Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over ...fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI.
Lack of adherence to immunosuppressive drugs is a risk factor for development of de novo donor-specific antibodies (dnDSA) and can contribute to antibody-mediated rejection and graft loss. Moreover, ...nonadherence is the main determinant of immunosuppressive drug level variability. High intrapatient variability of tacrolimus relates to a worse outcome in transplant recipients through unknown mechanisms. We hypothesized that a high within-patient variability of tacrolimus could increase the rate of dnDSA development and contribute to further death-censored graft loss (DCGL).
We included 310 adult renal transplants receiving twice-daily tacrolimus throughout their first posttransplant year, with (1) at least 3 blood trough levels available to calculate coefficient of variation (CV) from month 4 to 12, (2) graft survival longer than 1 year, and (3) absence of pretransplant DSA. The dnDSA were analyzed in sera at 1, 3, and 5 years and around 6 month before the last follow-up visit or graft loss by single-antigen beads.
During the follow-up, 53 patients lost their graft excluding death. A total of 116 patients (37.4%) had a CV greater than 30% and 39 (12.6%) developed dnDSA. Coefficient of variation greater than 30% (hazards ratio, 2.613; 95% confidence interval, 1.361-5.016; P = 0.004) independently related to DCGL. Acute rejection, re-transplant and CV greater than 30% (hazards ratio, 2.925; 95% confidence interval, 1.473-5.807; P = 0.002) were the only variables related to dnDSA development by Cox regression analysis.
Tacrolimus level variability is a strong risk factor for dnDSA development and DCGL. Variability must be added to the current monitoring of kidney transplant recipients due to its relationship with adherence and to graft outcome.
There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo‐controlled, double‐blind clinical trial to evaluate ...efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010‐023746‐67). Patients with transplant glomerulopathy and anti‐HLA donor‐specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) <20 mL/min per 1.73m2 and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m2) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions, and DSA at 1 year. The planned sample size was 25 patients per group. During 2012‐2015, 25 patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (−4.2 ± 14.4 vs. −6.6 ± 12.0 mL/min per 1.73 m2, P‐value = .475), increase of proteinuria (+0.9 ± 2.1 vs. +0.9 ± 2.1 g/day, P‐value = .378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA.
Intravenous immunoglobulins and rituximab did not modify glomerular filtration rate decline, daily proteinuria, HLA donor‐specific antibody intensity, and graft histological damage at one year in a prospective, randomized, placebo‐controlled clinical trial.
Background
Many cutaneous manifestations have been described in possible association with the COVID‐19 pandemic, including acral lesions resembling chilblains. The underlying pathomechanisms of ...COVID‐19 chilblains are not fully understood. The aim of this study was to describe the clinical, pathological, and laboratory findings of a series of patients who developed chilblains during the COVID‐19 outbreak and to investigate the possible factors that could be involved in the pathogenesis of these lesions.
Methods
We conducted a prospective cohort study that included 54 patients who presented with chilblains during the highest peak in the incidence of COVID‐19 in Cantabria (northern Spain). Skin biopsies were performed on 10 of these patients who presented with recent lesions. Laboratory investigations, including immunological analysis, serological studies, and the assessment of cryoproteins, were also performed.
Results
Most patients presented erythematous plaques located on the toes and/or purpuric macules located on the feet. Histopathological findings were compatible with those of idiopathic chilblains. Immunohistochemical evaluation showed C3d and C4d deposits in the vessel walls in seven cases. The autoimmunity panel was negative in most of our series. Cryoprotein testing showed positive cryofibrinogen in two‐thirds (66.7%) of the patients assessed. On follow‐up, most patients presented almost complete resolution, although six patients required prednisone and antiaggregant drug treatment.
Conclusions
This study shows, for the first time to our knowledge, a high prevalence of cryofibrinogenemia in patients with chilblains during the COVID‐19 pandemic. Cryofibrinogenemia could be implicated in the pathogenesis of chilblains related to COVID‐19.
Abstract
Background
The role of vitamin D status in COVID-19 patients is a matter of debate.
Objectives
To assess serum 25-hydroxyvitamin D (25OHD) levels in hospitalized patients with COVID-19 and ...to analyze the possible influence of vitamin D status on disease severity.
