patients. Several factors suggest pathogenicity, but further study is needed to define causality.