Flaxseed Oil (Linum usitatissimum) Prevents Cognitive and Motor Damage in Rats with Hyperammonemia.

Hyperammonemia is characterized by the excessive accumulation of ammonia in the body as a result of the loss of liver detoxification, leading to the development of hepatic encephalopathy (HE). These metabolic alterations carry cognitive and motor deficits and cause neuronal damage, with no effective treatment at present. In this study, we aimed to evaluate the effect of two subacute oral administrations of flaxseed oil (0.26 and 0.52 mL/kg) on short- and long-term memory, visuospatial memory, locomotor activity, motor coordination, and the neuronal morphology of the prefrontal cortex (PFC) via tests on Wistar rats with hyperammonemia. The goal was to identify its role in the regulation of cerebral edema, without liver damage causing cerebral failure. In contrast with an ammonium-rich diet, flaxseed oil and normal foods did not cause cognitive impairment or motor alterations, as evidenced in the short-term and visuospatial memory tests. Furthermore, the flaxseed oil treatment maintained a regular neuronal morphology of the prefrontal cortex, which represents a neuroprotective effect. We conclude that the oral administration of flaxseed oil prevents cognitive and motor impairments as well as neuronal alterations in rats with hyperammonemia, which supports the potential use of this oil to ameliorate the changes that occur in hepatic encephalopathy.

Transcriptomic Profiling Reveals Intense Host-Pathogen Dispute Compromising Homeostasis during Acute Rift Valley Fever Virus Infection.

Rift Valley fever virus (RVFV) (family Phenuiviridae) can cause severe disease, and outbreaks of this mosquito-borne pathogen pose a significant threat to public and animal health. Yet many molecular aspects of RVFV pathogenesis remain incompletely understood. Natural RVFV infections are acute, characterized by a rapid onset of peak viremia during the first days post-infection, followed by a rapid decline. Although in vitro studies identified a major role of interferon (IFN) responses in counteracting the infection, a comprehensive overview of the specific host factors that play a role in RVFV pathogenesis in vivo is still lacking. Here, the host in vivo transcriptional profiles in the liver and spleen tissues of lambs exposed to RVFV are studied using RNA sequencing (RNA-seq) technology. We validate that IFN-mediated pathways are robustly activated in response to infection. We also link the observed hepatocellular necrosis with severely compromised organ function, which is reflected as a marked downregulation of multiple metabolic enzymes essential for homeostasis. Furthermore, we associate the elevated basal expression of LRP1 in the liver with RVFV tissue tropism. Collectively, the results of this study deepen the knowledge of the in vivo host response during RVFV infection and reveal new insights into the gene regulation networks underlying pathogenesis in a natural host. IMPORTANCE Rift Valley fever virus (RVFV) is a mosquito-transmitted pathogen capable of causing severe disease in animals and humans. Outbreaks of RVFV pose a significant threat to public health and can result in substantial economic losses. Little is known about the molecular basis of RVFV pathogenesis in vivo, particularly in its natural hosts. We employed RNA-seq technology to investigate genome-wide host responses in the liver and spleen of lambs during acute RVFV infection. We show that RVFV infection drastically decreases the expression of metabolic enzymes, which impairs normal liver function. Moreover, we highlight that basal expression levels of the host factor LRP1 may be a determinant of RVFV tissue tropism. This study links the typical pathological phenotype induced by RVFV infection with tissue-specific gene expression profiles, thereby improving our understanding of RVFV pathogenesis.

Perspectives of Next-Generation Live-Attenuated Rift Valley Fever Vaccines for Animal and Human Use.

