De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT-EXT studies.

Donor-specific antibodies (DSAs) are associated with an increased risk of antibody-mediated rejection and graft failure. In BENEFIT and BENEFIT-EXT, kidney-transplant recipients were randomized to receive belatacept more intense (MI)-based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression for up to 7 years (84 months). The presence/absence of HLA-specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid-phase flow-cytometry screening. Samples from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of belatacept MI-treated, belatacept LI-treated, and cyclosporine-treated patients, respectively. The corresponding values in BENEFIT-EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan-Meier analysis, de novo DSA incidence was significantly lower in belatacept-treated vs cyclosporine-treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, belatacept-based immunosuppression was associated with numerically lower MFI vs cyclosporine-based immunosuppression. Although derived post hoc, these data suggest that belatacept-based immunosuppression suppresses de novo DSA development more effectively than cyclosporine-based immunosuppression.

Posttransplant reduction in preexisting donor-specific antibody levels after belatacept- versus cyclosporine-based immunosuppression: Post hoc analyses of BENEFIT and BENEFIT-EXT.

BENEFIT and BENEFIT-EXT were phase III studies of cytotoxic T-cell crossmatch-negative kidney transplant recipients randomized to belatacept more intense (MI)-based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression. Following study completion, presence/absence of HLA-specific antibodies was determined centrally via solid-phase flow cytometry screening. Stored sera from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of donor-specific antibodies (DSAs), and mean fluorescent intensity (MFI) of any DSAs present. The effect of belatacept-based and cyclosporine-based immunosuppression on MFI was explored post hoc in patients with preexisting DSAs enrolled to BENEFIT and BENEFIT-EXT. In BENEFIT, preexisting DSAs were detected in 4.6%, 4.9%, and 6.3% of belatacept MI-treated, belatacept LI-treated, and cyclosporine-treated patients, respectively. The corresponding values in BENEFIT-EXT were 6.0%, 5.7%, and 9.2%. In both studies, most preexisting DSAs were of class I specificity. Over the first 24 months posttransplant, a greater proportion of preexisting DSAs in belatacept-treated versus cyclosporine-treated patients exhibited decreases or no change in MFI. MFI decline was more apparent with belatacept MI-based versus belatacept LI-based immunosuppression in both studies and more pronounced in BENEFIT-EXT versus BENEFIT. Although derived post hoc, these data suggest that belatacept-based immunosuppression decreases preexisting DSAs more effectively than cyclosporine-based immunosuppression.

Ten-year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4-weekly or 8-weekly.

In the phase II IM103-100 study, kidney transplant recipients were first randomized to belatacept more-intensive-based (n = 74), belatacept less-intensive-based (n = 71), or cyclosporine-based (n = 73) immunosuppression. At 3-6 months posttransplant, belatacept-treated patients were re-randomized to receive belatacept every 4 weeks (4-weekly, n = 62) or every 8 weeks (8-weekly, n = 60). Patients initially randomized to cyclosporine continued to receive cyclosporine-based immunosuppression. Cumulative rates of biopsy-proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for belatacept more-intensive, belatacept less-intensive, and cyclosporine, respectively (belatacept more-intensive vs cyclosporine: hazard ratio [HR] = 0.95; 95% confidence interval [CI] 0.47-1.92; P = .89; belatacept less-intensive vs cyclosporine: HR = 1.61; 95% CI 0.85-3.05; P = .15). Cumulative BPAR rates from second randomization to year 10 for belatacept 4-weekly, belatacept 8-weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (belatacept 4-weekly vs cyclosporine: HR = 1.06, 95% CI 0.35-3.17, P = .92; belatacept 8-weekly vs cyclosporine: HR = 2.00, 95% CI 0.75-5.35, P = .17). Renal function trends were estimated using a repeated-measures model. Estimated mean GFR values at year 10 for belatacept 4-weekly, belatacept 8-weekly, and cyclosporine were 67.0, 68.7, and 42.7 mL/min per 1.73 m2 , respectively (P<.001 for overall treatment effect). Although not statistically significant, rates of BPAR were 2-fold higher in patients administered belatacept every 8 weeks vs every 4 weeks.

Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study.

