We introduce the European Union consensus report on the diagnosis and treatment of monoclonal gammopathy of renal significance (MGRS), a generic term to describe kidney disorders caused by a non-malignant monoclonal immunoglobulin clone. There are many subtypes of MGRS, with AL-amyloidosis being most prevalent. The consensus report aims at providing guidance to clinicians, pathologists and laboratory specialists who take care of patients with a (suspected) diagnosis of MGRS. This executive summary provides a condensed overview of the most important aspects of the diagnosis and management of patients with MGRS. Consultation of expert centers is strongly advised. Although most patients will benefit from hematological, clone-directed therapy, treatment decisions must be individualized, in view of the heterogeneity of patients between and within the MGRS subtypes. The final chapter discusses kidney transplantation in patients with MGRS. The working group acknowledges that most advice is based on low-quality evidence. The full report provides the rationale and a detailed discussion of the available literature. This executive summary is an introduction, and not a substitute for the full consensus report.

Pneumococcal vaccination is essential to prevent invasive Streptococcus pneumoniae infections in immunocompromised individuals, including kidney transplant recipients. Current recommendations favor single-dose immunization with higher-valent conjugate vaccines, including PCV20 or PCV21. Five years ago, sequential administration of the 13-valent conjugate vaccine (PCV13) followed by the 23-valent polysaccharide vaccine (PPSV23) represented standard of care. Long-term data on antibody persistence after this regimen remain limited. In this prospective 5-year follow-up study, 46 kidney transplant recipients previously vaccinated sequentially with PCV13 and PPSV23 were re-evaluated. Nine patients were lost to follow-up, and 11 had died during the observation period. The remaining 26 participants were re-enrolled and completed the 5-year assessment. Global and serotype-specific IgG anti-pneumococcal antibody concentrations were quantified and compared with baseline and 12-month post-vaccination levels. Clinical outcomes, including pneumococcal infections and allograft status, were recorded. Five years after vaccination, antibody concentrations remained above baseline levels in most participants. Mean IgG levels were still approximately threefold higher than pre-vaccination values. Even for serotype-specific responses, mean antibody levels showed minimal changes compared with those measured 12 months after the first vaccination, although absolute titers remained considerably lower than those observed in healthy individuals. No cases of pneumococcal pneumonia or vaccine-associated allograft rejection occurred during follow-up. Sequential vaccination elicits durable immune responses in kidney transplant recipients, persisting up to 5 years post-immunization. With the availability of new vaccines covering additional serotypes, and given the generally lower antibody responses in this high-risk population, a booster with PCV20 or PCV21 appears advisable to enhance and broaden protection.IMPORTANCEKidney transplant recipients are at high risk for invasive pneumococcal disease, yet long-term vaccine-induced immunity in this population remains poorly defined. This study provides one of the longest longitudinal assessments of humoral responses following sequential PCV13 and PPSV23 vaccination, extending to 5 years post-immunization. We demonstrate sustained but heterogeneous antibody persistence and serotype-dependent responses to PCV20 booster vaccination. These results are directly relevant to transplant clinicians, vaccinologists, and public health policy, offering critical insight into long-term pneumococcal immunity in immunocompromised hosts and guiding future vaccine scheduling in solid organ transplantation.

Kidney transplantation is the preferred treatment for suitable patients with end-stage renal disease; however, access to transplantation declines dramatically with increasing HLA sensitization. While the acceptable mismatch (AM) program by Eurotransplant improves transplantability for highly sensitized candidates, a clinically relevant subgroup with extremely low donor frequency or ineligible for AM remains disadvantaged. In carefully selected cases, the controlled delisting of unacceptable HLA antigens and the use of peri-transplant desensitization (e.g., imlifidase) may enable transplantation. In order to provide better guidance, this German expert consensus report was compiled by the Kidney and Immunology Commissions of the German Transplantation Society and the Organ Transplantation Commission of the German Society for Immunogenetics. Within the German legal framework of urgency and chances for success, the report proposes a practical guide for candidate selection, multidisciplinary governance, risk-adapted HLA delisting, assessment of organ offers, use of imlifidase, perioperative immunosuppression, prophylaxis for infection, post-transplant monitoring, and management of antibody-mediated rejection. These recommendations are intended for experienced transplant centers and aim to balance transplant opportunity against immunological risk in highly sensitized kidney transplant candidates. The primary scope of this article is highly sensitized adult wait-listed candidates considered for deceased-donor kidney transplantation after compatibility-preserving pathways have been exhausted or are unlikely to succeed; HLA-incompatible living-donor transplantation with imlifidase is addressed separately as a potential off-label scenario for selected highly sensitized patients.