Live-attenuated Rift Valley fever (RVF) vaccines transiently replicate in the vaccinated host, thereby effectively initiating an innate and adaptive immune response. Rift Valley fever virus (RVFV)-specific neutralizing antibodies are considered the main correlate of protection. Vaccination with classical live-attenuated RVF vaccines during gestation in livestock has been associated with fetal malformations, stillbirths, and fetal demise. Facilitated by an increased understanding of the RVFV infection and replication cycle and availability of reverse genetics systems, novel rationally-designed live-attenuated candidate RVF vaccines with improved safety profiles have been developed. Several of these experimental vaccines are currently advancing beyond the proof-of-concept phase and are being evaluated for application in both animals and humans. We here provide perspectives on some of these next-generation live-attenuated RVF vaccines and highlight the opportunities and challenges of these approaches to improve global health.

Incomplete bunyavirus particles can cooperatively support virus infection and spread.

Bunyaviruses lack a specific mechanism to ensure the incorporation of a complete set of genome segments into each virion, explaining the generation of incomplete virus particles lacking one or more genome segments. Such incomplete virus particles, which may represent the majority of particles produced, are generally considered to interfere with virus infection and spread. Using the three-segmented arthropod-borne Rift Valley fever virus as a model bunyavirus, we here show that two distinct incomplete virus particle populations unable to spread autonomously are able to efficiently complement each other in both mammalian and insect cells following co-infection. We further show that complementing incomplete virus particles can co-infect mosquitoes, resulting in the reconstitution of infectious virus that is able to disseminate to the mosquito salivary glands. Computational models of infection dynamics predict that incomplete virus particles can positively impact virus spread over a wide range of conditions, with the strongest effect at intermediate multiplicities of infection. Our findings suggest that incomplete particles may play a significant role in within-host spread and between-host transmission, reminiscent of the infection cycle of multipartite viruses.

Impacts of El Niño Southern Oscillation on the dengue transmission dynamics in the Metropolitan Region of Recife, Brazil.

BACKGROUND: This research addresses two questions: (1) how El Niño Southern Oscillation (ENSO) affects climate variability and how it influences dengue transmission in the Metropolitan Region of Recife (MRR), and (2) whether the epidemic in MRR municipalities has any connection and synchronicity. METHODS: Wavelet analysis and cross-correlation were applied to characterize seasonality, multiyear cycles, and relative delays between the series. This study was developed into two distinct periods. Initially, we performed periodic dengue incidence and intercity epidemic synchronism analyses from 2001 to 2017. We then defined the period from 2001 to 2016 to analyze the periodicity of climatic variables and their coherence with dengue incidence. RESULTS: Our results showed systematic cycles of 3-4 years with a recent shortening trend of 2-3 years. Climatic variability, such as positive anomalous temperatures and reduced rainfall due to changes in sea surface temperature (SST), is partially linked to the changing epidemiology of the disease, as this condition provides suitable environments for the Aedes aegypti lifecycle. CONCLUSION: ENSO may have influenced the dengue temporal patterns in the MRR, transiently reducing its main way of multiyear variability (3-4 years) to 2-3 years. Furthermore, when the epidemic coincided with El Niño years, it spread regionally and was highly synchronized.

Impacts of El Niño Southern Oscillation on the dengue transmission dynamics in the Metropolitan Region of Recife, Brazil

ABSTRACT Background: This research addresses two questions: (1) how El Niño Southern Oscillation (ENSO) affects climate variability and how it influences dengue transmission in the Metropolitan Region of Recife (MRR), and (2) whether the epidemic in MRR municipalities has any connection and synchronicity. Methods: Wavelet analysis and cross-correlation were applied to characterize seasonality, multiyear cycles, and relative delays between the series. This study was developed into two distinct periods. Initially, we performed periodic dengue incidence and intercity epidemic synchronism analyses from 2001 to 2017. We then defined the period from 2001 to 2016 to analyze the periodicity of climatic variables and their coherence with dengue incidence. Results: Our results showed systematic cycles of 3-4 years with a recent shortening trend of 2-3 years. Climatic variability, such as positive anomalous temperatures and reduced rainfall due to changes in sea surface temperature (SST), is partially linked to the changing epidemiology of the disease, as this condition provides suitable environments for the Aedes aegypti lifecycle. Conclusion: ENSO may have influenced the dengue temporal patterns in the MRR, transiently reducing its main way of multiyear variability (3-4 years) to 2-3 years. Furthermore, when the epidemic coincided with El Niño years, it spread regionally and was highly synchronized.

