Acute tubulointerstitial nephritis with or without uveitis: a novel form of post-acute COVID-19 syndrome in children (2023)

Multiorgan sequelae of coronavirus disease 2019 (COVID-19) beyond the acute phase of infection are increasingly described as clinical experience expands. In children, acute COVID-19 appears to be generally asymptomatic or mild. Yet, the multisystem inflammatory syndrome in children (MIS-C) may be a severe postinfectious complication following exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1Chou J. Thomas P.G. Randolph A.G. Immunology of SARS-CoV-2 infection in children.Nat Immunol. 2022; 23: 177-185Crossref PubMed Scopus (67) Google Scholar During the first pandemic year, we observed a striking increase in the incidence of acute tubulointerstitial nephritis (aTIN) without or with uveitis (TINUs) among children. Causes of aTIN include drugs, infections, and systemic diseases, but often remain undetermined. The rare TINUs syndrome associating aTIN and uveitis is considered to result from a still ill-characterized immune-mediated process. The observed increased incidence of idiopathic aTIN/TINUs prompted us to examine whether SARS-CoV-2 might be the initial trigger. Between April 1, 2020, and March 31, 2021, 48 children with a median age of 14.7 years (range, 9.4–17.6 years) were diagnosed with aTIN (n = 25) or TINUs (n = 23) of undetermined cause in France (Figure 1a and b) compared with the 8 to 10 cases/year of idiopathic aTIN recorded in 2018 to 2019, and 46 TINUs cases over an 18-year period between 2000 and 2018.2Chevalier A. Duflos C. Clave S. et al.Renal prognosis in children with tubulointerstitial nephritis and uveitis syndrome.Kidney Int Rep. 2021; 6: 3045-3053Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar This translates into 3- and 12-fold increases in the incidence of aTIN and TINUs, respectively (from 1 to 3 per million children, and from 0.12 to 1.4 per million children, respectively).Figure 1Incidence of nationwide pediatric acute tubulointerstitial nephritis (aTIN)/aTIN with uveitis (TINUs) cases in France and anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels and profiles in children with aTIN/TINUs. (a) Annual incidence of nationwide pediatric TINUs cases in France from 2000 to 2022. (b) Bimonthly incidence of nationwide pediatric aTIN/TINUs cases in France from April 2020 to November 2022. The approximate dates of circulation of the different strains of SARS-CoV-2 and the dates of launch of the vaccination campaigns according to age are shown in the figure. All analyzed cases of aTIN/TINUs were recorded during the circulation of the original virus and the Alpha variant. Interestingly, only 21 cases of aTIN/TINUs were later recorded between April 2021 and November 2022, when the Delta and the Omicron variants were the predominant viral strains. Of note, none of the patients had received any vaccination against SARS-CoV-2 before the diagnosis of aTIN/TINUs as the campaign for children aged >12 years was launched on June 15, 2021, in France. (Continued)View Large Image Figure ViewerDownload Hi-res image Download (PPT) The SARS-CoV-2 nasopharyngeal swab test result was negative in all children tested at diagnosis of aTIN/TINUs (37/48), and only 4 of 48 had presented symptoms of COVID-19 in the preceding weeks. Routine serologic SARS-CoV-2 testing targeting the nucleocapsid (N) protein was negative in all 29 tested children, and anti-spike (S) serology was positive only in patient 9 at onset of the kidney disease and before initiation of therapy, at the local centers (Supplementary Table S1). To investigate the potential association between aTIN/TINUs and COVID-19, we retrospectively performed SARS-CoV-2 serologic tests using a luciferase immunoprecipitation assay (LIPS) presenting a specificity of 100% and sensitivities ranging from 83.1% (LIPS-N) to 99.4% (LIPS-full S)3Grzelak L. Temmam S. Planchais C. et al.A comparison of four serological assays for detecting anti-SARS-CoV-2 antibodies in human serum samples from different populations.Sci Transl Med. 2020; 12eabc3103Crossref PubMed Google Scholar,4Sermet-Gaudelus I. Temmam S. Huon C. et al.Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 2020.Euro Surveill. 2021; 262001782Crossref PubMed Scopus (24) Google Scholar (Supplementary Methods and Supplementary Figure S1). Serum at the time of the aTIN/TINUs diagnosis was available for 16 children. Strikingly, all serum samples tested positive for high-level anti-N IgGs, whereas only one (patient 9) had positive anti-S IgGs (Figure 1c and Supplementary Table S1). As controls, 3 children diagnosed with ibuprofen-induced aTIN during the study period, which was not suspected to be related to a preceding COVID-19 infection, had negative LIPS results. Moreover, COVID-19 ELISpot was positive in the 5 children for whom peripheral blood cells were available. Together, these data were consistent with a SARS-CoV-2–specific immune response resulting from an infection because the patients had not yet been vaccinated against COVID-19, and the available vaccines exclusively elicit an anti-S antibody response. We also performed a pseudoneutralization assay to detect the presence of virus-neutralizing antibodies in 16 samples. Neutralizing activity against SARS-CoV-2 was only detected in 2 cases, in line with the absence of anti-S antibodies. We next compared the antibody titers and serologic profiles of patients in this study with those of age-matched controls (aged 9–17 years) hospitalized with mild COVID-19 or MIS-C during the same period (Figure 1c).4Sermet-Gaudelus I. Temmam S. Huon C. et al.Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 2020.Euro Surveill. 2021; 262001782Crossref PubMed Scopus (24) Google Scholar Children with MIS-C displayed predominantly the N+/S+ profile, with significantly higher antibody levels than the other 2 groups. Children with mild COVID-19 had higher levels of anti-S antibodies but lower levels of anti-N antibodies than children with aTIN/TINUs. We investigated whether the phenotype of the TINUs observed during the pandemic differed from those of the historical French pediatric cohort of TINUs from 2000–2018 (Supplementary Table S2).2Chevalier A. Duflos C. Clave S. et al.Renal prognosis in children with tubulointerstitial nephritis and uveitis syndrome.Kidney Int Rep. 2021; 6: 3045-3053Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar No statistically significant difference was observed. The typical presentation was sudden weight loss, polyuria, fever, and biological markers of inflammation. All patients had reduced estimated glomerular filtration rate at diagnosis (median, 31.9 ml/min per 1.73 m2 [range, 8.4–87.8 ml/min per 1.73 m2]), leading to kidney biopsy. Estimated glomerular filtration rate increased to 86.0 ml/min per 1.73 m2 (range, 66.8–134.5 ml/min per 1.73 m2) at 12-months follow-up, whereas 32% of patients had chronic kidney disease. Of note, none of the 6 patients with aTIN who were tested had autoantibodies to neutralizing type I interferons (Supplementary Figure S2). Thirty-nine (81%) patients underwent a kidney biopsy. Biopsies from the 16 patients with extensive serologic workup were blindly reassessed by 3 kidney pathologists (PI, MR, and J-PDVH; Supplementary Table S1). Light microscopy showed acute interstitial nephritis, characterized by an infiltrate of predominantly mononuclear cells associated with numerous tubulitis lesions and no Ig deposits, as classically observed in TINUs (Figure 2). We did not notice significant morphologic differences between our cohort and a series of 14 prepandemic TINUs, except a tendency toward more fibrosis and fewer eosinophils in the present series (Supplementary Table S3 and Supplementary Figures S3 and S4). To determine whether this kidney inflammation could be directly related to a specific pathogen, we performed metagenomic next-generation sequencing from 11 kidney biopsy samples, and no definite pathogens were identified (Supplementary Table S1). We next performed SARS-CoV-2 reverse transcriptase polymerase chain reaction and detected low viral loads of SARS-CoV-2 mRNA in 2 of 11 kidney samples. Of note, SARS-CoV-2 immunostaining of kidney biopsies was negative (Supplementary Figure S5). To our knowledge, this is the first study showing an increased incidence of pediatric aTIN and TINUs superimposed to the first wave of the COVID-19 pandemic. To date, the association of aTIN and COVID-19 has been suggested in a few cases.5Serafinelli J. Mastrangelo A. Morello W. et al.Kidney involvement and histological findings in two pediatric COVID-19 patients.Pediatr Nephrol. 2021; 36: 3789-3793Crossref PubMed Scopus (15) Google Scholar,6Eser-Ozturk H. Izci Duran T. Aydog O. Sullu Y. Sarcoid-like uveitis with or without tubulointerstitial nephritis during COVID-19.Ocul Immunol Inflamm. 2023; 31: 483-490Crossref PubMed Scopus (3) Google Scholar We inferred from our study that aTIN/TINUs could be considered as a novel form of post–COVID-19 disease in children. As a matter of fact, epidemiologic data, positive SARS-CoV-2 serologic test results, and ELISpot in all tested patients (16/16 and 5/5, respectively), and in situ detection of SARS-CoV-2 in 2 kidney biopsies, strongly support a causal link. COVID-19 was asymptomatic in 44 of 48 (90%) children at the acute phase, as reported in most post–COVID-19 MIS-C series.1Chou J. Thomas P.G. Randolph A.G. Immunology of SARS-CoV-2 infection in children.Nat Immunol. 2022; 23: 177-185Crossref PubMed Scopus (67) Google Scholar Notably, patients had a unique N+/S– serologic profile, which differs from those observed in adults with COVID-19 and children with MIS-C who develop both anti-S and anti-N IgGs. Similarly, children with mild COVID-19 predominantly generate anti-S IgGs.4Sermet-Gaudelus I. Temmam S. Huon C. et al.Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 2020.Euro Surveill. 