Background:HLA-G is a non-classical HLA class I molecule that promotes transplant tolerance. It engages the inhibitory receptor LILRB1 on immune effector cells, suppressing cytotoxic responses and inflammation, while promoting tolerogenic and regulatory immune phenotypes. Polymorphisms in the HLA-G 3' untranslated region (3'UTR) modulate HLA-G expression levels, and LILRB1 promoter variants influence receptor expression. The combined effect on kidney transplant (KTx) rejection has not been systematically studied. Methods:Living donor-recipient pairs undergoing KTx were genotyped for nine variants in the HLA-G 3'UTR region and two single nucleotide polymorphisms (SNPs) in the LILRB1 promoter (PROMO) regions. Haplotypes were arranged for both loci. Clinical endpoints were biopsy-proven T cell-mediated rejection (TCMR) within one year and antibody-mediated rejection (AMR) within five years post-transplant. Results:Donor positivity for HLA-G 3'UTR-1 or UTR-2 or negative for UTR-3 haplotype were associated with a significantly higher risk of TCMR in both univariate or multivariate analyses. Recipients lacking the LILRB1-PROMO CG haplotype also had an increased TCMR risk. The combination of an HLA-G 3'UTR-2 positive donor with a LILRB1-PROMO CG haplotype negative recipient was found to be an independent predictor of TCMR. In contrast, HLA-G 3'UTR variants were not associated with AMR, while the presence of the recipient LILRB1-PROMO CG haplotype emerged as an independent AMR risk factor. Conclusions:Donor HLA-G 3'UTR and recipient LILRB1-PROMO haplotypes define a functional immunogenetic axis that differentially influence TCMR and AMR. These results support the clinical potential of HLA-G/LILRB1 genetic profiling to improve donor selection in living KTx and to guide the development of novel rejection therapies.

Cytotoxic CD8+ T cells are essential mediators of immune responses against viral infections and tumors. Upon antigen encounter, antigen-specific CD8+ T cells undergo clonal expansion and produce effector cytokines, processes that require dynamic metabolic adaptation. However, profiling antigen-specific T cells at single-cell resolution remains technically challenging. We present a spectral flow cytometry-based workflow enabling metabolic profiling of antigen-specific CD8+ T cells identified via major histocompatibility complex (MHC) class I tetramers or CD137 upregulation. The approach integrates the analysis of metabolic protein expression to infer pathway activity, uptake of fluorescent probes to measure functional metabolism and metabolite utilization, and assays evaluating cellular energy metabolism. Applied to human and mouse samples, this method defined the metabolic profiles of cytomegalovirus-, SARS-CoV-2-, and tumor-specific CD8+ T cells across distinct activation states and tissues. By detailing each component of the workflow, we provide practical guidance for applying metabolic spectral flow cytometry to dissect disease mechanisms and therapeutic responses.

OBJECTIVES:Giant cell arteritis (GCA) is a serious inflammatory rheumatic disease driven by T-cells which are regulated by B-cells with anti-inflammatory activity. However, the role of these regulatory B-cells has not been studied in detail. The aim of this study is to investigate the anti-inflammatory B-cell compartment in patients with GCA. METHODS:Peripheral blood mononuclear cells (PBMC) of GCA Patients (n=47) and healthy controls (HC) (n=49) were isolated to assess the granzyme B (GrB) and Interleukin- 10 (IL-10) production of regulatory B-cells (Breg) after in vitro stimulation. RESULTS:The fraction of GrB producing Breg in GCA patients was diminished as compared to HC, and this was independent of current disease activity. In contrast, there were no significant differences between patients and HC with regard to IL-10 producing Breg. In GCA patients with active disease, CD4+ T-cells produced less IFNγ than HC. Regarding other T-cell derived pro-inflammatory cytokines, a trend towards a lower expression as compared to HC was seen. CONCLUSIONS:Regulatory B-cells were differentially altered in patients with GCA. While GrB producing Breg were persistently diminished, IL-10 producing Breg showed no differences between patients and controls. This may indicate a lack of B-cell based suppressive capacity which has influence on the T-cell compartment.

