Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.

PURPOSE OF REVIEW: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC. RECENT FINDINGS: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis. SUMMARY: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy.

Macrophage Migration Inhibitory Factor (MIF) Makes Complex Contributions to Pain-Related Hyperactivity of Nociceptors after Spinal Cord Injury.

Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms are often assumed to be in the central nervous system, rodent studies have revealed mechanistic contributions from primary nociceptors. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity (OA) that promotes ongoing pain. A major question is whether extrinsic chemical signals help to drive OA after SCI. People living with SCI exhibit acute and chronic elevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models. Probable nociceptors isolated from male rats and exposed to a MIF concentration reported in human plasma (1 ng/ml) showed hyperactivity similar to that induced by SCI, although, surprisingly, a ten-fold higher concentration failed to increase excitability. Conditioned behavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. A MIF inhibitor, Iso-1, reversed SCI-induced hyperexcitability. Unlike after SCI, acute MIF-induced hyperexcitability was only partially abrogated by inhibiting ERK signaling. Unexpectedly, MIF concentrations that induced hyperactivity in nociceptors from Naïve animals, after SCI induced a long-lasting conversion from a highly excitable nonaccommodating type to a rapidly accommodating, hypoexcitable type, possibly as a homeostatic response to prolonged depolarization. Treatment with conditioned medium from cultures of dorsal root ganglion (DRG) cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from Naïve rats. Thus, changes in systemic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain.Significance Statement:Chronic neuropathic pain is a major challenge for people with spinal cord injury (SCI). Pain can drastically impair quality of life, and produces substantial economic and social burdens. Available treatments, including opioids, remain inadequate. This study shows that the cytokine macrophage migration inhibitory factor (MIF) can induce pain-like behavior and plays an important role in driving persistent ongoing electrical activity in injury-detecting sensory neurons (nociceptors) in a rat SCI model. The results indicate that SCI produces an increase in MIF release within sensory ganglia. Low MIF levels potently excite nociceptors, but higher levels trigger a long-lasting hypoexcitable state. These findings suggest that therapeutic targeting of MIF in neuropathic pain states may reduce pain and sensory dysfunction by curbing nociceptor hyperactivity.

3-Dimensional Printed Alternative to the Standard Synthetic Flocked Nasopharyngeal Swabs Used for Coronavirus Disease 2019 Testing.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), can be detected in respiratory samples by real-time reverse transcriptase polymerase chain reaction (RT-PCR) or other molecular methods. Accessibility of diagnostic testing for COVID-19 has been limited by intermittent shortages of supplies required for testing, including flocked nasopharyngeal (FLNP) swabs. METHODS: We developed a 3-dimensional printed nasopharyngeal (3DP) swab as a replacement of the FLNP swab. The performance of 3DP and FLNP swabs were compared in a clinical trial of symptomatic patients at 3 clinical sites (n = 291) using 3 SARS-CoV-2 emergency use authorization tests: a modified version of the Centers for Disease Control and Prevention (CDC) RT-PCR Diagnostic Panel and 2 commercial automated formats, Roche Cobas and NeuMoDx. RESULTS: The cycle threshold-C(t)-values from the gene targets and the RNase P gene control in the CDC assay showed no significant differences between swabs for both gene targets (P = .152 and P = .092), with the RNase P target performing significantly better in the 3DP swabs (P < .001). The C(t) values showed no significant differences between swabs for both viral gene targets in the Roche cobas assay (P = .05 and P = .05) as well as the NeuMoDx assay (P = .401 and P = .484). The overall clinical correlation of COVID-19 diagnosis between all methods was 95.88% (Kappa 0.901). CONCLUSIONS: The 3DP swabs were equivalent to standard FLNP in 3 testing platforms for SARS-CoV-2. Given the need for widespread testing, 3DP swabs printed onsite are an alternate to FLNP that can rapidly scale in response to acute needs when supply chain disruptions affect availability of collection kits.

Effects of Remote Ischemic Conditioning on Hand Engagement in individuals with Spinal cord Injury (RICHES): protocol for a pilot crossover study.

