Worldwide, vaccination against severe acute respiratory syndrome coronavirus 2 has reduced the case fatality rate of coronavirus disease 2019 (COVID-19) in patients with kidney disease,1 but vaccination hesitancy remains a problem for various reasons. In patients with glomerular disease, there is the concern that vaccination may trigger a relapse of disease activity and a further decline in residual kidney function. In the absence of reliable data, advising patients on the individual risks and benefits has been challenging. Up until January 2022, numerous case reports and series reported 40 relapses of glomerulonephritis, kidney vasculitis, or podocytopathies in a temporal association with a coronavirus vaccine.2 Minimal change disease (MCD) relapsed preferentially after the first vaccine dose, whereas other entities relapsed after the second or third dose.2 However, in data on the background incidence of glomerular disease in nonvaccinated controls of the same population, the role of the vaccine as a trigger of a relapse has remained questionable. In this issue of JASN, Canney et al. report data from a British Columbia Canadian clinical and pathology registry, which followed a large sample of 1105 patients with glomerulonephritis, kidney vasculitis, and podocytopathies from December 14, 2020, to September 21, 2021. The study aimed to investigate whether the rollout of COVID-19 vaccines affect the relapse risk of these disease entities. Most patients received a mRNA vaccine (67% BNT162b2, 30% mRNA-1273), with the remainder (3%) receiving ChAdOx1. During this period, they defined a disease relapse as an increase of serum creatinine and proteinuria. A total of 134 (12.1%) patients experienced a relapse during the 281 days of follow-up. Among these, 24 relapses were considered as vaccine-associated relapses, defined as relapses occurring within a period of 30 days after vaccine administration. Overall, the authors found no increase of disease relapse after the first dose of COVID-19 vaccine administration (hazard ratio=0.65; 95% confidence interval, 0.32 to 1.32) but a two-fold increase after subsequent doses (hazard ratio=2.16; 95% confidence interval, 1.03 to 4.51). The risk of a disease flare during 210 days of follow-up in the absence of COVID-19 vaccine exposure ranged from 6% in membranous nephropathy (MN) to 19% in lupus nephritis (LN). The absolute risk after administration of a second or third vaccine dose of developing a disease relapse varied from 1%–2% in ANCA-associated vasculitis, MCD, MN, and FSGS to 3%–5% in IgA nephropathy and LN.3 Further sensitivity analysis extending the time period to 45 days after vaccination (see Figure 1) and restriction analysis to patients who received at least one vaccine (92% of the cohort) or two vaccines (89%) confirmed the association of glomerular disease relapse with administration of a second or third vaccine dose.3Figure 1.: A total of 1105 patients with established glomerulonephritis were followed in the registry. Most patients received two doses of COVID-19 vaccines. Relapses occurred in 134 patients during a follow-up period of 281 days, of whom 24 had a relapse within 30 days of vaccine administration. There is an increased risk after administration of the second or third dose of COVID-19 vaccine administration, and a minimal increased absolute risk for all entities studied. The histopathology picture was kindly provided by Dr. Victoria Bardsley (Department of Pathology, Addenbrooke's Hospital, Cambridge, United Kingdom) and shows active necrosis in a patient with established ANCA-GN undergoing kidney biopsy 24 days after her fourth vaccine dose. IgAN, IgA nephropathy.There are several limitations of the work presented by Canney et al.3 The registry did not capture hematuria, which may be dispensable in podocytopathies but would add to specificity for a relapse of glomerulonephritis and kidney vasculitis. A survey in Japan identified 27 cases presenting with gross hematuria after COVID-19 vaccination.4 Among the 27 patients, only four underwent a kidney biopsy, and only one relapse was associated with an increase in serum creatinine.4 Gross hematuria usually occurs within the first days after vaccination, and usually resolves without specific therapy.5 These findings could imply that Canney et al. might have missed some relapses of glomerulonephritis, which anyway may have consequences for future kidney function decline. In the report by Canney et al., none of the 24 patients with a recurrence of glomerular disease after COVID-19 vaccination required a kidney biopsy, and only four (17%) of the patients had a change in immunosuppression, defined by a changing pattern in prescription.3 This again argues that most of the disease relapses were mild in nature, although their long-term effect on kidney function decline would warrant further follow-up. Notably, only three patients received a third vaccine dose because administration of booster doses was uncommon during the study period, whereas many countries are now offering fifth and sixth doses to immunocompromised patients. Subanalysis investigating differences between approved