ANCA-vasculitis (AAV) is a small-vessel vasculitis characterized by the presence of autoantibodies against proteinase-3 (PR3) or myeloperoxidase (MPO). The dynamics of the T-cell response within tissues is studied best in animal models. It was the aim to analyze the lesional T-cell dynamics in the experimental autoimmune vasculitis model. Female Wistar Kyoto-rats were immunized with human MPO emulsified in complete Freund's adjuvant. Control animals received complete Freund's adjuvant without MPO. Selected groups received anti-IL17A treatment. Lesional T-cells from kidneys were assessed by flow cytometry (FACS), realtime polymerase chain reaction (PCR) and EliSpot. All animals immunized with MPO developed signs of vasculitis. At week six, lung damage expressed as petechial bleeding score and renal damage quantified by albuminuria were highest. As analyzed by FACS, the fraction of renal Th17 cells peaked at week six in MPO rats equaling the proportion of Th1 cells. MPO-specific renal Th1 and Th17 cells were detectable by EliSpot at weeks four and six post-immunization in MPO-immunized rats being absent in control rats. Neutralization of IL-17A did not affect the development of humoral and cellular anti-MPO immunity. Likewise, pulmonary and renal vasculitis were not ameliorated. In summary, the dynamics of the lesional T-cell response in the EAV model shows a major participation of MPO-specific Th17 and Th1 cells in renal vasculitis. Simple cytokine neutralization was not efficacious in this disease model so that combined neutralization approaches should be studied further.

Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in people who are immunocompromised, such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in people who are immunosuppressed have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific CD8+ T cells in patients who are immunocompromised and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific CD8+ T cells in KTRs with noncontrolled CMV infection. These dysregulations comprise impaired glycolysis and increased mitochondrial stress, which is associated with an intensified expression of the nicotinamide adenine dinucleotide nucleotidase (NADase) CD38. Inhibiting NADase activity of CD38 reinvigorated the metabolism and improved cytokine production of CMV-specific CD8+ T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of CD8+ T cells could be targeted by inhibiting CD38 to reverse hyporesponsiveness in individuals who fail to control chronic viral infection.

Background/Objectives: Our previous retrospective single-center cohort study found, at 3-year follow-up, a trend toward low tacrolimus trough levels and an increased risk of de novo donor-specific anti-HLA antibodies (DSAs) and of antibody-mediated rejection (ABMR) in CYP3A5-expressing patients. Determining CYP3A5-expression status immediately after renal transplant would allow early genotype-based dosage adjustment of tacrolimus and might prevent the occurrence of de novo DSAs and ABMR, improving transplant outcome. Methods: 160 renal allograft recipients who underwent renal transplant at the University Hospital Essen between May 2019 and May 2022 were genotyped for the CYP3A5 rs776746 polymorphism within the first two weeks after transplant, and genotype-based dose adjustment of tacrolimus was performed for the follow-up of 2 years. Results: CYP3A5 expression was detected in 33 (21%) of the 160 patients. Tacrolimus trough levels were similar in CYP3A5 expressers and nonexpressers over the entire 2-year follow-up period. However, we observed a trend toward slightly higher tacrolimus trough levels in CYP3A5 expressers, who, as expected, required tacrolimus dosages twice as high as did nonexpressers during follow-up. Calcineurin inhibitor (CNI) nephrotoxicity-free survival rates were comparable between CYP3A5 expressers and nonexpressers (p = 0.49). Rejection-free survival rates (p = 0.89), de novo anti-HLA antibody-free survival rates (p = 0.57) and de novo DSA-free survival rates (p = 0.61) did not differ between the two groups. Conclusions: Early detection of CYP3A5-expression status and resultant genotype-based adjustment of tacrolimus dosage after renal transplant protected patients from transplant rejection and de novo DSA formation and was not associated with increased incidence of CNI toxicity among CYP3A5 expressers.

HLA-G, an important immune-checkpoint (IC) molecule that exerts inhibitory signalling on immune effector cells, has been suggested to represent a key player in regulating the immune response to Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2). Since specific single-nucleotide polymorphisms (SNP) in the HLA-G 3'untranslated region (UTR), which arrange as haplotypes, are crucial for the regulation of HLA-G expression, we analysed the contribution of these genetic variants as host factors in SARS-CoV-2 infection during acute and post-acute phases. HLA-G gene polymorphisms in the 3'UTR were investigated by sequencing in an unvaccinated Coronavirus Disease 2019 (COVID-19) cohort during acute SARS-CoV-2 infection (N = 505) and in the post-acute phase (N = 253). The HLA-G 3'UTR haplotype known as UTR-3 (p = 0.002) and the variant rs17875408 (also known as +3422) T variant (p = 0.004) are independent prognostic risk factors for fatal COVID-19. The +3422T variant (p = 0.006) predicted also the early loss of neutralising SARS-CoV-2 antibodies. In addition, the HLA-G 3'UTR haplotype UTR-7 (p = 0.023) emerged as an independent prognostic factor for increased susceptibility to Long-COVID symptoms after SARS-CoV-2 infection. Our study highlights that due to the variability of the 3'UTR genetic background, HLA-G has the potential to contribute to the progression of SARS-CoV-2 infection, extending to the development of Long-COVID symptoms, despite the likely alterations in the microenvironment and associated HLA-G-specific regulatory elements over the course of the disease. By spotlighting HLA-G, the importance of the genetic background of IC and their pivotal role in modulating immune responses during and after COVID-19 are emphasised.