In the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), extended criteria donor kidney recipients were randomized to receive belatacept-based (more intense [MI] or less intense [LI]) or cyclosporine-based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent-to-treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 belatacept MI-treated, 138 of 175 belatacept LI-treated and 108 of 184 cyclosporine-treated patients contributed data to these analyses. Hazard ratios (HRs) comparing time to death or graft loss were 0.915 (95% confidence interval [CI] 0.625-1.339; p = 0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI 0.634-1.356; p = 0.70) for belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m2 for belatacept MI, belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or eGFR <20 mL/min per 1.73 m2 were 0.754 (95% CI 0.536-1.061; p = 0.10) for belatacept MI versus cyclosporine and 0.706 (95% CI 0.499-0.998; p = 0.05) for belatacept LI versus cyclosporine. Acute rejection rates and safety profiles of belatacept- and cyclosporine-based treatment were similar. De novo donor-specific antibody incidence was lower for belatacept (p ≤ 0.0001). Relative to cyclosporine, belatacept was associated with similar death and graft loss and improved renal function at 7 years after transplant and had a safety profile consistent with previous reports.

Reduced risk of cytomegalovirus infection in solid organ transplant recipients treated with sirolimus: a pooled analysis of clinical trials.

INTRODUCTION: Cytomegalovirus (CMV) is an opportunistic infection that causes substantial morbidity and mortality in transplant recipients. This pooled analysis of Wyeth clinical trials explored the incidence of CMV infection in solid organ transplant recipients treated with sirolimus versus comparator immunosuppressant drugs. METHODS: Wyeth-conducted, multicenter, randomized, comparative trials with at least one non-sirolimus-containing arm and at least 6 months' complete data were included. Cases of CMV were investigator-identified. The occurrence of CMV in sirolimus-treated patients was assessed versus all other comparator agents, versus antimetabolite agents, and versus calcineurin inhibitors. RESULTS: Nine trials in recipients of renal, liver, and cardiac transplants met the inclusion criteria; eight enrolled de novo allograft recipients, and one was a conversion trial. The primary pooled analysis revealed an odd ratio for CMV infection of 0.64 (95% confidence interval [CI] 0.42 to 1.0, P = .047) on sirolimus versus comparator immunosuppressant drugs. The subanalysis of sirolimus versus antimetabolites showed an odds ratio for CMV of 0.39 (95% CI 0.19 to 0.81, P = .012), and for sirolimus versus calcineurin inhibitors the odds ratio was 0.58 (95% CI 0.34 to 1.01, P = .054). CONCLUSION: This pooled analysis demonstrated a reduced risk of CMV infection among sirolimus-treated patients as compared to those receiving alternative forms of immunosuppression in Wyeth-sponsored clinical trials in solid organ transplantation. This risk reduction persisted in subgroup analyses stratified by class of comparator treatment.

Seizure evolution and amino acid imbalances in murine succinate semialdehyde dehydrogenase (SSADH) deficiency.

Mice with targeted deletion of the GABA catabolic enzyme succinic semialdehyde dehydrogenase (SSADH) manifest lethal tonic-clonic seizures, amenable to pharmacologic rescue, at 3-4 weeks of life. In the current report, we characterized amino acid profiles in SSADH(-/-) brain utilizing whole brain and regional extracts (frontal and parietal cortex, hippocampus, and cerebellum) to develop hypotheses concerning epileptogenesis. Of 35 amino acids quantified, we found significant dysregulation in SSADH(-/-) mice for 11 (GABA, glutamate, glutamine, alanine, aspartate, serine, taurine, cystathionine, methionine, homocarnosine, and arginine) as compared to age-matched littermates both before, and following, the period of generalized convulsive seizures and status epilepticus. Our results reveal imbalanced amino acid levels potentially involved in the transition from absence seizures to generalized convulsive seizures resulting in SSADH(-/-) mice. We conclude that the SSADH(-/-) mouse represents a unique epileptic model with the potential to reveal novel aspects of excitatory/inhibitory interactions in the genesis of seizures.

Processing of grammatical gender in normal and aphasic speakers of Russian.

Sensitivity to grammatical gender was investigated in 22 Russian-speaking aphasic patients, compared with young controls. Experiment 1 used a cued shadowing paradigm to assess gender priming (facilitation and/or inhibition of lexical access by a prenominal modifier with congruent, incongruent or neutral gender). Experiment 2 used a grammaticality judgment paradigm with similar stimuli. Normals showed significant interactions between gender and priming in Experiment 1 (facilitation for feminine and neuter nouns but not for masculines) and Experiment 2 (larger effects of context on feminine and neuter nouns) that we interpret as a Markedness Effect. Patients showed significant priming in Experiment 1 and above-chance accuracy in Experiment 2, but failed to show reduced effects for the least-marked masculine gender (the Markedness Effect) in either experiment. Context effects were not related to specific aphasic symptoms or subtypes in either experiment. However, canonical correlation revealed differential effects of specific aphasic symptoms on judgment accuracy (false alarms vs. misses). We conclude that knowledge of grammatical gender is spared in Russian aphasics, but gender processing is deviant. A possible model to account for these differences is discussed.

