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Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.

Introduction: Comprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains challenging owing to the complexity of functional studies with mutant proteins. This study was designed: 1) To identify a tool for rapid functional determination of complement gene variants; 2) To uncover inherited complement dysregulation in aHUS patients who do not carry identified gene variants., Methods: To address the above goals, we employed an ex-vivo assay of serum-induced C5b-9 formation on ADP-activated endothelial cells in 223 subjects from 60 aHUS pedigrees (66 patients and 157 unaffected relatives)., Results: Sera taken from all aHUS patients in remission induced more C5b-9 deposition than control sera, independently from the presence of complement gene abnormalities. To avoid the possible confounding effects of chronic complement dysregulation related to aHUS status, and considering the incomplete penetrance for all aHUS-associated genes, we used serum from unaffected relatives. In control studies, 92.7% of unaffected relatives with known pathogenic variants exhibited positive serum-induced C5b-9 formation test, documenting a high sensitivity of the assay to identify functional variants. The test was also specific, indeed it was negative in all non-carrier relatives and in relatives with variants non-segregating with aHUS. All but one variants in aHUS-associated genes predicted in-silico as likely pathogenic or of uncertain significance (VUS) or likely benign resulted as pathogenic in the C5b-9 assay. At variance, variants in putative candidate genes did not exhibit a functional effect, with the exception of a CFHR5 variant. The C5b-9 assay in relatives was helpful in defining the relative functional effect of rare variants in 6 pedigrees in which the proband carried more than one genetic abnormality. Finally, for 12 patients without identified rare variants, the C5b-9 test in parents unmasked a genetic liability inherited from an unaffected parent., Discussion: In conclusion, the serum-induced C5b-9 formation test in unaffected relatives of aHUS patients may be a tool for rapid functional evaluation of rare complement gene variants. When combined with exome sequencing the assay might be of help in variant selection, to identify new aHUS-associated genetic factors., Competing Interests: MN has received honoraria from Alexion Pharmaceuticals for giving lectures, and for participating in advisory boards, and she has received research grants from Omeros, Gemini, Novartis and BioCryst Pharmaceuticals. AB has received honoraria from Alexion Pharmaceuticals and BioCryst Pharmaceuticals. GR has consultancy agreements with AbbVie, Alexion Pharmaceuticals, Novartis Pharma and BioCryst Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gastoldi, Aiello, Galbusera, Breno, Alberti, Bresin, Mele, Piras, Liguori, Santarsiero, Benigni, Remuzzi and Noris.)

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU., Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study., Results: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment., Interpretation: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Context: In animal models, disruption of thyroid hormone (TH) receptor-β (TRβ) reduces the long/medium wavelength (L/M) and increases the short-wavelength (S) cones. Retinal photoreceptor (RP) functions are unknown in patients with resistance to TH syndrome (RTHβ) with dominant-negative TRβ mutations., Objective: To investigate RP functions in RTHβ., Design, Setting, and Participants: Case-control study involving 27 RTHβ patients and 31 age/sex-matched controls, conducted in two tertiary referral centers in Italy., Main Outcome Measures: Color vision sensitivity assessed by Farnsworth; central macular thickness (CMT) of the outer retinal layer measured by spectral-domain optical coherence tomography; and retinal function tested by full-field electroretinogram (ERG) and S-cone ERG., Results: Color sensitivity was worse in RTHβ patients than controls (P = 0.002). CMT was overlapping between the study groups but directly correlated with sex hormone-binding globuline levels in RTHβ. We found a significant reduction in amplitude of the cone (P = 0.024) and of the rod response (P = 0.006) in the ERG of RTHβ patients compared with controls. The response of the L/M cones measured by a specialized ERG test was lower in RTHβ than controls (P = 0.027), whereas no differences were found in the S-cone response. No correlations were found between TH levels, total error score, or electrophysiological results. Furthermore, no differences were found between patients with maternal or de novo/paternal inheritance., Conclusions: We report, to our knowledge, the first in vivo evidence of functional defects of RP in RTHβ. These changes occur independently of endogenous TH levels or the prenatal exposure to high or normal maternal TH., (Copyright © 2017 Endocrine Society)