Background: Vaccination against Streptococcus pneumoniae is advised for transplant recipients to reduce morbidity and mortality associated with invasive pneumococcal disease. However, data on alloantibodies after sequential vaccination (with a pneumococcal conjugate vaccine followed by a polysaccharide vaccine) are still lacking. Methods: In the current study, we determined HLA class I and II and major histocompatibility class I-related chain A (MICA) antibodies in 41 clinically stable kidney transplant recipients. These antibodies were measured prior to and post sequential pneumococcal vaccination over a period of 12 months. Alloantibodies were measured by Luminex bead-based assays, and pneumococcal IgG antibodies were measured by ELISA. Results: Over a 12-month period, the sequential analysis revealed no significant change in alloantibodies. One patient developed de novo donor-specific antibodies (DSA) 1.5 months after the first vaccination, with mean fluorescence intensities of up to 2300. These DSA became undetectable in the follow-up, and the patient showed no signs of allograft rejection. Another patient experienced a biopsy-proven borderline rejection 7 months after the first vaccination but did not develop de novo DSA. Both maintained stable kidney function. As expected, the pneumococcal antibodies increased significantly after vaccination (p < 0.0001). Conclusions: Given the overall risk of alloimmune responses in transplant recipients, we would not attribute the two noticeable patient courses to vaccination. Thus, we consider sequential vaccination immunologically safe.

Renal involvement is a clinically relevant organ manifestation of sarcoidosis, leading to increased morbidity and complications. Although the exact incidence remains unknown, renal disease is likely to occur in up to one third of all sarcoidosis patients. Every patient with newly diagnosed sarcoidosis should receive a renal work-up and screening for disrupted calcium metabolism.Amid various forms of glomerulonephritis, granulomatous interstitial nephritis is the most common one, but it rarely leads to renal impairment. Histologically, granulomas can be absent. Nephrocalcinosis and nephrolithiasis are frequent forms when hypercalcaemia or hypercalciuria occur. Drugs used for treatment of systemic sarcoidosis can also cause renal damage.Due to its high heterogeneity, renal sarcoidosis can be difficult to treat. Glucocorticoids and various immunosuppressive treatments have been proven to be effective based on case series, but clinical trials are lacking. A treatment guideline for renal sarcoidosis is urgently needed.In this review article, we present an overview of the different forms of renal sarcoidosis and the diagnostic steps to confirm renal involvement; in addition, we provide insights on the management and available treatments. A better understanding regarding the pathogenesis of sarcoidosis is the key for the development of more specific, targeted therapies.

Tissues often experience hypoxia at sites of inflammation due to malperfusion, massive immune cell recruitment, and increased oxygen consumption. Organisms adapt to these hypoxic conditions through the transcriptional activation of various genes. In fact, there is significant crosstalk between the transcriptional responses to hypoxia and inflammatory processes. This interaction, named inflammatory hypoxia, plays a crucial role in various diseases including malignancies, chronic inflammatory lung diseases, and sepsis. To further elucidate the crosstalk between hypoxia and inflammation in vivo and assess its potential for innovative therapies, our study aimed at investigating the impact of acute hypoxic conditions on inflammation-induced immune responses. To this end, we exposed healthy human subjects to hypoxia either before (hypoxia priming) or after a single intravenous (i.v.) injection of 0.4 ng/kg LPS. Our data show that hypoxia exposure prior to LPS injection (hypoxia priming) amplified the proinflammatory response. This was reflected by an increase in body temperature, plasma noradrenaline levels, and the production of proinflammatory cytokines (i.e., IL-6 and TNF-α), compared with LPS control conditions. These effects were not observed when participants were exposed to hypoxia after LPS administration, demonstrating that the interaction between hypoxia and inflammation highly depends on the timing of both stimuli. Our findings suggest that acute hypoxia (i.e., hypoxia priming) modulates transient inflammation, leading to an enhanced proinflammatory response in healthy human subjects. This highlights the need for further investigations to understand the pathology of various hypoxia-inducible factor (HIF)-associated inflammatory diseases and to develop suitable, innovative therapies.NEW & NOTEWORTHY To our knowledge, this is the first in vivo study investigating the effects of hypoxia preceding (hypoxia priming) or following LPS administration on the endotoxin-induced inflammatory response in healthy human subjects. The data show that hypoxia priming amplified the proinflammatory response, reflected by an increased body temperature, increased plasma noradrenaline levels, and higher production of proinflammatory cytokines (i.e., IL-6 and TNF-α) compared with LPS control conditions.