Key points are not available for this paper at this time.
Biopsy-proven acute tubulointerstitial nephritis (aTIN) has been found in 15%–27% of patients with acute kidney disease (AKD).1 The causes of aTIN include medications, infections, and systemic diseases but often remain undetermined. The broad application of tumor immunotherapy and the emergence of post-acute coronavirus disease 19 (COVID-19) syndrome during the global pandemic and the post-epidemic era, characterized by enhanced immune-inflammatory reactions, are closely linked to the increasing prevalence of aTIN as a novel form of acute kidney injury (AKI).2,3 This is despite the fact that the preceding infection might be asymptomatic, as described in the literature.4 Cases of immune checkpoint inhibitor (ICI)-induced aTIN, new-onset or relapse of tubulointerstitial nephritis and uveitis (TINU) syndrome (with or without uveitis), primary Sjögren's syndrome (pSS), sarcoidosis, and IgG4-related nephritis have been frequently reported. Increasing evidence has confirmed that T-cell-mediated cellular immunity serves as the main mechanism of ICI-related aTIN, which shares similar features with other causes of drug-induced aTIN, albeit with a longer latency period. Published studies have revealed that most cases of ICI-aTIN show moderate to marked CD3+ T-cell interstitial infiltration with CD4+ and CD8+ phenotypes, accompanied by mild B-cell infiltration. Notably, CD163+ M2 macrophage infiltration has also been observed and is considered evidence of a persistent inflammatory process, which likely drives the chronicity of kidney injury and results in interstitial fibrosis. It has been reported that tertiary lymphoid structure (TLS) signatures are closely linked to ICI-aTIN, supported by histopathological identification as a clue to persistent inflammation. Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-γ, and tumor necrosis factor (TNF) superfamily signatures have been detected. Another case reported IgG4-positive cell infiltration around TLS in the early stage of IgG4-aTIN.5 Therefore, non-invasive biomarkers, including urinary chemokine (C-X-C motif) ligand 9 (CXCL9) and TNF-α, are suggested to discriminate active interstitial nephritis from those without. In addition, the unique mechanism of ICIs may influence the reprogramming of the immune system, leading to a loss of tolerance and hence intensifying the susceptibility of tubular cells to other drugs (e.g., proton pump inhibitors, PPI). Short-term glucocorticoids appear to be a potentially effective treatment strategy for aTIN. The increased risk of chronic kidney disease (CKD) is difficult to avoid in survivors receiving long-term ICI treatment.6 Research has documented that aTIN can be triggered by various peri- or post-infectious conditions, including those associated with viral infections such as COVID-19 and influenza, as well as bacterial infections such as uropathogenic Escherichia coli (UPEC).7 Studies on renal biopsies from individuals recovering from mild COVID-19 infection have shown no detectable virus using metagenomic next-generation sequencing and reverse transcription polymerase chain reaction techniques, with only minimal in situ viral detection. Despite the absence of active viral replication, all patients exhibited a robust and prolonged immune response, as evidenced by a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology with a distinctive N+/S- profile, which is distinct from the pattern seen in multisystem inflammatory syndrome in children. The histological findings, characterized by a significant lymphohistiocytic infiltrate and a lack of immune complex deposits, suggest that the pathogenesis of post-acute COVID-19 aTIN may be primarily driven by a cell-mediated immune response. The analysis of heritability based on single nucleotide polymorphisms (SNPs) has revealed that the HLA-DQA1*0104/DQB1*0503/DRB1*1405 haplotype is a notable risk factor for the development of drug-induced aTIN and TINU.8 This particular genetic configuration may contribute to renal tubulointerstitial inflammation by increasing the antigen-presenting capability of renal tubular cells. In contrast, patients with pSS- and IgG4-related aTIN present a different pattern of tested human leukocyte antigen (HLA) alleles when compared to those with TINU and drug-induced aTIN.8 The occurrence of relapses in pSS and IgG4-related diseases following post-acute COVID-19 syndrome confirms the nature of cellular autoimmunity in these immune-mediated diseases. Beyond the effect of steroids as the mainstay, B-cell depletion treatments that target CD20, B-lymphocyte stimulator (Blys), and a proliferation-inducing ligand (APRIL), such as rituximab and telitacicept (Blys/APRIL dual inhibition), have achieved exciting results in controlling IgG4-related