​​​​​​ Background: Most spinal cord injuries (SCI) are not full transections, indicating that residual nerve circuits are retained. Rehabilitation interventions have been shown to beneficially reorganize motor pathways in the brain, corticospinal tract, and at the spinal level. However, rehabilitation training require a large number of repetitions, and intervention effects may be absent or show transient retention. Therefore, the need remains for an effective approach to synergistically improve the amount and duration of neuroplasticity in combination with other interventions. Remote ischemic conditioning (RIC) demonstrates several potential advantages as a candidate for such an approach. Therefore, we propose a protocol to investigate RIC coupled with physical training to promote neuroplasticity in hand muscles. Methods: This will be a prospective randomized-order crossover trial to be performed in eight able-bodied participants and eight participants with chronic cervical SCI. Patients will participate in two experimental sessions consisting of either active or sham RIC preceding a bout of pinch movement exercise. Serial evaluations will be conducted at baseline, after RIC, immediately after pinch exercise, and follow up 15-minutes later. The primary outcome is the change in corticospinal excitability (primarily measured by the motor evoked potential of abductor pollicis brevis muscle). Secondary outcomes will include maximal volitional pinch force, and inflammatory biomarkers. To ensure safety, we will monitor tolerability and hemodynamic responses during RIC. Discussion: This protocol will be the first to test RIC in people with cervical SCI and to investigate whether RIC alters corticospinal excitability. By sharing the details of our protocol, we hope other interested researchers will seek to investigate similar approaches - depending on overlap with the current study and mutual sharing of participant-level data, this could increase the sample size, power, and generalizability of the analysis and results. Trial registration: ClinicalTrial.gov, ID: NCT03851302; Date of registration: February 22, 2019.

Acute Manipulations of Clathrin-Mediated Endocytosis at Presynaptic Nerve Terminals.

Acute perturbations of clathrin and associated proteins at synapses have provided a wealth of knowledge on the molecular mechanisms underlying clathrin-mediated endocytosis (CME). The basic approach entails presynaptic microinjection of an inhibitory reagent targeted to the CME pathway, followed by a detailed ultrastructural analysis to identify how the perturbation affects the number and distribution of synaptic vesicles, plasma membrane, clathrin-coated pits, and clathrin-coated vesicles. This chapter describes the methodology for acutely perturbing CME at the lamprey giant reticulospinal synapse, a model vertebrate synapse that has been instrumental for identifying key protein-protein interactions that regulate CME in presynaptic nerve terminals with broader extension to nonneuronal cell types.

A Review of Robotics in Neurorehabilitation: Towards an Automated Process for Upper Limb.

Robot-mediated neurorehabilitation is a growing field that seeks to incorporate advances in robotics combined with neuroscience and rehabilitation to define new methods for treating problems related with neurological diseases. In this paper, a systematic literature review is conducted to identify the contribution of robotics for upper limb neurorehabilitation, highlighting its relation with the rehabilitation cycle, and to clarify the prospective research directions in the development of more autonomous rehabilitation processes. With this aim, first, a study and definition of a general rehabilitation process are made, and then, it is particularized for the case of neurorehabilitation, identifying the components involved in the cycle and their degree of interaction between them. Next, this generic process is compared with the current literature in robotics focused on upper limb treatment, analyzing which components of this rehabilitation cycle are being investigated. Finally, the challenges and opportunities to obtain more autonomous rehabilitation processes are discussed. In addition, based on this study, a series of technical requirements that should be taken into account when designing and implementing autonomous robotic systems for rehabilitation is presented and discussed.

Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution.

Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ∼500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms.

National survey of Filipinos on acceptance of incentivized organ donation.