Methods
Retrospective case–control study of 216 COVID-19 patients and 197 population-based controls. Serum 25OHD levels were measured in both groups. The association of serum 25OHD levels with COVID-19 severity (admission to the intensive care unit, requirements for mechanical ventilation, or mortality) was also evaluated.
Results
Of the 216 patients, 19 were on vitamin D supplements and were analyzed separately. In COVID-19 patients, mean ± standard deviation 25OHD levels were 13.8 ± 7.2 ng/mL, compared with 20.9 ± 7.4 ng/mL in controls (P < .0001). 25OHD values were lower in men than in women. Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (P < .0001). 25OHD inversely correlates with serum ferritin (P = .013) and D-dimer levels (P = .027). Vitamin D-deficient COVID-19 patients had a greater prevalence of hypertension and cardiovascular diseases, raised serum ferritin and troponin levels, as well as a longer length of hospital stay than those with serum 25OHD levels ≥20 ng/mL. No causal relationship was found between vitamin D deficiency and COVID-19 severity as a combined endpoint or as its separate components.
Conclusions
25OHD levels are lower in hospitalized COVID-19 patients than in population-based controls and these patients had a higher prevalence of deficiency. We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease.
Autoantibodies are a hallmark of autoimmunity and, specifically, antinuclear antibodies (ANAs) are the most relevant autoantibodies present in systemic autoimmune rheumatic diseases (SARDs). Over the ...years, different methods from LE cell to HEp-2 indirect immunofluorescence (IIF), solid-phase assays (SPAs), and finally multianalyte technologies have been developed to study ANA-associated SARDs. All of them provide complementary information that is important to provide the most clinically valuable information. The identification of new biomarkers together with multianalyte platforms will help close the so-called "seronegative gap" and to correctly classify and diagnose patients with SARDs. Finally, artificial intelligence and machine learning is an area still to be exploited but in a next future will help to extract patterns within patient data, and exploit these patterns to predict patient outcomes for improved clinical management.
The simplicity and low cost of rapid point-of-care tests greatly facilitate large-scale population testing, which can contribute to controlling the spread of the COVID-19 virus. We evaluated the ...applicability of a self-testing strategy for SARS-CoV2 in a population-based, cross-sectional study in Cantabria, Spain, between April and May 2020. For the self-testing strategy, participants received the necessary material for the self-collection of blood and performance of a rapid antibody test using lateral flow immunoassay at home without the supervision of healthcare personnel. A total of 1,022 participants were enrolled. Most participants correctly performed the COVID-19 self-test the first time (91.3% 95% CI 89.4-92.9). Only a minority of the participants (0.7%) needed the help of healthcare personnel, while 6.9% required a second kit delivery, for a total valid test result in 96.9% of the participants. Incorrect use of the self-test was not associated with the educational level, age over 65, or housing area. Prevalence of IgG antibodies against SARS-CoV2 for subjects with a valid rapid test result was 3.1% (95% CI 2.2-4.4), similar to the seroprevalence result obtained using a conventional approach carried out by healthcare professionals. In conclusion, COVID-19 self-testing should be considered as a screening tool.
Antineutrophil cytoplasmic antibodies (ANCA) are the serological hallmark of some idiopathic systemic vasculitides. Besides the investigation of ANCA-associated vasculitis (AAV) and constant effort ...for a standardized nomenclature and classification of the AAV, a main focus of research during the last few years has been to constantly improve the performance of enzyme immunoassays. With the latest so called third generation ELISA, this goal seemed to be fulfilled. The International Consensus Statement on Testing and Reporting of ANCA gave recommendations for standardized strategies for the serological diagnosis of ANCA. New developments now target the system immanent drawbacks of the respective diagnostic methods, be it the need for batching and the long time to result for ELISA, or the high likelihood of error and subjectivity of indirect immunofluorescence (IIF). Random access technology and multiplexing for solid phase assays as well as digital imaging for IIF are tools which may help to expedite and simplify routine diagnostics in the lab and in emergency settings. Recent findings indicate that PR3-ANCA have clinical utility beyond the diagnosis of AAV. PR3-ANCA can also serve as an aid for the differentiation between ulcerative colitis (UC) and Crohn’s disease (CrD) and the stratification of UC patients. This review provides a detailed review of what is known about ANCA and highlights the latest research and state-of-the-art developments in this area.
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