mRNA vaccines (BNT162b2 versus mRNA-1273) would provide important information because mRNA-1273 elicits a better humoral vaccine response,6 without increasing the rate of side effects7 and thus presumably also the risk of disease flare-ups. The work by Canney et al.3 highlights that disease relapses after mRNA COVID-19 vaccines are infrequent and that most of these disease relapses are self-limiting without a need to perform a repeat kidney biopsy or modification of immunosuppression. This is important information when discussing the pros and cons of vaccination with our patients, and it increases confidence in stating that mRNA vaccines are safe to use in most patients. COVID-19 vaccines are effective, even in immunosuppressed individuals. Analysis of the VISION network reported a vaccine effectiveness against hospitalization in the pre-Omicron era of 77% versus 90%.8 Reduced vaccine responses are reported in patients with ongoing "high-dose" immunosuppression, namely higher doses of steroids, alkylating agents, rituximab, mycophenolate mofetil, or calcineurin inhibitors,2 and in the absence of a humoral response or a low antibody response to prior COVID-19 vaccines, further booster doses, ideally with the adapted bivalent mRNA vaccines, should be offered. There is a clear benefit to vaccination in individuals with glomerular diseases because these patients often have worsening of kidney function,9 higher frequencies of severe forms of COVID-19,2 and reduced viral clearance,10 leading to prolonged days of hospitalization. However, there is limited information about the use of a third and fourth vaccine doses, which are now regularly recommended to patients with glomerular disorders. Repetitive stimulation of the immune system may further increase the frequency of disease relapses, and the cumulative risk upon several vaccine doses may reach a higher degree of clinical significance. Even with this study, we remain with this uncertainty—whether patients with a disease relapse after a COVID-19 vaccine will develop further relapses when subsequent doses are administered. The latter scenario seems likely, and prevaccine administration of low-dose immunosuppression (i.e., steroids) might be considered in such cases. Potential differences in relapse risk between mRNA and viral-vectored vaccines remain to be clarified. Disclosures H.-J. Anders reports consultancy fees and lecture fees from AstraZeneca, Bayer, Boehringer-Ingelheim, GSK, Janssen, Kezar, Novartis, Otsuka, Previpharma, Sanofi, and Vifor; research funding from Boehringer-Ingelheim; honoraria from Lilly and Otsuka; and an advisory or leadership role for JASN and Nephrology Dialysis Transplantation. A. Kronbichler reports consultancy for Catalyst Biosciences, Delta4, Otsuka, UriSalt, Vifor, and Walden Biosciences; research funding for Otsuka and Vifor; honoraria from Otsuka and Vifor; and an advisory or leadership role for the Catalyst Biosciences (advisory board), European Renal Association (scientific advisory board), Immunonephrology Working Group Young Nephrologists' Platform, Otsuka (advisory board), and Vifor Pharma (advisory board); and honoraria from Delta4, Otsuka, and Vifor. Funding H.-J. Anders is funded by the Deutsche Forschungsgemeinschaft (AN372/30-1).
Toll-like receptor (TLR)-9 recognizes CpG motifs in microbial DNA. TLR9 signalling stimulates innate antimicrobial immunity and modulates adaptive immune responses including autoimmunity against chromatin, e.g., in systemic lupus erythematosus (SLE). This review summarizes the available data for a role of TLR9 signalling in lupus and discusses the following questions that arise from these observations: 1) Is CpG-DNA/TLR9 interaction involved in infection-induced disease activity of lupus? 2) What are the risks of CpG motifs in vaccine adjuvants for lupus patients? 3) Is TLR9 signalling involved in the pathogenesis of lupus by recognizing self DNA?
Epigenetic modifications (e.g. DNA methylation) in NAFLD and their contribution to disease progression and extrahepatic complications are poorly explored. Here, we use an integrated epigenome and transcriptome analysis of mouse NAFLD hepatocytes and identify alterations in glyoxylate metabolism, a pathway relevant in kidney damage via oxalate release-a harmful waste product and kidney stone-promoting factor. Downregulation and hypermethylation of alanine-glyoxylate aminotransferase (Agxt), which detoxifies glyoxylate, preventing excessive oxalate accumulation, is accompanied by increased oxalate formation after metabolism of the precursor hydroxyproline. Viral-mediated Agxt transfer or inhibiting hydroxyproline catabolism rescues excessive oxalate release. In human steatotic hepatocytes, AGXT is also downregulated and hypermethylated, and in NAFLD adolescents, steatosis severity correlates with urinary oxalate excretion. Thus, this work identifies a reduced capacity of the steatotic liver to detoxify glyoxylate, triggering elevated oxalate, and provides a mechanistic explanation for the increased risk of kidney stones and chronic kidney disease in NAFLD patients.
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