BACKGROUND: The increasing number of patients requiring transplantation has brought about a shortage of donor kidneys. Incentives can potentially improve organ donation. There is a need to know if the public can accept incentivized organ donation. OBJECTIVES: To evaluate knowledge and opinions on organ donation and compensating the donor/donor family and to determine factors affecting consent. METHODS: The third survey in 2009 covered 15 regions, 29 provinces, and 14 cities in the National Capital Region. There were 1500 respondents interviewed using a structured questionnaire. Analysis used Statistical Package for Social Science and chi-square. RESULTS: Of the respondents, 63% were females and 74% were married. Nearly half were between 26 and 45 years old. Fewer than 5% were unschooled. Monthly household income was less than USD $222.00 in 70% of respondents. A majority knew about donation from 2001 to 2009. Fewer than 20% knew about deceased donors. Those who wanted to become donors decreased. Sixty-five percent were willing to donate a brain-dead relative's organs. Respondents felt that kidney donors deserve a token of gratitude. Options included livelihood (32%), cash (31%), and educational assistance (26%). Sixty percent wanted the donor assistance termed a "token of gratitude." Consent for donation was positively correlated (P < .05) with higher education and monthly income. CONCLUSION: Awareness on organ transplantation and donation increased. Factors that promote organ donation are higher education and monthly income. A majority of Filipinos felt that the donor deserves a token of gratitude. Public acceptance of incentivized organ donation may be pursued. Strategies to improve the national advocacy campaign for deceased donation are needed.

Safety and efficacy of generic cyclosporine arpimune in Filipino low-risk primary kidney transplant recipients.

BACKGROUND: In the Philippines, maintenance of immunosuppression may not always be affordable, leading to acute rejection and graft loss. The availability of the generic cyclosporine Arpimune could be economically beneficial, but its safety and efficacy should be established. METHODS: This prospective cohort study enrolled 30 renal transplant patients who received Arpimune with mycophenolate/prednisone. Their results were compared up to 6 months with 30 matched control patients who received Neoral during the same period. Areas under the receiver operating characteristic curves (AUC) after intake of Arpimune and therapeutic drug monitoring using cyclosporine levels 2 hours after each dose were done. Pearson correlation was performed to determine linearity of relationship between the generic cyclosporine concentrations and AUC 0-4. Chi-square test was used in obtaining cyclosporine Arpimune concentrations. RESULTS: The abbreviated concentration AUC of Arpimune was similar to that of Neoral, and the 2-hour sampling point (r = 0.813; P < .001) showed the best correlation. Calculated creatinine clearance (mL/min) versus Neoral was 71.36 ± 13 versus 68.03 ± 16.6 (P = .61) at 1 month, 70.4 ± 14.8 versus 64.2 ± 11.4 (P = .12) at 3 months, and 74.02 ± 15.8 versus 62.03 ± 12.1 (P = .002) at 6 months. Two Arpimune versus 4 Neoral patients (P = .67) developed biopsy-proven acute rejection. One septic death occurred in the Arpimune group. Graft survival was 100% in both groups. Hyperlipidemia was the most frequent side effect for both. CONCLUSIONS: The AUC of Arpimune was similar to that of Neoral. Use of the generic cyclosporine Arpimune provided effective immunosuppression in the 6 months after transplantation. Renal allograft function was similar to that of Neoral, with minimal rates of acute rejection and adverse events.

Regeneration in the era of functional genomics and gene network analysis.

What gives an organism the ability to regrow tissues and to recover function where another organism fails is the central problem of regenerative biology. The challenge is to describe the mechanisms of regeneration at the molecular level, delivering detailed insights into the many components that are cross-regulated. In other words, a broad, yet deep dissection of the system-wide network of molecular interactions is needed. Functional genomics has been used to elucidate gene regulatory networks (GRNs) in developing tissues, which, like regeneration, are complex systems. Therefore, we reason that the GRN approach, aided by next generation technologies, can also be applied to study the molecular mechanisms underlying the complex functions of regeneration. We ask what characteristics a model system must have to support a GRN analysis. Our discussion focuses on regeneration in the central nervous system, where loss of function has particularly devastating consequences for an organism. We examine a cohort of cells conserved across all vertebrates, the reticulospinal (RS) neurons, which lend themselves well to experimental manipulations. In the lamprey, a jawless vertebrate, there are giant RS neurons whose large size and ability to regenerate make them particularly suited for a GRN analysis. Adding to their value, a distinct subset of lamprey RS neurons reproducibly fail to regenerate, presenting an opportunity for side-by-side comparison of gene networks that promote or inhibit regeneration. Thus, determining the GRN for regeneration in RS neurons will provide a mechanistic understanding of the fundamental cues that lead to success or failure to regenerate.

