A systematic review and meta-analysis of COVID-19 in kidney transplant recipients:Lessons to be learned

Kidney transplant recipients (KTR) may be at increased risk of adverse COVID-19 outcomes, due to prevalent comorbidities and immunosuppressed status. Given the global differences in COVID-19 policies and treatments, a robust assessment of all evidence is necessary to evaluate the clinical course of COVID-19 in KTR. Studies on mortality and acute kidney injury (AKI) in KTR in the World Health Organization COVID-19 database were systematically reviewed. We selected studies published between March 2020 and January 18th 2021, including at least five KTR with COVID-19. Random-effects meta-analyses were performed to calculate overall proportions, including 95% confidence intervals (95% CI). Subgroup analyses were performed on time of submission, geographical region, sex, age, time after transplantation, comorbidities, and treatments. We included 74 studies with 5559 KTR with COVID-19 (64.0% males, mean age 58.2 years, mean 73 months after transplantation) in total. The risk of mortality, 23% (95% CI: 21%-27%), and AKI, 50% (95% CI: 44%-56%), is high among KTR with COVID-19, regardless of sex, age and comorbidities, underlining the call to accelerate vaccination programs for KTR. Given the suboptimal reporting across the identified studies, we urge researchers to consistently report anthropometrics, kidney function at baseline and discharge, (changes in) immunosuppressive therapy, AKI, and renal outcome among KTR

Complement component C3 and C5b-9 deposition on hypoxia reperfused endothelial cells by non-HLA antibodies against RhoGDI2: A player involved in graft failure?

Antibodies against Rho GDP-dissociation inhibitor 2 (RhoGDI2) are associated with inferior graft survival in transplant patients receiving a kidney from deceased donors. Although this suggests that these antibodies contribute to graft injury because of ischemia, it remains unknown whether they are also pathogenically involved in the process of graft loss. To study this, we firstly analyzed the IgG subclass profile of anti-RhoGDI2 antibodies in kidney transplant recipients, and whether antibody titers change over time or because of acute rejection. Next, we investigated the expression of RhoGDI2 on primary kidney and lung endothelial cells (ECs) upon hypoxia reperfusion. In addition, the complement-fixing properties of anti-RhoGDI2 antibodies were studied using imaging flow cytometry. Anti-RhoGDI2 antibodies in patients are mainly IgG1, and titers remained stable and seemed not be changed because of rejection. Antibodies against RhoGDI2, which surface expression seemed to increase upon hypoxia reperfusion, co-localized with C3 on ECs. Binding of human IgG1 monoclonal anti-RhoGDI2 antibodies as well as patient derived antibodies, resulted in complement activation, suggesting that these antibodies are complement fixing. This study suggested a potential pathogenic role of anti-RhoGDI2 antibodies in kidney graft loss. During ischemia reperfusion, the ability of these antibodies to fix complement could be one of the mechanisms resulting in tissue injury

Renal transplant patient survives a donor-derived abdominal invasive mucormycosis (Lichtheimia ramosa)

Mucormycosis is a life-threatening invasive fungal infection, most commonly described in severely immunocompromised patients. It is characterized by rapid invasive growth of the fungus and often with fatal outcome. We report a case of a renal transplant recipient diagnosed with a donor-derived invasive mucormycosis. In this patient, we used a step-wise approach of withdrawal of immunosuppressants, antifungal induction therapy, extensive surgical debridement of all (potentially) infected tissue, abdominal irrigation of liposomal amphotericin B and interferon gamma. Due to rapid diagnosis and intensive therapy the patient survived

Chiral Polymerization in Open Systems From Chiral-Selective Reaction Rates

We investigate the possibility that prebiotic homochirality can be achieved exclusively through chiral-selective reaction rate parameters without any other explicit mechanism for chiral bias. Specifically, we examine an open network of polymerization reactions, where the reaction rates can have chiral-selective values. The reactions are neither autocatalytic nor do they contain explicit enantiomeric cross-inhibition terms. We are thus investigating how rare a set of chiral-selective reaction rates needs to be in order to generate a reasonable amount of chiral bias. We quantify our results adopting a statistical approach: varying both the mean value and the rms dispersion of the relevant reaction rates, we show that moderate to high levels of chiral excess can be achieved with fairly small chiral bias, below 10%. Considering the various unknowns related to prebiotic chemical networks in early Earth and the dependence of reaction rates to environmental properties such as temperature and pressure variations, we argue that homochirality could have been achieved from moderate amounts of chiral selectivity in the reaction rates.Comment: 15 pages, 6 figures, accepted for publication in Origins of Life and Evolution of Biosphere

ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies:a propensity-matched analysis

BACKGROUND: Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. METHODS: We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. RESULTS: 296 ABOi were compared to 1184 center and propensity matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group and PRA). Patient survival was better compared to deceased donor (hazard ratio (HR) for death of HR 0.69 [0.49-0.96], and not-significantly different from ABOc living donor recipients (HR 1.28 [0.90-1.81]). Rate of graft failure was higher compared to ABOc living donor transplantation (HR 2.63 [1.72-4.01]). Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab treated recipients (p <0.001). CONCLUSIONS: ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared to matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to non-sensitized patients