Comparison of Neutralizing Dengue Virus B Cell Epitopes and Protective T Cell Epitopes With Those in Three Main Dengue Virus Vaccines.

The four serotypes of Dengue virus (DENV1-4) are arboviruses (arthropod-borne viruses) that belong to the Flavivirus genus, Flaviviridae family. They are the causative agents of an infectious disease called dengue, an important global public health problem with significant social-economic impact. Thus, the development of safe and effective dengue vaccines is a priority according to the World Health Organization. Only one anti-dengue vaccine has already been licensed in endemic countries and two formulations are under phase III clinical trials. In this study, we aimed to compare the main anti-dengue virus vaccines, DENGVAXIA®, LAV-TDV, and TAK-003, regarding their antigens and potential to protect. We studied the conservation of both, B and T cell epitopes involved in immunological control of DENV infection along with vaccine viruses and viral isolates. In addition, we assessed the population coverage of epitope sets contained in each vaccine formulation with regard to different human populations. As main results, we found that all three vaccines contain the main B cell epitopes involved in viral neutralization. Similarly, LAV-TDV and TAK-003 contain most of T cell epitopes involved in immunological protection, a finding not observed in DENGVAXIA®, which explains main limitations of the only licensed dengue vaccine. In summary, the levels of presence and absence of epitopes that are target for protective immune response in the three main anti-dengue virus vaccines are shown in this study. Our results suggest that investing in vaccines that contain the majority of epitopes involved in protective immunity (cellular and humoral arms) is an important issue to be considered.

Visualizing the ribonucleoprotein content of single bunyavirus virions reveals more efficient genome packaging in the arthropod host.

Bunyaviruses have a genome that is divided over multiple segments. Genome segmentation complicates the generation of progeny virus, since each newly formed virus particle should preferably contain a full set of genome segments in order to disseminate efficiently within and between hosts. Here, we combine immunofluorescence and fluorescence in situ hybridization techniques to simultaneously visualize bunyavirus progeny virions and their genomic content at single-molecule resolution in the context of singly infected cells. Using Rift Valley fever virus and Schmallenberg virus as prototype tri-segmented bunyaviruses, we show that bunyavirus genome packaging is influenced by the intracellular viral genome content of individual cells, which results in greatly variable packaging efficiencies within a cell population. We further show that bunyavirus genome packaging is more efficient in insect cells compared to mammalian cells and provide new insights on the possibility that incomplete particles may contribute to bunyavirus spread as well.

Comparison of neutralizing dengue virus B cell epitopes and protective T cell epitopes with those in three main dengue virus vaccines

The four serotypes of Dengue virus (DENV1-4) are arboviruses (arthropod-borne viruses) that belong to the Flavivirus genus, Flaviviridae family. They are the causative agents of an infectious disease called dengue, an important global public health problem with significant social-economic impact. Thus, the development of safe and effective dengue vaccines is a priority according to the World Health Organization. Only one anti-dengue vaccine has already been licensed in endemic countries and two formulations are under phase III clinical trials. In this study, we aimed to compare the main anti-dengue virus vaccines, DENGVAXIA®, LAV-TDV, and TAK-003, regarding their antigens and potential to protect. We studied the conservation of both, B and T cell epitopes involved in immunological control of DENV infection along with vaccine viruses and viral isolates. In addition, we assessed the population coverage of epitope sets contained in each vaccine formulation with regard to different human populations. As main results, we found that all three vaccines contain the main B cell epitopes involved in viral neutralization. Similarly, LAV-TDV and TAK-003 contain most of T cell epitopes involved in immunological protection, a finding not observed in DENGVAXIA®, which explains main limitations of the only licensed dengue vaccine. In summary, the levels of presence and absence of epitopes that are target for protective immune response in the three main anti-dengue virus vaccines are shown in this study. Our results suggest that investing in vaccines that contain the majority of epitopes involved in protective immunity (cellular and humoral arms) is an important issue to be considered.

