A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies.

Antibody-mediated rejection (AMR) remains a major cause of graft failure, with significant health and economic burden. Despite being recognized >25 years ago, AMR treatment remains unstandardized, and no therapy has gained robust regulatory approval. While uncontrolled series have shown promise, few well-designed trials exist, with most yielding negative results. In the absence of strong trial data, a Transplantation Society expert consensus recommended potential treatment options with low levels of evidence, tailored to clinical phenotypes. Here, we re-evaluate the current evidence for AMR treatment decisions. We conclude that steroids, rituximab, bortezomib, and interleukin-6 (IL-6) antagonists lack sufficiently robust evidence to support their use in AMR. For early AMR, antibody depletion using immunoadsorption could be considered as an alternative to plasmapheresis. High-dose intravenous immunoglobulin (IVIG) may be added, though the supporting evidence remains limited. While previous trials primarily targeted the cause of AMR, recent data on the successful reversal of AMR activity by CD38 antibodies—particularly recent phase 2 trial results—suggest that targeting the cellular inflammation resulting from antibody binding to the endothelium could be a rational approach. Along these lines, in severe early AMR, complement inhibition may also be an option. Ongoing phase 2 trials evaluating prolonged courses of high-dose IVIG, the neonatal Fc receptor blocker efgartigimod, the tyrosine kinase inhibitor fostamatinib, and the complement inhibitor BIVV020, along with phase 3 trials of the anti-IL-6 receptor antibody tocilizumab and the CD38 antibody felzartamab, offer hope for effective, approved therapies targeting different aspects of AMR pathobiology.

Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3A^V/F158 [rs396991], KLRC2^wt/del, KLRK1^HNK/LNK [rs1049174], rs9916629-C/T). Forty-four patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2^wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] versus 0 [0-1] in KLRC2^wt/del recipients; p=0.001) and remained significant in a proportional odds multivariable model (odds ratio [OR]: 7.84, 95% confidence interval [CI]: 2.37-30.47, p=0.001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms.

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73–1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66–1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental.

Background.: Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection. Methods.: We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes (FCGR3A ^V/F158 [rs396991], KLRC2 ^wt/del, KLRK1 ^HNK/LNK [rs1049174], and rs9916629-C/T). Results.: MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2 ^del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P = 0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P = 0.052). Conclusions.: Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection.

Background: Current guidelines recommend interpreting concentrations of NPs (natriuretic peptides) irrespective of the time of presentation to the emergency department. We hypothesized that diurnal variations in NP concentration may affect their diagnostic accuracy for acute heart failure. Methods: In a secondary analysis of a multicenter diagnostic study enrolling patients presenting with acute dyspnea to the emergency department and using central adjudication of the final diagnosis by 2 independent cardiologists, the diagnostic accuracy for acute heart failure of BNP (B-type NP), NT-proBNP (N-terminal pro-B-type NP), and MR-proANP (midregional pro-atrial NP) was compared among 1577 daytime presenters versus 908 evening/nighttime presenters. In a validation study, the presence of a diurnal rhythm in BNP and NT-proBNP concentrations was examined by hourly measurements in 44 stable individuals. Results: Among patients adjudicated to have acute heart failure, BNP, NT-proBNP, and MR-proANP concentrations were comparable among daytime versus evening/nighttime presenters (all P =nonsignificant). Contrastingly, among patients adjudicated to have other causes of dyspnea, evening/nighttime presenters had lower BNP (median, 44 [18–110] versus 74 [27–168] ng/L; P <0.01) and NT-proBNP (median, 212 [72–581] versus 297 [102–902] ng/L; P <0.01) concentrations versus daytime presenters. This resulted in higher diagnostic accuracy as quantified by the area under the curve of BNP and NT-proBNP among evening/nighttime presenters (0.97 [95% CI, 0.95–0.98] and 0.95 [95% CI, 0.93–0.96] versus 0.94 [95% CI, 0.92–0.95] and 0.91 [95% CI, 0.90–0.93]) among daytime presenters (both P <0.01). These differences were not observed for MR-proANP. Diurnal variation of BNP and NT-proBNP with lower evening/nighttime concentration was confirmed in 44 stable individuals ( P <0.01). Conclusions: BNP and NT-proBNP, but not MR-proANP, exhibit a diurnal rhythm that results in even higher diagnostic accuracy among evening/nighttime presenters versus daytime presenters. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT01831115, NCT02091427, and NCT02210897.