Risk factors for hyperlipidemia in long-term pediatric renal transplant recipients.

Hyperlipidemia (HL) is a common problem in adult renal transplant (TP) recipients, contributing to an increased risk of cardiovascular disease and chronic TP nephropathy. There are multiple causes of HL post renal TP in adult patients, including pre TP HL, immunosuppressive agents, renal dysfunction, hypoalbuminemia secondary to nephrotic syndrome, obesity, and conditions that lead to end-stage renal disease (ESRD). We evaluated the incidence and risk factors of HL in 62 pediatric renal TP recipients (15.4+/-4.2 years, range-3.0-22.3 years) with long-term (6.7+/-3.1 years) functioning [glomerular filtration rate (GFR) 66.7+/-23.2 ml/min per 1.73 m(2)] allografts. The mean serum cholesterol (C) level was 205. 5+/-43.6 mg/dl. Thirty-two patients (51.6%) exhibited elevated serum C levels. The mean serum triglyceride (TG) level was 157.3+/-88.4 mg/dl. Serum TG levels were elevated in 32 patients (51.6%). In patients with elevated serum levels of either C or TG, the mean low-density lipoprotein level (LDL) was 138.6+/-44.1 mg/dl (normal <130 mg/dl) and the high-density lipoprotein (HDL) level 54.6+/-15.9 mg/dl (normal>34 mg/dl). Of those patients studied, 45.5% had high LDL levels, whereas 9.1% exhibited low HDL levels. The two risk factors for elevated serum C levels in our patient population were pre-TP HL and increased years since TP. The only risk factor for elevated serum TG levels was reduced GFR. A family history of HL had a significant deleterious impact upon serum levels of C (P=0.01), but did not affect serum TG levels (P=0.7). Years on dialysis prior to TP, history of prior TP, gender, body mass index, and disease leading to ESRD had no influence upon the development of post-TP HL. We conclude that post-renal TP HL is a significant problem in pediatric renal TP recipients.

Identification of an invariant response: stable contact with schwann cells induces veil extension in sensory growth cones.

Growth cones sense cues by filopodial contact, but how their motility is altered by contact remains unclear. Although contact could alter motile dynamics in complex ways, our analysis shows that stable contact with Schwann cells induces motility changes that are remarkably discrete and invariant. Filopodial contact invariably induces local veil extension. Even when contacts are brief, veils always extend before the filopodia retract. Contact at filopodial tips suffices for induction. Moreover, veils extend significantly sooner than on filopodia contacting laminin, which often detach without extending veils. The overall behavioral responses of the growth cone, such as increased area and turning, result from integrating multiple discrete responses. Cycles of veil induction enlarge the growth cone and often lead it onto the cell. Invariant veil induction is abolished by blocking N-cadherin signaling. We propose an axonal guidance model in which different guidance cues act by inducing different but discrete and invariant responses.

Use of calcium-channel blockers in pediatric renal transplant recipients.

Hypertension (HTN) is a significant problem in pediatric renal transplant (TP) recipients, predisposing the individuals to the development of cardiovascular disease and graft dysfunction. Calcium channel blockers (CCB) are considered excellent agents to treat post-TP HTN. We compared the efficacy and adverse effects of the two most commonly prescribed CCBs in our pediatric renal TP population: nifedipine (Procardia, or P) and amlodipine (Norvasc, or N). All patients (n = 24) had been started on a CCB for systolic (SBP) and/or diastolic BP (DBP) > 95%. There were no other changes in adjunctive antihypertensive medications or doses during the cross-over period. Post-TP, pretreatment (pretx) SBP was 137.6 +/- 10.9 mmHg. The post-treatment SBP were (in mmHg): 128.5 +/- 11.9 (all patients, n = 24) (p = 0.009 vs. pretx); 126.4 +/- 10.0 (P alone, n = 15) (p = 0.007 vs. pretx); 132.8 +/- 14.4 (P + other antihypertensive(s), n = 9) (p = 0.331, NS vs. pretx). The post-TP, pretreatment DBP was 88.2 +/- 11.1 mmHg. The post-treatment DBP were (in mmHg): 78.5 +/- 6.9 (all patients, n = 24) (p = 0.03 vs. pretx); 77.2 +/- 7.4 (P alone, n = 15) (p = 0.008 vs. pretx); 80.7 +/- 6.1 (P + other antihypertensive(s), n = 9) (p = 0.063, NS vs. pretx). P and N were equally effective in reducing SBP (p = 0.843, NS) and DBP (p = 0.612, NS). Cyclosporin A (CyA) dose (p = 0.81) and trough levels (p = 0.19) were similar in P- and N-treated patients. Calculated GFR was virtually identical in P- and N-treated patients (p = 0.89). Patients (or parents of) reported a higher incidence of various side-effects while receiving P, including headache, flushing, dizziness and leg cramps. Furthermore, 22/24 (91.7%) reported some degree of gingival hyperplasia during treatment with P, and all these patients reported a stabilization or reduction of hypertrophy after the switch from P to N. We conclude that CCBs (N) are efficacious drugs for the purpose of BP control and renal protection in pediatric renal TP recipients.