Anti-dengue Vaccines: From Development to Clinical Trials.

Dengue Virus (DENV) is an arbovirus (arthropod-borne virus). Four serotypes of DENV are responsible for the infectious disease called dengue that annually affects nearly 400 million people worldwide. Although there is only one vaccine formulation licensed for use in humans, there are other vaccine formulations under development that apply different strategies. In this review, we present information about anti-dengue vaccine formulations regarding development, pre-clinical tests, and clinical trials. The improvement in vaccine development against dengue is much needed, but it should be considered that the correlate of protection is still uncertain. Neutralizing antibodies have been proposed as a correlate of protection, but this ignores the key role of T-cell mediated immunity in controlling DENV infection. It is important to confirm the accurate correlate of protection against DENV infection, and also to have other anti-dengue vaccine formulations licensed for use.

Multimeric single-domain antibody complexes protect against bunyavirus infections.

The World Health Organization has included three bunyaviruses posing an increasing threat to human health on the Blueprint list of viruses likely to cause major epidemics and for which no, or insufficient countermeasures exist. Here, we describe a broadly applicable strategy, based on llama-derived single-domain antibodies (VHHs), for the development of bunyavirus biotherapeutics. The method was validated using the zoonotic Rift Valley fever virus (RVFV) and Schmallenberg virus (SBV), an emerging pathogen of ruminants, as model pathogens. VHH building blocks were assembled into highly potent neutralizing complexes using bacterial superglue technology. The multimeric complexes were shown to reduce and prevent virus-induced morbidity and mortality in mice upon prophylactic administration. Bispecific molecules engineered to present two different VHHs fused to an Fc domain were further shown to be effective upon therapeutic administration. The presented VHH-based technology holds great promise for the development of bunyavirus antiviral therapies.

History of Envenoming Therapy and Current Perspectives.

Each year, millions of humans fall victim to animal envenomings, which may either be deadly or cause permanent disability to the effected individuals. The Nobel Prize-winning discovery of serum therapy for the treatment of bacterial infections (tetanus and diphtheria) paved the way for the introduction of antivenom therapies for envenomings caused by venomous animals. These antivenoms are based on polyclonal antibodies derived from the plasma of hyperimmunized animals and remain the only specific treatment against animal envenomings. Following the initial development of serum therapy for snakebite envenoming by French scientists in 1894, other countries with high incidences of animal envenomings, including Brazil, Australia, South Africa, Costa Rica, and Mexico, started taking up antivenom production against local venomous animals over the course of the twentieth century. These undertakings revolutionized envenoming therapy and have saved innumerous patients worldwide during the last 100 years. This review describes in detail the above-mentioned historical events surrounding the discovery and the application of serum therapy for envenomings, as well as it provides an overview of important developments and scientific breakthroughs that were of importance for antibody-based therapies in general. This begins with discoveries concerning the characterization of antibodies, including the events leading up to the elucidation of the antibody structure. These discoveries further paved the way for other milestones in antibody-based therapies, such as the introduction of hybridoma technology in 1975. Hybridoma technology enabled the expression and isolation of monoclonal antibodies, which in turn formed the basis for the development of phage display technology and transgenic mice, which can be harnessed to directly obtain fully human monoclonal antibodies. These developments were driven by the ultimate goal of producing potent neutralizing monoclonal antibodies with optimal pharmacokinetic properties and low immunogenicity. This review then provides an outline of the most recent achievements in antivenom research, which include the application of new biotechnologies, the development of the first human monoclonal antibodies that can neutralize animal toxins, and efforts toward creating fully recombinant antivenoms. Lastly, future perspectives in the field of envenoming therapies are discussed, including rational engineering of antibody cross-reactivity and the use of oligoclonal antibody mixtures.