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, determined by extensive laboratory testing. AM patients have superior long-term graft survival compared to highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants 1995-2005, we selected deceased donor single transplants with minimum one HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of one HLA-B plus one HLA-DR, or two HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to non-sensitized patients, independent of other risk factors for rejection. Contrasting to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low risk transplants for highly sensitized patients with rejection rates similar to non-immunized individuals. This article is protected by copyright. All rights reserved.</p

Modeling complement activation on human glomerular microvascular endothelial cells

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare kidney disease caused by dysregulation of the complement alternative pathway. The complement dysregulation specifically leads to damage to the glomerular endothelium. To further understand aHUS pathophysiology, we validated an ex vivo model for measuring complement deposition on both control and patient human glomerular microvascular endothelial cells (GMVECs). METHODS: Endothelial cells were incubated with human test sera and stained with an anti-C5b-9 antibody to visualize and quantify complement depositions on the cells with immunofluorescence microscopy. RESULTS: First, we showed that zymosan-activated sera resulted in increased endothelial C5b-9 depositions compared to normal human serum (NHS). The levels of C5b-9 depositions were similar between conditionally immortalized (ci)GMVECs and primary control GMVECs. The protocol with ciGMVECs was further validated and we additionally generated ciGMVECs from an aHUS patient. The increased C5b-9 deposition on control ciGMVECs by zymosan-activated serum could be dose-dependently inhibited by adding the C5 inhibitor eculizumab. Next, sera from five aHUS patients were tested on control ciGMVECs. Sera from acute disease phases of all patients showed increased endothelial C5b-9 deposition levels compared to NHS. The remission samples showed normalized C5b-9 depositions, whether remission was reached with or without complement blockage by eculizumab. We also monitored the glomerular endothelial complement deposition of an aHUS patient with a hybrid complement factor H (CFH)/CFH-related 1 gene during follow-up. This patient had already chronic kidney failure and an ongoing deterioration of kidney function despite absence of markers indicating an aHUS flare. Increased C5b-9 depositions on ciGMVECs were observed in all samples obtained throughout different diseases phases, except for the samples with eculizumab levels above target. We then tested the samples on the patient's own ciGMVECs. The C5b-9 deposition pattern was comparable and these aHUS patient ciGMVECs also responded similar to NHS as control ciGMVECs. DISCUSSION: In conclusion, we demonstrate a robust and reliable model to adequately measure C5b-9-based complement deposition on human control and patient ciGMVECs. This model can be used to study the pathophysiological mechanisms of aHUS or other diseases associated with endothelial complement activation ex vivo

Longitudinal Fluctuations in Protein Concentrations and Higher-Order Structures in the Plasma Proteome of Kidney Failure Patients Subjected to a Kidney Transplant

Using proteomics and complexome profiling, we evaluated in a year-long study longitudinal variations in the plasma proteome of kidney failure patients, prior to and after a kidney transplantation. The post-transplant period was complicated by bacterial infections, resulting in dramatic changes in the proteome, attributed to an acute phase response (APR). As positive acute phase proteins (APPs), being elevated upon inflammation, we observed the well-described C-reactive protein and Serum Amyloid A (SAA), but also Fibrinogen, Haptoglobin, Leucine-rich alpha-2-glycoprotein, Lipopolysaccharide-binding protein, Alpha-1-antitrypsin, Alpha-1-antichymotrypsin, S100, and CD14. As negative APPs, being downregulated upon inflammation, we identified the well-documented Serotransferrin and Transthyretin, but added Kallistatin, Heparin cofactor 2, and interalpha-trypsin inhibitor heavy chain H1 and H2 (ITIH1, ITIH2). For the patient with the most severe APR, we performed plasma complexome profiling by SEC-LC-MS on all longitudinal samples. We observed that several plasma proteins displaying alike concentration patterns coelute and form macromolecular complexes. By complexome profiling, we expose how SAA1 and SAA2 become incorporated into high-density lipid particles, replacing largely Apolipoprotein (APO)A1 and APOA4. Overall, our data highlight that the combination of in-depth longitudinal plasma proteome and complexome profiling can shed further light on correlated variations in the abundance of several plasma proteins upon inflammatory events

Direct Mass Spectrometry-Based Detection and Antibody Sequencing of Monoclonal Gammopathy of Undetermined Significance from Patient Serum: A Case Study

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a predominant monoclonal antibody (i.e., M-protein) in serum, without clinical symptoms. Here we present a case study in which we detect MGUS by liquid-chromatography coupled with mass spectrometry (LC-MS) profiling of IgG1 in human serum. We detected a Fab-glycosylated M-protein and determined the full heavy and light chain sequences by bottom-up proteomics techniques using multiple proteases, further validated by top-down LC-MS. Moreover, the composition and location of the Fab-glycan could be determined in CDR1 of the heavy chain. The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and multiple myeloma, with fine molecular detail. The ability to detect monoclonal gammopathies and determine M-protein sequences straight from blood samples by mass spectrometry provides new opportunities to understand the molecular mechanisms of such diseases