Development and in vitro studies of a polyethylene terephthalate-gold nanoparticle scaffold for improved biocompatibility.

Polyethylene terephthalate (PET) mesh is one of the most commonly used synthetic biomaterials for tension-free hernia repair. In an effort to improve the biocompatibility of PET mesh, gold nanoparticles (AuNP) in various concentrations were conjugated to the PET surface to develop PET-AuNP scaffolds. These novel scaffolds were characterized with Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) to assess the addition of functional groups, presence of AuNPs, and thermal stability of the modified PET mesh, respectively. The biocompatibility of the PET-AuNP scaffolds was evaluated through in vitro cell culture assays. The cellularity of cells exposed to the PET-AuNP scaffolds, as well as the scaffolds' ability to reduce reactive oxygen species, was assessed using L929 murine fibroblasts. Antimicrobial properties of AuNPs conjugated to PET mesh were tested against the bacteria Pseudomonas aeruginosa. Results from the FT-IR showed presence of COOH groups while SEM displayed bonding of AuNPs to the PET surface. DSC results indicated that the PET more than likely did not undergo any detrimental degradation due to the surface modification. Results from the in vitro studies showed that AuNPs, in optimal concentrations (1× concentrations), enhanced cellularity, reduced ROS, and reduced bacteria adhesion to PET. These studies demonstrated enhanced biocompatibility of the AuNP conjugated PET mesh over pristine PET mesh.

Membrane trafficking events underlying axon repair, growth, and regeneration.

Two central challenges for the field of neurobiology are to understand how axons grow and make proper synaptic connections under normal conditions and how they repair their membranes and mount regenerative responses after injury. At the most reductionist level, the first step toward addressing these challenges is to delineate the cellular and molecular processes by which an axon extends from its cell body. Underlying axon extension are questions of appropriate timing and mechanisms that establish or maintain the axon's polarity, initiate growth cone formation, and promote axon outgrowth and synapse formation. After injury, the problem is even more complicated because the neuron must also repair its damaged membrane, redistribute or manufacture what it needs in order to survive, and grow and form new synapses within a more mature, complex environment. While other reviews have focused extensively on the signaling events and cytoskeletal rearrangements that support axon outgrowth and regeneration, we focus this review instead on the underlying membrane trafficking events underlying these processes. Though the mechanisms are still under active investigation, the key roles played by membrane trafficking events during axon repair, growth, and regeneration have been elucidated through elegant comparative studies in both invertebrate and vertebrate organisms. Taken together, a model emerges indicating that the critical requirements for ensuring proper membrane sealing and axon extension include iterative bouts of SNARE mediated exocytosis, endocytosis, and functional links between vesicles and the actin cytoskeleton, similar to the mechanisms utilized during synaptic transmission. This article is part of a Special Issue entitled 'Neuronal Function'.

A national program toward improving renal health: advancing organ donation awareness.

BACKGROUND: Despite the national advocacy campaign for kidney transplantation from deceased donors in the Philippines 96% of kidneys transplanted into 721 kidney transplants from 1999 to 2001 came from living donors. A national survey on the knowledge, attitudes and perceptions of Filipinos on organ donation in 2001 showed factors that disadvantaged deceased organ donation to be poor understanding of "brain death," religion, and fear of the operation. These concerns were addressed and another survey was conducted in 2005. OBJECTIVES: To compare knowledge, attitudes, and perceptions of Filipinos on organ donation between 2001 and 2005, and compare the number of kidney transplants from deceased donors between 2001 until 2008. METHODS: Two surveys in 15 regions of the Philippines were conducted using multistage sampling. Using a structured questionnaire there were 2000 respondents in 2001, and 2140 in 2005. Analysis was performed using chi-square analysis. RESULTS: The majority of respondents knew about kidney donation. Between 2001 and 2005, there was increased awareness that transplants came from both living and deceased donors (37% to 41%) and a decline in those believing transplants came only from deceased donors (14% to 9%). Willingness to become a living (59% to 87%) or a deceased donor (35% to 49%) increased. The increase in transplantation from deceased donors from an average of 10 per year from 1999 to 2001 to 31 per year from 2006 to 2008. CONCLUSION: Increased awareness about kidney donation among Filipinos, improved consent to become an organ donor, and an increase in kidney transplantation from deceased donors occurred from 2001 to 2008.