disease (IgG4-RD) and pSS.9–12 Data from a Chinese IgG4-RD cohort13 and sarcoidosis case series14 suggest that a combination of steroid-sparing therapies is effective in reducing disease relapse and maintaining clinical remission. This evidence supports the value of a multifaceted approach to treatment in managing these complex conditions. Perazella et al. summarized the updated medications related to aTIN,15 which are usually attributed to allergic or immune-mediated pathogenesis. Proton pump inhibitors, 5-aminosalicylates (usually for inflammatory bowel disease IBD), and vedolizumab (also for IBD), have been implicated as culprits of aTIN. On the other hand, nonsteroidal anti-inflammatory drugs (NSAIDs) and contrast-related kidney injuries are mainly due to their nephrotoxic or ischemic effects, manifesting as tubular injuries. Today, renal biopsy remains the gold standard for the diagnosis of aTIN. Typical presentations, including renal glycosuria with generalized tubular dysfunction, sterile pyuria (or white blood cell casts), and renal tubular acidosis, are crucial clues for the clinical diagnosis of aTIN. Eosinophiluria is typically linked to drug-induced acute interstitial nephritis, but detecting it via Wright's staining is challenging, and the range of conditions causing eosinophiluria is not yet fully understood.16 Erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP), as representatives of systemic inflammatory markers, might be helpful but lack specificity.17 Based on the hypothesis that aTIN is mediated by specific T-cell subsets, we propose that measuring the levels of T-cell-derived cytokines could serve as biomarkers to differentiate aTIN from other etiologies of acute kidney injury. Noninvasive examinations, such as the combination of biomarkers like urinary TNF-α, CXCL-9, and serum soluble interleukin-2 receptor (sIL-2R), have been confirmed as promising methods for early diagnosis, monitoring, and guiding the treatment. For example, patients diagnosed with acute interstitial nephritis exhibited significantly higher levels of urinary TNF-α compared to those with alterative diagnoses, including acute tubular injury.18 Furthermore, urinary TNF-α has been identified as a potential biomarker that could assist in diagnosing ICI-associated TIN.19 Recently, the role of imaging in diagnosis has been explored. Historically, 67gallium scintigraphy was proposed, but the caveat is that it requires several days for the lesion to manifest on imaging. In the current era of routine positron emission tomography-computed tomography (PET-CT) imaging in cancer patients, it can be considered a prompter diagnosis of interstitial nephritis.20,21 It deserves attention that, in addition to acute injury from allergic or immune-mediated inflammation, we should raise awareness of those with long-lasting or recurrent features that could result in an increased risk of chronic kidney disease in the future. Moreover, studies have shown that patients with genetic variants, e.g., uromodulin (UMOD), Fanconi anemia-associated nuclease 1 (FAN1), and ubiquitin-like modifier activating enzyme 1 (UBA1), show increased chemosensitivity to nephrotoxic agents.22,23 For instance, UMOD is recognized as a protective factor in the transition from AKI to CKD. Higher levels of UMOD are associated with smaller declines in evaluated glomerular filtration rate (eGFR) and a reduced incidence of composite kidney outcome, which includes CKD incidence, CKD progression, or end-stage renal disease, in a cohort of hospitalized patients. In a mouse model of renal repair, a greater expression of UMOD in the loop of Henle was observed, which corresponded with a decrease in fibrosis.24,25 However, genetic diseases can be identified by whole-genome sequencing in patients with chronic tubulointerstitial nephritis. In summary, the increasing prevalence of aTIN in the context of tumor immunotherapy and post-COVID-19 syndrome presents significant clinical challenges. This commentary highlights the complex interplay between immune checkpoint inhibitors, genetic predispositions, and the persistent inflammatory processes that contribute to aTIN. The role of noninvasive biomarkers and advanced imaging techniques in early diagnosis and monitoring is emphasized, as is the potential benefits of targeted immunomodulatory therapies. The evolving landscape of aTIN management underscores the need for a multidisciplinary approach that integrates clinical acumen with the latest research findings to optimize patient outcomes. As we continue to navigate the post-pandemic era, a deeper understanding of the mechanisms underlying aTIN will be crucial for developing more effective treatment strategies and mitigating the long-term risks of chronic kidney disease.
Shen et al. (Mon,) studied this question.