Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results.

In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7-36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15-24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88-89%) or new T2 lesions (70-78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20-0.21, and 68-73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3-5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.

Proof of concept studies for tissue-protective agents in multiple sclerosis.

BACKGROUND: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). METHODS AND OBJECTIVES: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. RESULTS: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. CONCLUSIONS: The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia.

FTY720 is a novel immunomodulator investigated in de novo renal transplantation and other therapeutic areas including multiple sclerosis. This 1-year multicenter, randomized, phase III study in 668 de novo renal transplant patients compared FTY720 2.5 mg plus full-dose cyclosporine (FDC) or FTY720 5.0 mg plus reduced-dose cyclosporine (RDC), with mycophenolate mofetil (MMF) plus FDC. The primary efficacy endpoint was the composite incidence of first treated biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation at month 12. Primary efficacy with FTY720 2.5 mg and MMF (32.4% and 30.2%; p = NS), plus mortality and BPAR incidence, were comparable. Patients receiving FTY720 5.0 mg plus RDC were discontinued from treatment due to increased risk of acute rejection (primary endpoint incidence 47.3%). FTY720 was associated with lower creatinine clearance (month 12: 53.1, 56.0 vs. 65.1 mL/min; p < 0.001) and more macular edema cases (2.2% and 1.3% vs. 0%), whereas cytomegalovirus infections were higher with MMF (6.2% and 10.6% vs. 18.1% p < 0.0001 and p = 0.0139, respectively). FTY720 2.5 mg provided comparable rejection prophylaxis over 12 months versus MMF; however, FTY720 5.0 mg did not support a 50% reduction in cyclosporine exposure. The cause of macular edema cases and lower creatinine clearance with FTY720 in de novo transplantation needs further investigation.

Mycophenolic acid area under the curve values in African American and Caucasian renal transplant patients are comparable.

The possibility of an effect of ethnicity on the pharmacokinetics of mycophenolic acid, the immunosuppressive metabolite of the prodrug mycophenolate mofetil, was studied over 90 days following renal transplantation in African American (n = 13) and Caucasian patients (n = 20). Since renal dysfunction and time after transplant surgery are two factors known to alter mycophenolic acid pharmacokinetics, two-way analysis of variance of the data at each time point with ethnicity and renal function status as covariates was used to evaluate the possibility of an ethnicity effect on the pharmacokinetic parameters. No statistically significant difference based on ethnicity was detected for the primary pharmacokinetic parameters, abbreviated mycophenolic acid area under the concentration-time curve (MPA AUC), or the predose trough concentration on study days 4, 7, 14, 28, or 90. A statistically significant decrease in MPA AUC and increase in oral apparent clearance were observed in renally impaired patients regardless of ethnicity on days 4, and 4 and 7, respectively. The suggested mechanism for these differences is uremia-induced increased MPA free fraction, leading to a temporary increased clearance for this restrictively cleared drug.

Identification of alpha3, alpha4, and alpha5 chains of type IV collagen as alloantigens for Alport posttransplant anti-glomerular basement membrane antibodies.

BACKGROUND: Alport syndrome is a hereditary disorder of basement membranes especially affecting the kidneys, ears, and eyes. Some patients who undergo renal transplantation lose their kidneys as a result of posttransplant anti-glomerular basement membrane (anti-GBM) disease. METHODS: In the present study, we analyzed serum from 21 unselected Alport patients who underwent renal transplantation. Eleven samples were from patients without posttransplant anti-GBM nephritis, and 10 were from patients with this disease. RESULTS: Thirteen serum samples [10 alport posttransplant nephritis serum (APTN) and three Alport posttransplant serum (APT)] revealed linear binding to the GBM by indirect immunofluorescence. By using direct ELISA and immunoblotting with GBM constituents and type IV collagen NC1 domains from bovine, human, and recombinant sources, we detected anti-GBM antibodies in all Alport patients in varying titers. Five samples showed specific reactivity to the alpha3 chain, four to the alpha5 chain, six to both alpha3 and alpha5 chains, one to the alpha3 and alpha4 chains, and two to the alpha3, alpha4, and alpha5 chains of type IV collagen. The varied spectrum of reactivities was present equally in nephritic and non-nephritic sera. Ten control samples from non-Alport transplant patients did not exhibit specific binding to the GBM. CONCLUSIONS: These results suggest that the absence of alpha3, alpha4, and alpha5 chains of type IV collagen in the Alport kidney leads to alloantibodies in all Alport patients who receive transplants, irrespective of whether they develop nephritis or not. Although all Alport transplant patients develop this humoral response, only a select few develop anti-GBM disease. We suggest that this difference could be attributable to a genotypic effect on the ability of some individuals to launch a cell-mediated immune response.

Clinical management of early progressive renal failure.

In the era of managed health care, the primary physician will be required to play an active role in the management of patients with early renal failure. This section provides a comprehensive and practical approach to the management of such patients. Early recognition of renal failure and monitoring its progression require an understanding of the pitfalls of commonly used diagnostic tests. Tight control of hypertension, angiotensin-converting enzyme inhibition, and dietary protein restriction play important roles in delaying the progression of renal disease. Avoidance of additional renal insults such as nephrotoxic drugs and radiographic contrast prevents acceleration of renal demise. A variety of clinical manifestations, including dyselectrolytemias, hypertension, malnutrition, secondary hyperparathyroidism, and anemia may develop in patients with early renal failure. Timely referral to a nephrologist will facilitate planning for renal replacement therapy and may favorably affect eventual outcomes.