A national program for nondirected kidney donation from living unrelated donors: the Philippine experience.

OBJECTIVES: The objectives of this study are to describe the mechanism of the program and to present initial donor outcome. METHODS: This is a descriptive study evaluating the performance of a national program for nondirected kidney donation from living unrelated donors (LURDs) in the Philippines in its 3-year implementation. It explains the mechanism of the program and socioeconomic and clinical profiling of donors. Frequencies and percentages were used to measure donor demographic data, medical follow-up compliance rate, and employment predonation and postdonation. Diagnostic laboratory criteria were required to show donor clinical profiles. RESULTS: In 2002, the local Health Department issued an administrative order to create a National Transplant Ethics Committee (NTEC) to address issues of rampant organ sale and donor exploitation. It also set guidelines and intended to oversee transplantation from LURDs. Salient points to the program are as follows: (1) prohibition of sale; (2) accreditation of transplantation centers; (3) enrollment of waitlisted patients in both deceased donor and nondirected LURD program; (4) ethics committee evaluation of LURDs; (5) creation of a national kidney transplant wait list and live donor registry allowing centralized, nondirected kidney allocation; (6) 10% cap on allocation to foreigners; (7) creation of a kidney donor monitoring unit with free 10-year annual medical follow-up for feedback evaluation on donor outcome; and (8) allowance of gratitudinal gifts such as health and life insurance, reimbursement for lost income, educational plan, and job placement to LURDs run by a foundation. From 2004 to 2006, 695 potential donors enrolled; 97 were accepted and deemed medically fit to donate. The remaining 598 were rejected due to demand for outright sale (103), medical unsuitability (77), disapproval by the Ethics Committee (12), and retracted consent (406). Of the 97 qualified donors, 79 had donated, 9 were being evaluated, and 9 await allocation at the end of 2006. Donor demographics show the following: 54% (381) single, 77% (538) males, and 70% (488) aged 21-40 years old. Sixty-eight of 79 became small-scale entrepreneurs postdonation. Also, 53% (42 of 79) complied with medical follow-up requirements. Mean serum creatinine level at 6 months, 1 years, and 2 years were 1.3, 1.33, and 1.05 mg/dL, respectively. Two donors had trace protein and 1 had (+1) protein. DISCUSSION AND CONCLUSIONS: The majority of the donors are single males, aged 21-40 years with blue collar jobs. Major reasons for dropouts are retracted consent and medical unsuitability. Donors have improved socioeconomic status. In this study, 53% complied with expected medical follow-up, showing mean serum creatinine within normal range. Proteinuria appeared in 2 of 79 donors. This regulated approach provides a rational, accessible, and equitable donor allocation program. It safeguards the rights of donors and avoids donor exploitation and proliferation of unregulated organ sale. Data collection on their postoperative renal function will show long-term outcome of kidney donation from live donors.

Efficacy of risk stratification in tailoring immunosuppression regimens in kidney transplant patients at the national kidney and transplant institute.