2021; 262001782Crossref PubMed Scopus (24) Google Scholar The presence of anti–SARS-CoV-2 IgGs in all tested children in the present series further exemplifies the postinfectious nature of COVID-19–related aTIN/TINUs. Moreover, the lack of detection of SARS-CoV-2 mRNA in most kidney samples further supports a resolved infection. Of interest, the clinical and histologic features in the present series were similar to those of prepandemic TINUs, and affected mostly adolescents.2Chevalier A. Duflos C. Clave S. et al.Renal prognosis in children with tubulointerstitial nephritis and uveitis syndrome.Kidney Int Rep. 2021; 6: 3045-3053Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar This suggests that SARS-CoV-2–induced aTIN/TINUs cases share common pathogenic pathways with other forms. We therefore propose that SARS-CoV-2 could prime autoinflammation through molecular mimicry,7Davis H.E. McCorkell L. Vogel J.M. Topol E.J. Long COVID: major findings, mechanisms and recommendations.Nat Rev Microbiol. 2023; 21: 133-146Crossref PubMed Scopus (267) Google Scholar as reported in other post–COVID-19 long-term symptoms. SARS-CoV-2 uses the receptors angiotensin-converting enzyme 2 and transmembrane protease serine 2 for cell entry and protein S priming, respectively. More important, these 2 proteins are expressed in kidney tubules and in eye components.8Martin G. Wolf J. Lapp T. et al.Viral S protein histochemistry reveals few potential SARS-CoV-2 entry sites in human ocular tissues.Sci Rep. 2021; 1119140Crossref Scopus (9) Google Scholar,9Lely A. Hamming I. van Goor H. Navis G. Renal ACE2 expression in human kidney disease.J Pathol. 2004; 204: 587-593Crossref PubMed Scopus (198) Google Scholar Therefore, we hypothesize that both tissues were infected during the acute phase, triggering an overly potent and long-lasting detrimental immune response, despite subsequent clearance of the virus. Of note, the presence of a predominant lymphohistiocytic infiltrate and the absence of Ig deposits are in favor of a cell-mediated mechanism. Overall, our relatively large cohort of this rare disease provides additional insights into the pathophysiology of TINUs and suggests that SARS-CoV-2 should be considered among the infectious agents responsible for pediatric aTIN/TINUs. The limitations of this study are mainly the recruitment through biopsy-based registry, potentially subject to selection bias; the retrospective design, precluding fresh sampling for functional immunologic testing, including T-cell response to interferon; and the absence of available serologic samples from prepandemic patients with aTIN/TINUs. However, the 3 contemporaneous children with ibuprofen-related aTIN/TINUs had a negative SARS-CoV-2 LIPS serology. Interestingly, the aTIN/TINUs incidence declined after April 2021. The vaccination campaign, herd immunity, and emergence of new variants might have contributed to this trend. Nevertheless, our data should raise awareness that post–COVID-19 aTIN/TINUs may be responsible for chronic kidney damage in adolescents that may compromise kidney function in adulthood. All the authors declared no competing interests. We are grateful to the patients and families for their participation in this study. We are also grateful to Prof. Alain Fischer for his critical review of the manuscript and his wise and relevant advice. MAv and PI contributed equally to the work. MAv designed the study, handled regulatory ethics submissions, collected and analyzed clinical and serologic data, collected available samples, and wrote the first draft of the manuscript. MAv contacted PI to collaborate on this study. PI analyzed the histology data, designed and interpreted microbiological molecular data, and wrote the manuscript. ST and AC contributed equally to the work. ST performed and analyzed the serologic assays and edited the manuscript. AC collected and analyzed clinical data and edited the manuscript. PB performed the interferon experiments. MAt performed the pseudoneutralization assay. AJ and JF performed the next-generation sequencing on kidney biopsies. NDR and PP assisted with serologic testing. NK proof edited the manuscript in English and critically reviewed its scientific content. MR and J-PDVH analyzed the kidney histology. MPR reviewed the ophthalmologic data and examined the patients where possible. JZ and J-LC critically reviewed the manuscript with their expertise in immunology. ME led the virological experiments. IS-G coordinated the COVID-19 cohort in children locally, handled regulatory ethics submissions, analyzed the data, and edited the manuscript. OB designed the study, coordinated all experiments, and wrote the manuscript. All the authors observed the patients, collected clinical data, facilitated the study, and declare they have seen and approved the final version of the manuscript. Download .docx (7.34 MB) Help with docx files Supplementary File (Word)