Innovative Immunization Strategies for Antivenom Development.

Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with antivenom. Current antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation antivenoms.

Pros and cons of different therapeutic antibody formats for recombinant antivenom development.

Antibody technologies are being increasingly applied in the field of toxinology. Fuelled by the many advances in immunology, synthetic biology, and antibody research, different approaches and antibody formats are being investigated for the ability to neutralize animal toxins. These different molecular formats each have their own therapeutic characteristics. In this review, we provide an overview of the advances made in the development of toxin-targeting antibodies, and discuss the benefits and drawbacks of different antibody formats in relation to their ability to neutralize toxins, pharmacokinetic features, propensity to cause adverse reactions, formulation, and expression for research and development (R&D) purposes and large-scale manufacturing. A research trend seems to be emerging towards the use of human antibody formats as well as camelid heavy-domain antibody fragments due to their compatibility with the human immune system, beneficial therapeutic properties, and the ability to manufacture these molecules cost-effectively.

Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients.

Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4+CD25hiCD127lo/-FOXP3+ T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA+ "naïve" Tregs, while the expression of Helios, a marker used to identify stable FOXP3+ thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008.

Pretransplant angiotensin II type 1-receptor antibodies are a risk factor for earlier detection of de novo HLA donor-specific antibodies.

BACKGROUND: Angiotensin II type 1 receptor antibodies (AT1Rabs) have been associated with significantly reduced graft survival. Earlier graft loss has been observed in patients who had pretransplant AT1Rabs and posttransplant donor-specific antibodies (DSA). METHODS: The main goal of this retrospective cohort study was to examine the association between AT1Rabs and the time period to detection of de novo human leukocyte antigen (HLA-DSA) posttransplantation in living donor kidney transplant recipients (KTR). The analysis included 141 KTRs. Pretransplant frozen serum samples were tested for AT1Rabs by ELISA and HLA-DSA by SAB (Luminex) at both the pre- and post-KT time points. RESULTS: The median AT1Rab level was 9.13 U (interquartile range 5.22-14.33). After a mean follow-up period of 3.55 years, 48 patients were found to harbour de novo HLA-DSAs. The presence of AT1Rabs [hazard ratio (HR) 1.009, 95% confidence interval (CI) 1.002-1.01, P = 0.010], male-to-male transplantation (HR 2.57, 95% CI 1.42-4.67, P = 0.002) and antecedent borderline changes or acute cellular rejection (ACR) (HR 2.47, 95% CI 1.29-4.75, P = 0.006) were significantly associated with de novo DSA detection. A dose-dependent association between AT1Rab levels (<10 U, 10.1-16.9 U, 17-29.9 U and >30 U) and de novo DSA detection was observed (log-rank P = 0.0031). After multivariate analysis of AT1Rab levels (continuous variable), AT1Rabs >30 U, male-to-male transplantation, donor age, higher class I percentage of Panel Reactive Antibody and antecedent borderline changes or ACR remained as independent significant risk factors for the detection of de novo DSAs. CONCLUSIONS: The findings suggest that higher levels of pretransplant circulating antibodies against AT1R (>30 U) in kidney graft recipients constitute an independent risk factor for earlier de novo HLA-DSA detection during the posttransplant period.