Processing of grammatical gender in a three-gender system: experimental evidence from Russian.

Four experiments investigated the effect of grammatical gender on lexical access in Russian. Adjective-noun pairs were presented auditorily, using a cued-shadowing technique in which subjects must repeat the second word (the target noun), following adjectives that are either concordant or discordant with the noun's gender. Experiment 1 demonstrates gender priming with unambiguous adjectives and phonologically transparent masculine or feminine nouns. Experiment 2 examines priming for transparent nouns against a neutral baseline (possible only for feminines and neuters), revealing that priming is due primarily to inhibition from discordant gender. Experiment 3 demonstrates gender priming with phonologically opaque masculine and feminine nouns. Experiment 4 returns to transparent masculine and feminine nouns with a different kind of baseline, using three versions of a single word root (prost--simple, in the feminine adjectival form prostaja, masculine adjectival form prostoj, and the adverbial form prosto), and shows that gender can also facilitate lexical access, at least for feminine nouns. We conclude that Russian listeners can exploit gender agreement cues "on-line," helping them to predict the identity of an upcoming word.

Characteristics of women-only and mixed-gender drug abuse treatment programs.

Specialized substance abuse treatment programs have been developed for women within the past two decades. This article presents the results of a secondary analysis of a regional database of drug abuse treatment programs that compared the characteristics of women-only (WO) and mixed-gender (MG) programs across three treatment modalities. In general, WO programs differed from MG programs in their policies regarding fees, sources of payment, special populations served, services offered, and treatment capacity, process, and duration. The differences in program characteristics reflect broader societal gender differences, including women's generally lower economic status and primary responsibility for child-rearing.

Adverse effects of mycophenolate mofetil in pediatric renal transplant recipients with presumed chronic rejection.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to be superior to azathioprine in reducing the incidence of acute rejection in adult renal transplant recipients. Although MMF is also being widely used in pediatric transplant patients, data documenting its safety are limited. METHODS: A retrospective review of the transplant records at St. Christopher's Hospital for Children was conducted to identify patients who had received MMF. RESULTS: Twenty-four children were switched from azathioprine to MMF, 4.8+/-2.9 years after transplantation. After an additional 0.8+/-0.4 years, MMF had been discontinued in 13 patients (54%) because of adverse effects (AE). The only variable that predicted the development of AE was a lower calculated creatinine clearance at the time of initiation of MMF. CONCLUSIONS: In pediatric renal transplant recipients with impaired renal function, the use of MMF at the recommended dose is associated with an unacceptably high incidence of AE; in such patients, the MMF dose may require modification for the level of renal function.

Matching clients' needs with drug treatment services.

This paper reports results of a study that investigated whether matching drug treatment services with client needs improved outcomes for a sample of 171 clients who participated in community-based drug treatment programs. Clients were initially assessed on multiple problem areas (alcohol use, drug use, medical, psychological, family/social, legal, employment, housing) and on areas of special needs or stated preferences for services (e.g., transportation, child care, language). A 6-month follow-up interview reassessed clients' problems/needs in all areas and collected information on the services received. The results showed that some services significantly improved client outcome for those who had expressed needs for such services. Notably, services meeting the need for vocational training, child care, transportation, and housing showed beneficial effects. A higher level of needs and services matching (defined either by the ratio of services received to services desired, or by the total level of met versus unmet needs in the eight problem areas) significantly predicted longer treatment retention.

Anti-lymphocyte antibodies late in the course of pediatric renal transplantation.

