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Abstract Background A percutaneous kidney biopsy (PKB) allows nephrologists to make informed decisions for treating various kidney diseases; however, the risk of bleeding complications should be considered, given the vascularity of the kidney. Many studies have reported risk factors for bleeding events after a PKB. However, while urinary N-acetyl-β-D-glucosaminidase (NAG) is a useful biomarker of kidney disease severity, little is known about whether or not urinary NAG is related to the bleeding risk. Methods Medical records of patients who underwent a PKB at the National Defense Medical College Hospital between October 2018 and October 2023 were retrospectively studied. Hemoglobin (Hb) loss ≥ 1 g/dL was defined as a bleeding event. Results Of the 213 patients, 110 (51.6%) were men, and the median age was 56 years old (interquartile range 40–71). The most frequent diagnosis on a PKB was IgA nephropathy (N = 72; 34.0%). Fifty-four patients (25.3%) experienced Hb loss ≥ 1 g/dL after a PKB, and urinary NAG/Cr levels before the biopsy were able to predict a bleeding event, with an area under the receiver operating characteristic curve of 0.65 (p = 0.005). Using the optimal cutoff value of 35 U/gCr, urinary NAG/Cr was found to be an independent risk factor by multiple logistic regression analysis (odds ratio 3.21, 95% confidence interval 1.42–7.27, p = 0.005). Even after adjusting for previously-reported risk factors, the elevated urinary NAG/Cr ratio remained a statistically significant variable. Compared with the pathological findings, only the severity of multilayered elastic laminae of the small muscular artery was associated with both urinary NAG/Cr levels (p = 0.008) and bleeding events (p = 0.03). Conclusion Urinary NAG successfully predicted not only the severity of kidney disorders but also bleeding events after a PKB. Arteriosclerosis in the kidneys may be the mechanism underlying these increased bleeding events.

IntroductionThe maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn’s disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses.Results and discussionHowever, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2) or dendritic cells (Atg16l1ΔCd11c) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7.ConclusionIn conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants.

Abstract Fecal calprotectin (FC) is a promising biomarker for diagnosis and treatment of inflammatory bowel disease, ulcerative colitis (UC), and Crohn’s disease. An enzyme immunoassay (EIA) is widely used for FC detection, though the considerable lag time, up to several days, causes clinical management delay. This study was performed to examine the new rapid kit fCAL-turbo, which is based on a particle-enhanced turbidimetric immunoassay (15 min), by comparing FC values with other EIAs (EliA, PhiCal, Bühlmann) and endoscopic scores. Using 94 samples, fCAL-turbo showed strong significant positive correlations with the other kits (Spearman’s r = 0.9178–0.9886). Of 74 UC patients, 69 underwent an endoscopy and fCAL-turbo reflected endoscopic activity with a moderate correlation with Mayo endoscopic subscore (MES) (r = 0.6945, others r = 0.6682–0.7013). Receiver operating characteristic analyses based on MES 0 versus 1–3 showed a similar efficacy as compared to the other kits (cut-off and area under the curve: 89.70 µg/g and 0.8592, respectively, others 62.35–138.4 µg/g and 0.8280–0.8611, respectively). Furthermore, multiple regression analysis confirmed that fCAL-turbo results significantly contributed to prediction of MES 0 with a higher t-value as compared to the other biomarkers. fCAL-turbo showed strong correlations with the other kits and also demonstrated excellent performance for predicting endoscopic remission of UC.

Heatstroke can cause multiple organ failure and systemic inflammatory response syndrome as the body temperature rises beyond the body’s ability to regulate temperature in a hot environment. Previous studies have indicated that heatstroke-induced acute kidney injury (AKI) can lead to chronic kidney disease. Therefore, there is an urgent need to elucidate the mechanism of heatstroke-induced AKI and to establish methods for its prevention and treatment. Recent reports have revealed that innate immunity, including neutrophils, macrophages, lymphocytes, and mast cells, is deeply involved in heat-induced AKI. In this review, we will discuss the roles of each immune cell in heat-induced renal injury and their potential therapeutic use.

Abstract Background Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) developed for treatment of patients with chronic myeloid leukemia (CML). The drug has been shown to act as a potent multikinase inhibitor by blocking not only the BCR-ABL1 gene sequence but also the SRC kinase family, though unexpected adverse events such as pleural effusion have recently been reported in patients undergoing treatment with dasatinib. Hemorrhagic colitis is a unique gastrointestinal adverse events associated with dasatinib and its pathogenesis remains poorly understood. Case presentation We report here a case of dasatinib-induced asymptomatic colitis in a patient with CML, who showed no exacerbation in careful observations and maintained deep molecular response (DMR) during a 3-year period. In addition, we performed transcriptome analysis of inflamed colonic mucosa specimens to clarify the possible mechanism of colitis that develops in association with dasatinib administration. Our results demonstrated that differential gene expression, especially lymphocyte-associated genes and chemokines, is substantially involved in inflammation of colonic mucosa in affected patients. Conclusion Dasatinib induces immune-mediated colitis following lymphocyte infiltration.