OBJECTIVES: To evaluate the efficacy of tailored immunosuppressive regimens prescribed according to a risk stratification scoring system based on the number of HLA mismatches, donor source, panel-reactive antibodies (PRA), and repeat transplant. METHODS: Patients in a retrospective cohort of 329 kidney transplantations performed from October 2004 to December 2005 were assigned scores of 0, 2, 4, or 6 with higher scores for > or =1 HLA mismatches, PRA > 10%, repeat transplant, and unrelated or deceased donor. Added scores of < or =4 comprised the low-risk group who received a Calcineurin inhibitor (CNI)-based regimen without induction, whereas a score > or = 6 denoted high risk including a CNI-based regimen with an interleukin-2 receptor antibody. The efficacy analysis compared the incidences of biopsy-proven acute rejection episodes (BPAR) at 1 year. RESULTS: Only 227 (69%) of 329 patients had a complete data set and 84 were excluded because they did not follow the prescribed protocol, yielding 113 low- and 30 high-risk patients in the final population. Low-risk patients had a mean PRA of 5.4%, living related donors in 68%, and primary transplants. High-risk patients had a mean PRA of 18.8% (range = 10%-97%), living nonrelated donors in 84%, four deceased donors, and four repeat transplants. The overall 1-year incidence of BPAR was 5.7%. No significant difference (P = .081) was observed in 1-year BPAR between the low- (4.5%) and high-risk (9.8%) groups. Likewise, no significant difference in the 1-year mean serum creatinine was observed according to the CNI. The mean creatinine was 1.12 for cyclosporine and 1.38 for tacrolimus treatment (P = .06) in the low-risk group and 1.08 for cyclosporine and 1.2 for tacrolimus (P = .61) in the high-risk cohort. CONCLUSION: There was no significant difference in acute rejection rates between the immunologically low- or high-risk patients using tailored immunosuppression, which was effective to minimize its occurrence with good renal function at 1 year.

Everolimus with reduced-dose cyclosporine in de novo renal transplant recipients: Philippine experience.

OBJECTIVE: The objective of this study was to describe the appropriate dose of everolimus to achieve target trough concentrations in standard-risk Filipino kidney transplant recipients. METHODOLOGY: We reviewed all kidney transplant recipients from December 1, 2006 to June 15, 2007 who were given everolimus (1.5 mg/d) in combination with low-dose cyclosporine (5 mg/kg/d) and prednisone but without induction therapy for their immunosuppressive doses, trough levels, as well as hematologic and blood chemistry profiles. Target everolimus trough concentration was 3-8 ng/mL and C2 level was 1000-1400 ng/mL for the first 3 months. RESULTS: Among 148 patients who underwent transplantation during the study period, 26 comprised the study population but only 15 patients completed the 3-month follow-up and are the subject of this report. Their mean age was 33 years, average PRA 2%, and mean HLA mismatches 3. All were from living donors. At 7 days posttransplantation, all patients achieved or exceeded the target everolimus trough and cyclosporine C2 level. At 1 and 3 months posttransplantation the mean everolimus dose was 1.17 and 0.78 mg/d, respectively, whereas the cyclosporine dose was 195 and 148 mg/d, respectively. Three patients showed elevated alanine aminotransferase (ALT) and all patients had hypercholesterolemia after 1 month, which improved with everolimus dose reduction (half required statins). One patient experienced a Banff Grade IA acute rejection episode at 2 months posttransplantation with a serum creatinine value of 2 mg/dL after steroid pulsing. CONCLUSIONS: Most standard-risk Filipino kidney transplant recipients required a maintenance everolimus dose of 1 mg/d at 1 month. The cyclosporine dose requirement was also lower. A larger sample size is needed to provide a level of significance compared with other populations.

Rituximab in highly sensitized kidney transplant recipients.