Beyond the immediate post-transplant period, physicians are often reluctant to use anti-lymphocyte preparations to treat episodes of acute renal functional deterioration attributable to acute rejection. This is due to the perception that such episodes are less likely to be reversible, and to concern regarding the potential adverse effects of anti-lymphocyte antibodies, including opportunistic infections, lymphoproliferative disorders, and the development of human anti-mouse antibodies. Records were reviewed for all 365 renal transplants performed in 267 patients at our center from 1971 to 1996. Anti-lymphocyte antibodies were used in an attempt to reverse 6 episodes of corticosteroid-resistant acute rejection in 5 children at a mean interval of 24.5 months following transplantation. The mean serum creatinine at initiation of therapy with the anti-lymphocyte agents was 2.9 mg/dl. Following treatment, the mean serum creatinine decreased to 1.3 mg/dl (P=0.03, Student's t-test). Two patients developed uncomplicated opportunistic infections after completion of anti-lymphocyte therapy; none have developed lymphoproliferative disorders or antibodies to OKT3. We conclude that in the correct clinical setting with corticosteroid-resistant acute rejection, the use of anti-lymphocyte antibodies should not be withheld solely on the basis of length of time since transplantation.

Predictive value of race in post-transplantation recurrence of focal segmental glomerulosclerosis in children.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease (ESRD) in children, and one of the most difficult to manage because of its high recurrence rate post-transplantation (Tx). Several predictive factors have been associated with disease recurrence (DR) although one in particular, the role of recipient race, has not been adequately evaluated. Herein we report our experience with DR in the post-Tx period in eight patients. METHODS: Records were reviewed for all renal transplants performed at St Christopher's Hospital for Children from 1971 to 1997. RESULTS: Twenty patients received 27 allografts for ESRD due to FSGS. Ten (37%) grafts went to African-American (AA) children, and 16 (59%) to those of Caucasian (C) origin. DR was observed in eight (30%) grafts after Tx. No differences were noted between the patients who developed DR and those who did not, with respect to age at diagnosis or time to ESRD. DR was observed in one (10%) of 10 grafts in AA, compared to seven (41%) of 17 grafts in the other (O) racial groups (P=0.19). At last follow-up, the only AA recipient with DR has maintained stable renal function, while three (43%) of seven in O have lost their grafts. CONCLUSION: In conclusion, in our population post-Tx recurrence of FSGS occurred more frequently and represented a greater threat to graft survival in O recipients than in those of AA descent. Recipient race should therefore be taken into consideration during pre-Tx counselling of families of children with FSGS.

Drug-user treatment programs in a large metropolitan area.

This paper discusses the results of a comprehensive survey of one of the largest drug-user treatment systems in the United States--the system in Los Angeles County, California, which contains more than 300 programs, covers over 4,000 square miles, and serves clients from a notably heterogeneous population of almost nine million people. The survey reported on here was distinct from similar surveys in that it provided simultaneously comprehensive and in-depth descriptions of formal treatment programs in a defined local area. The authors believe that this survey is the first local drug-user treatment program survey of its scope and magnitude in the United States.

Predicting drug treatment entry among treatment-seeking individuals.

This study examined factors related to drug treatment program entry among 276 drug abusers seeking treatment referral. Six-month follow-up interviews determined that 171 (62.0%) followed through with the treatment referral. The analyses indicated that treatment-entry and non-entry subjects did not differ in predisposing factors (age, gender, race/ethnicity, education), type of drug use, or years of use. A logistic regression analysis indicated that characteristics at baseline predicting subsequent treatment entry include legal pressure, lower levels of psychological distress and family or social problems, and prior successful treatment experience. Legal coercion was an effective factor promoting treatment entry. Drug abusers having prior successful treatment experience were also more likely to reenter treatment. However, those with more severe problems (drug related and others) seemed less likely to enter treatment, indicating that psychological distress and family problems may undermine motivation to follow through on treatment referral.

Consideration of special populations in the drug treatment system of a large metropolitan area.

This article provides a descriptive overview of the characteristics of a large metropolitan drug treatment system in relation to special populations of substance abusers enrolled in the system and the services provided. The findings are based on self-report responses to a comprehensive survey of 294 drug treatment programs in Los Angeles County. The special populations are grouped by health status, ethnic background, language needs, and gender-related needs. The groups are not mutually exclusive. Survey results indicated a generally high proportion of programs capable of meeting the unique needs of a variety of special population clients and most programs having some mix of special population clients in their current caseload. The types of services offered varied by modality and by special populations being served. Implications for program planning and service delivery include consideration of whether or not to offer specialized programs for unique client types.