Introduction: In diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs) and triggers their activation. Methods: We orally administered ʟ-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of ʟ-carnitine on kidney mtROS production, circulating mtDNA content, and kidney CD11b high/CD11b low Mφ functions. Results: In db/db mice, mtROS production increased in proximal tubular cells and kidney CD11b low Mφs; both Mφ types showed enhanced TLR9 expression. ʟ-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11b low Mφs (p < 0.01), with improved SOD2 expression in the kidney (p < 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (p < 0.01), thereby lowering TNF-α production in CD11b high Mφs (p < 0.05) and ROS production by CD11b low Mφs (p < 0.01). Collectively, these changes alleviated DN symptoms. Discussion/Conclusion: The positive effects of ʟ-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.

Abstract Background The pathophysiologic role of exogenous granulocyte-colony stimulating factor (G-CSF) administration is reportedly linked to the progression of glomerulonephritis. However, the relationship between endogenous G-CSF overproduction and the progression of glomerulopathy has not been well investigated. Case presentation A 76-year-old woman presented with neutrophilia at a medical check-up and thorough examination revealed a high level of serum G-CSF. She subsequently developed mild renal dysfunction and proteinuria. Her renal biopsy showed lobulation of the glomeruli with mesangial proliferation and glomerular capillary walls with a double contour but no immune complex deposition, suggesting membranoproliferative glomerulonephritis-like glomerulopathy. Thereafter, her proteinuria levels fluctuated in parallel with the changes in her blood neutrophil count and finally reduced considerably in association with her decreased neutrophil count. Conclusions The unique features of this case suggest that endogenous overproduction of G-CSF could play an important role in the pathogenesis of active glomerulonephritis.

Abstract Lupus nephritis is a crucial complication of systemic lupus erythematosus. In this study, we investigated the roles of mouse natural killer T (NKT) cells in lupus nephritis. From 24 weeks of age, NZB/NZW F1 mice were injected with alpha-galactosylceramide (α-GalCer) or vehicle once a week for four weeks. In the α-GalCer group, the levels of proteinuria and blood urea nitrogen were significantly lower than those in the vehicle group. The histological evaluation showed a decrease in glomerular immune complex deposits and an alleviation of podocyte injury. The proportion of NKT cells in the mononuclear cell (MNC) fraction in the α-GalCer group was significantly decreased in the liver, kidney, and spleen. The proliferation and cytokine production in α-GalCer-stimulated liver MNCs were markedly diminished in the α-GalCer group (anergy). The IFN-γ production in liver MNCs stimulated by concanavalin A or an anti-CD3 antibody did not differ between the two groups, whereas the IL-4 production was significantly lower in the α-GalCer group. In addition, the IgM production in CpG-oligodeoxynucleotide-stimulated spleen MNCs was significantly lower in the α-GalCer group. These results suggest that α-GalCer suppressed Th2 immune responses in NKT cells and B cell function, thereby slowing the progression of lupus nephritis.

Abstract Background Podocyte phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic adult membranous nephropathy (MN). Histological PLA2R staining in the renal tissue has proven to be useful for the detection of idiopathic MN. However, glomerular PLA2R deposits have also been recently observed in several patients with secondary MN, such as hepatitis B virus-associated, hepatitis C virus-associated, and neoplasm-associated MN. Certain inflammatory environments have been suggested to lead to abnormal expression of PLA2R epitopes, with the resulting production of PLA2R autoantibodies. Case presentation We report two patients diagnosed with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis with MN-lesions, in whom ANCA titers for myeloperoxidase (MPO) were persistently positive. The first patient was a 52-years-old man who presented with interstitial pneumonitis. Microscopic hematuria and proteinuria were found when the interstitial pneumonitis became more severe. Renal biopsy findings yielded a diagnosis of ANCA-associated glomerulonephritis (mixed class) with MN-lesions. The second patient was a 63-years-old woman who had been treated for relapsing polychondritis. Her renal tissue showed evidence of focal ANCA-associated glomerulonephritis with MN-lesions. Interestingly, both MPO and PLA2R were detected in the glomerular subepithelial deposits of both patients. Immunoglobulin G (IgG) 1 and IgG2 were positive in the glomeruli of patient 2, and all subclasses of IgGs were positive in patient 1. Conclusion The present cases suggest that ANCA-associated glomerulonephritis could expose PLA2R, leading to the development of MN-lesions.