Focal acute tubular necrosis in a renal allograft.

Nuclear imaging is used to evaluate renal allografts demonstrating delayed function after transplantation. Interpretation of the nuclear scan in the context of clinical data, provides helpful information in the management of the transplant recipient. The better quality of images obtained with technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) has made it the radiotracer of choice compared to technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) for imaging of the renal allograft. Tc-99m MAG3 is cleared from the kidney by tubular secretion, whereas Tc-99m DTPA is cleared by glomerular filtration. In this report, we discuss a unique abnormality found on nuclear imaging of a renal allograft. Utilizing our understanding of the characteristic handling of various radiotracers by the kidney, we were able to demonstrate that the renal scan was consistent with an area of focal acute tubular necrosis in the newly transplanted kidney.

Effect of anti-lymphocyte induction therapy on renal allograft survival: a meta-analysis.

Induction immunosuppression with antilymphocyte antibodies has not been shown to improve cadaveric kidney allograft survival in randomized, controlled trials despite widespread use. This meta-analysis of randomized, controlled trials assessed the effectiveness of induction therapy in prolonging allograft survival. Studies of induction therapy were identified in Medline (1986 through 1996), using the terms "monoclonal antibodies" or "antilymphocyte serum," and "kidney transplantation," "human," and "clinical trial." Bibliographies, pharmaceutical manufacturers, the United Network for Organ Sharing, National Institutes of Health, and study authors were also consulted. Seven of 247 identified studies met the following inclusion criteria: (1) an adult study population; (2) assessment of antilymphocyte antibodies in the immediate posttransplant period; (3) a control arm of cyclosporine, azathioprine, and prednisone in the immediate posttransplant period; and (4) presentation of survival data. Two readers independently extracted protocol and survival data from each study. Summary odds ratios (fixed and random effects) and a rate ratio from proportional hazards regression at 2 yr were estimated to examine the effect of induction therapy on allograft survival. The summary odds ratios were both 0.66 (confidence interval [CI], 0.45 to 0.96; P = 0.03), and the rate ratio was 0.69 (CI, 0.49 to 0.97; P = 0.03), indicating a beneficial effect of induction therapy on allograft survival. Allograft survival was 85.6% (CI, 82.1 to 89.1%) in the induction therapy group and 79.6% (CI, 75.6 to 83.6%) in the conventional therapy group. These results were stable in a sensitivity analysis based on study quality. Allograft survival was prolonged with induction therapy compared with conventional immunosuppression. These data indicate a potential role for the routine use of induction therapy in renal transplantation to optimize the survival of cadaveric allografts.

Will tolerance become a clinical reality?

The goal of transplant physicians is to create a state of antigen-specific tolerance in the recipient, whereby the graft is not rejected and the patient will not need a lifetime of medical therapy. Although the immunosuppressive medications used are effective in lowering the incidence of rejection, they produce significant side effects and do not induce a state of transplantation tolerance. Progress toward inducing transplantation tolerance has been made in animal models, primarily by the exploitation of the natural mechanisms that vertebrates have to maintain self-tolerance. These same strategies are being employed in clinical trials and consequently are promising and challenging for the future.

OKT3 induction therapy: influence of duration on rejections and infections.

Anti-lymphocytes induction therapy in renal transplants remains controversial relative to efficacy and cost benefit. It has been suggested that shortening the duration of induction therapy from 14 to 7 d would provide adequate efficacy at less cost. Our objective was to compare the efficacy and complications of short (7 d or less, group A) versus standard (14 d or more, group B) duration of OKT3 induction therapy in renal allograft recipients. We performed a retrospective review of all renal allografts performed between July 1989 and September 1994. Two groups were identified based on the duration of OKT3 induction therapy. There were no significant differences between group A or B in the distribution of age, sex, race, degree of HLA matching, and etiology or renal failure. Patients in group B experienced fewer rejections at 3 and 12 months (p = 0.0236 and p = 0.0065, respectively) as well as fewer viral infections during the first year of follow-up (p = 0.0435). No difference on the mean number of bacterial or fungal infections existed between the two groups. There were no statistically significant differences in patient or graft survival, although patients in group B had a tendency towards increased 1-yr graft survival.

Myocardial systolic function in systemic lupus erythematosus: a study based on radionuclide ventriculography.

We assessed left ventricular systolic function by means of radionuclide ventriculography in 20 consecutive unselected patients with systemic lupus erythematosus. All patients had normal left ventricular systolic function (defined as ejection fraction greater than 45%) in a resting state. Regional wall motion abnormalities were, however, seen in 4 patients (20%). Of these 20 patients, 8 were able to exercise on a bicycle ergometer. These patients were subjected to exercise radionuclide ventriculography. Of these 8 patients, 3 (37.5%) had an abnormal ventriculographic response to exercise (as evidenced by a subnormal rise in ejection fraction or a fall, appearance of a new regional wall motion abnormality or worsening of a pre-existing one). This probably reflects subclinical left ventricular dysfunction unmasked by the stress of exercise. The clinical significance of these abnormalities on long-term myocardial function and their possible reversibility with remission of the disease needs to be assessed in future studies.