OBJECTIVES: Rituximab, an anti-CD20 monoclonal antibody therapy, depletes B cells and suppresses antibody production. This study sought to describe the efficacy and safety of rituximab among seven highly sensitized kidney transplant patients. METHODOLOGY: A highly sensitized patient was defined as panel-reactive antibody (PRA) >30%, more than three pregnancies, or history of positive tissue crossmatch. Demographics, immunological risk profile, and immunosuppression were collected on all highly sensitized patients transplanted from March to July 2007 and given rituximab. We noted graft function as well as clinical events posttransplantation. RESULTS: The seven patients included in the study showed a mean age of 39 years (range = 17-60) and a mean follow-up of 3 months (range = 1.5-5). Their average PRA was 62% with mean HLA mismatches of three. Five patients (71%) were retransplantations; one had a history of a positive crossmatch, and two had multiple pregnancies. Two had donor-specific antibody, but negative tissue crossmatches. All had living donors. Six patients received a single dose of rituximab (375 mg/m2) 1 day prior to transplantation and one received two doses after 19 sessions of plasmapheresis. All were given tacrolimus, mycophenolate, and steroids combined with induction therapy using 30 mg alemtuzumab in 33%; two doses of 20 mg basiliximab in 33%; and seven doses of 1 mg/kg/dose of daclizumab in 14%. Mean shown creatinine levels were 1.1 and 1.2 mg/dL at 1 and 6 months posttransplantation. Two recipients experienced acute humoral rejections within 1 month after transplantation. Both were given steroid pulsing, one of whom was steroid-resistant necessitating alemtuzumab therapy and plasmapheresis. Graft function of both improved with creatinine values of 1.3 mg/dL on discharge. No episodes of infection were noted. CONCLUSIONS: Rituximab can be safely administered and may be effective to improve outcomes among highly sensitized kidney transplant patients.

Alemtuzumab induction with tacrolimus monotherapy in de novo renal transplantation.

OBJECTIVES: Alemtuzumab is increasingly being used as induction therapy for kidney transplantation, allowing immunosuppression minimization. This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients. METHODS: This retrospective cohort of primary standard risk renal transplant recipients were given alemtuzumab induction and low-dose tacrolimus maintenance immunosuppression (target trough 7 to 10 ng/mL for the first 6 months and 5 to 7 ng/mL thereafter). Serum creatinine values, acute rejection episodes, and graft survival were noted at week 1 as well as months 3, 6, 12, and 18. RESULTS: At the time of analysis, 47 patients were at 6 months, 28 at 12 months, and 6 patients at 18 months from transplant. Mean follow-up was 12.53 months (range, 6 to 23). Mean serum creatinine was 1.47 +/- 0.65 mg/dL at 3 months, 1.56 +/- 0.84 at 6 months, 1.45 +/- 0.37 at 12 months, and 1.74 +/- 0.35 at 18 months. The 1-year clinical acute rejection rate was 21% (6/28), occurring at 0 to 3 months in 2 (33%), 4 to 6 months in 1 (17%), and >6 months in 3 patients (50%). Biopsy-proven acute rejection was 14% (4/28). The episodes were classified as borderline in one, Banff 2A in two, and Banff 3 in one patients. One patient had both acute cellular and acute humoral rejection; half responded to steroid pulse therapy. The 1-year patient survival rate was 90%. The 1-year death-censored graft survival rate was 98%. CONCLUSION: Alemtuzumab induction with tacrolimus monotherapy is an acceptable option in standard risk patients. BPAR was 14%, but renal function remained satisfactory at 18 months posttransplant.

Use of alemtuzumab (Campath-1H) as induction therapy in pediatric kidney transplantation.

Alemtuzumab (Campath-1H) is a monoclonal antibody directed against CD52-positive B and T lymphocytes. Initial results of its use as an induction agent in adult renal transplantation have been encouraging. We report a case series of four low-risk pediatric renal transplantation patients who received 20 to 40 mg of alemtuzumab as induction followed by a steroid-free regimen consisting of a calcineurin inhibitor and mycophenolate mofetil. No infusion-related reactions occurred. Patients were aged 9 to 14 years with a mean creatinine of 1.2 mg/dL (range = 0.5-2.3 mg/dL) at a mean follow-up of 10 months (range = 4-16 months). One patient experienced biopsy-proven acute cellular rejections at 4 and 12 months posttransplantation, which were steroid sensitive. Lymphopenia post-alemtuzumab induction started to improve at 3 months posttransplantation. Two patients who received 40 mg of alemtuzumab experienced repeated infections that responded to 7-day courses of antibiotics. There was no cytomegalovirus disease detected. From these preliminary results, alemtuzumab seems to show a promising role to achieve adequate graft function with a steroid-free regimen among low-risk pediatric patients.