Impacto en la morbilidad y estancia hospitalaria del paciente quirúrgico no traumatizado con terapia transfusional / Impact of Transfusional Therapy on Morbidity and Length of Stay in Non-Trauma Surgical Patients

Introduccion: La transfusión de hemoderivado ha sido asociada con un número importante de complicaciones. El objetivo del estudio es determinar el riesgo asociado a la tranfusión de hemocomponentes en la morbilidad, mortalidad y estancia hospitalaria de los pacientes que ameritaron amputación supracondílea de la extremidad inferior. Materiales Y Metodos: Revisión retrospectiva, observacional, descriptiva de pacientes que ameritaron amputación supracondilea de la extremidad inferior realizada de enero del 2009 a enero del 2013. Se analizó edad, genero, nivel de hemoglobina pre y post operatoria, número de unidades trasfundidas, niveles de creatinina pre y post transfusión, nitrógeno de urea sérico, y la presencia de comorbilidades. Resultados Fueron incluidos un total de 56 pacientes, 75% (41) eran masculinos con un promedio de edad de 75 años. No hubo diferencia estadísticamente significativa en las características demográficas y comorbilidades previo a la transfusión. Un total de 21 pacientes (38%) fueron trasfundidos con al menos una unidad de hemocomponentes. Los pacientes que recibieron terapia transfusional tienen estadía hospitalaria más larga comparada contra los no trasfundidos (49 vrs 16 días, p=0.001), más alta frecuencia de infección de herida operatoria (61.9% vrs 3.0%,p=0.001), más alta incidencia de descompensación metabólica (47.6% vrs. 9.1%,p=0.001), y complicaciones pulmonares (33.3% vrs. 0%, p=0.001). No hubo diferencia estadísticamente significativa con relación a la mortalidad. Conclusion: La transfusión de hemocomponentes durante el perioperatorio en pacientes que van a amputación supracondilea de la extremidad inferior está asociado de manera estadísticamente significativa con infección de herida operatoria, descompensación metabólica, complicaciones pulmonares y prolonga la estancia hospitalaria.

Introduction: Blood components transfusion has been associated with an increased risk of developing complications. The aim of the study is to determine the impact that the use of blood transfusion hason themorbidity, mortality and length of hospital stay in patients that require an above knee amputation. Materials and Methods: A retrospective, descriptive observational review of patients who required an above knee amputation between January 2009 and January 2013, was carried out. The analyzed variables were age, gender, hemoglobin levels before and after transfusion, number of units transfused, levels of creatinine before and after transfusion, blood urea nitrogen and the presence of co-morbidities. Results:A total of 56 patients were included 75%(41) were male and the mean age was 75 years. There was no statistically significant difference in patient demographics and co-morbidities prior to transfusion. A total of 21 patients (38%) were transfused with at least one unit of blood or blood components. Patients who were transfused had a longer hospital stay (49 versus 16 days, p=0.001), higher rate of surgical site infection (61.9% versus 3.0%,p=0.001). A higher incidence of metabolic derangements (47.6% versus 9.1%,p=0.001) and pulmonary complications (33.3% versus 0%, p=0.001). Mortality was equal amongst both groups. Conclusion:The transfusion of blood and blood components during the perioperative period in patients undergoing above knee amputation is associated with a statistically significant increase in the number of surgical site infections, metabolic derangements, pulmonary complications and length of hospital stay.

Pre-transplant angiotensin II type 1receptor antibodies: a risk factor for decreased kidney graft function in the early post-transplant period?

Angiotensin II type 1 receptor antibodies (AT1Rab) are associated to a significantly lower graft survival and a higher risk of acute rejection after kidney transplantation. This study aimed to evaluate graft function and BPAR during the 1st year post-transplant (PT) in adult kidney transplant recipients (KTR), between 03/2009 and 08/2012. Pre-KT sera were screened for AT1Rab (ELISA) and HLA-DSA (Luminex). Three groups were analyzed: AT1Rab only (n = 13); HLA-DSA only (n = 8); and no AT1Rab or HLA-DSA (n = 90). No differences were observed in clinical characteristics across groups. A higher percentage of BPAR was observed in the AT1Rab positive group, but this difference was not significant. KTR with AT1Rab had a lower mean eGFR (20 mL/min/1.73m2) when compared to KTR with no Abs at 12 months. The significant difference in eGFR was observed since the 1st month PT. Multivariate analysis showed 4 factors independently and significantly associated with eGFR at 12mos PT: BPAR (-18.7 95%, CI -28.2 to -9.26, p<0.001), AT1Rab (-10.51, CI -20.9 to -0.095, p = 0.048), donor age (-0.42, CI -0.75 to -0.103 p = 0.010), and recipient age (-0.36, CI -0.67 to -0.048, p = 0.024). In this study AT1Rab in pre-transplant sera from KTR, was an independent and significant risk factor contributing to a lower eGFR 12 months. PT. This finding deserves to be confirmed in a larger KTR population.

Pre-transplant angiotensin II type 1 receptor antibodies: A risk factor for decreased kidney graft function in the early post-transplant period?

Angiotensin II type 1 receptor antibodies (AT,Rab) are associated with a significantly lower graft survival and a higher risk of acute rejection after kidney transplantation. This study aimed to evaluate graft function and biopsy proven acute rejection (BPAR) during the first year post-transplant in adult renal transplant recipients (RTR), between 03/2009 and 08/2012. Pre-transplant sera were screened for AT1Rab (via enzyme linked immunosorbent assay) and donor specific anti-human leukocyte antigen antibodies (HLA-DSA, via Luminex). Three groups were analyzed: AT1Rab only (n=13); HLA-DSA only (n=8); and no AT1Rab or HLA-DSA (n=90). No differences were observed in clinical characteristics across groups. A higher percentage of BPAR was observed in the AT1Rab positive group, but this difference was not significant. RTR with AT1Rab had a lower median estimated glomerular filtration rate (eGFR=20 ml/min/1.73m2) when compared to RTR with no antibodies at 12 months. A significant difference in eGFR was observed since the first month post-transplant. Multivariate analysis showed four factors independently and significantly associated with eGFR at 12 months post-transplant: BPAR (beta -18.7, 95% CI -28.2 to -9.26, p<0.001), AT,Rab (beta -10.51, 95% CI -20.9 to -0.095 p=0.048), donor age (beta -0.42, 95% CI -0.75 to -0.103, p=0.010), and recipient age (3 -0.36, 95% CI -0.67 to -0.048, p= 0.024). In this study, AT1Rab in pre-transplant sera from RTR was an independent and significant risk factor contributing to a lower eGFR at 12 months posttransplant. This finding deserves to be confirmed in a larger RTR population.

Pre-nephrectomy angiotensin II type 1 receptor antibodies in living kidney donors: A concern?

Angiotensin II type 1 receptor (AT1R) autoantibodies (AT1Rab) have been associated with pre-eclampsia and malignant hypertension. Overactivity of the angiotensin-II/AT1R complex has also been implicated in cardiac, renal, and vascular remodeling, leading to mortality and morbidity from cardiovascular disease. Pre-donation prevalence and possible post-donation effects of AT1Rab in living kidney donors (LKD) are unknown. In this study, sera obtained the day before nephrectomy and kept frozen at -70 degrees C from 113 strictly normotensive and non-obese LKD were tested for AT1Rab by OneLambda detection assay. AT1Rab titers >or=17 international units were considered positive. Pre-donation renal function [estimated glomerular filtration rate (eGFR)] and blood pressure at 1 and 12 months post-donation were recorded in every patient. Ten of 113 (8.8%) LKD yielded a positive AT1Rab result. History of sensitization events was similar in both groups. There was no difference in renal function between LKD with positive and negative AT1Rab results, 1 (mean eGFR 73.8 versus 72.4 mL/min/1.73m2) and 12 months post-donation (mean eGFR 74.1 versus 74.5 mL/min/1.73m2). During follow-up, none of the LKD developed hypertension (defined as blood pressure >130/85), nor did they require antihypertensive drugs. AT1Rab are apparently indolent in healthy adults after short-term follow-up. Longer observation of all LKD will be necessary to draw final conclusions.