Abstract Background Amyloid A amyloidosis is one of the most common forms of amyloidosis. It is secondary to rheumatoid arthritis, which is difficult to manage and has a poor prognosis. We present a patient with rheumatoid arthritis and amyloid A amyloidosis who was treated with tocilizumab, a humanized monoclonal antibody against interleukin 6 receptor, resulting in improvement in both proteinuria and gastrointestinal symptoms; however, amyloid deposition remained. Case presentation A 67-year-old woman who had previously been treated for rheumatoid arthritis presented with abdominal pain and diarrhea. Right renal cell carcinoma was found, and amyloid A amyloidosis was diagnosed concomitantly based on colon biopsy. The renal cell carcinoma was resected, and the non-cancerous part of the renal tissue also showed amyloid A deposition. Following surgery, protein levels in the urine increased to the nephrotic range, and administration of tocilizumab was initiated, which resulted in resolution of the proteinuria. The patient’s gastrointestinal symptoms were also alleviated. However, repeat colon biopsy showed amyloid deposition. Conclusions This case of amyloid A amyloidosis suggests that amyloid deposition indicates only structural change of the affected tissue, and that it is not amyloid deposition per se that causes the clinical symptoms of amyloidosis.

Background and study aims Foveolar-type adenoma is described as a very rare tumor that occurs in individuals without Helicobacter pylori (HP) infection and diagnosed as adenocarcinoma in the Japanese Classification of Gastric Carcinoma (JCGC). However, we have frequently encountered patients with foveolar-type adenoma that endoscopically resembles a hyperplastic polyp, suggesting that it has just been overlooked to date. Here, we analyzed clinicopathological characteristics of a special subtype of foveolar-type adenoma showing specific endoscopic findings. Patients and methods From a total of 212 patients with gastric cancer resected during a 22-month period, we enrolled 14 (6.6 %) diagnosed with foveolar-type adenoma (adenocarcinoma in JCGC). HP infection status was determined by eradication history, HP serum IgG antibody level, urea breath test, and endoscopic and histological findings. All lesions were observed using white-light endoscopy and narrow-band imaging with magnification endoscopy (NBIME). Endoscopically resected lesions were histologically examined. Results None of 14 patients had a current or past history of HP infection. All lesions were visualized on non-atrophic gastric mucosa as small reddish protrusions with fine granular surface, showing a raspberry-like appearance. NBIME showed papillary or gyrus-like microstructures with irregular capillary. Lesions were histologically diagnosed as foveolar-type adenoma showing MUC5AC-positive gastric mucin phenotype. Ki-67 was overexpressed (median labeling index 69.9 %, range 28.4 – 92.1 %), though all lesions were an intraepithelial tumor without stromal invasion. p53 over-staining was not seen in any. Conclusions Raspberry-like lesions on non-atrophic gastric mucosa in HP-uninfected individuals should be evaluated for the possibility of a special subtype of foveolar-type adenoma.

Background and study aims Characteristic endoscopic findings, such as linear furrows, rings, and whitish exudates, indicate the presence of esophageal eosinophilia (EE), though no specific findings are known to distinguish eosinophilic esophagitis (EoE) from proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). Here, we present a novel endoscopic finding in some EE patients possessing a linear longitudinal arrangement of whitish nodules with the appearance of the back of an Ankylosaurus dinosaur, termed Ankylosaurus back sign (ABS), and evaluations of its significance in affected patients. Patients and methods Fifty-five patients diagnosed with EE (≥ 15 eosinophils/high power field) who were treated at our hospital and shown to evaluate a PPI response were enrolled. Endoscopic findings at baseline and clinical parameters were retrospectively reviewed. Furthermore, the clinicopathological features of patients with ABS, as well as the relationship between its presence and PPI response were evaluated. Results Fifty-five patients (47 males, 8 females) with EE (17 with EoE, 38 with PPI-REE) were evaluated, of whom 50 (90.9 %) had linear furrows, the most frequently found feature, while ABS was found in 9 (16.4 %). Inter-observer agreement was substantial for ABS (κ 0.77). Interestingly, all patients with ABS had PPI-REE. Our findings revealed that the presence of ABS was closely associated with reflux esophagitis (RE) in patients with PPI-REE. Conclusions Although ABS was less frequent than typical endoscopic findings such as linear furrows in EE, this novel finding was closely associated with PPI-REE accompanied with RE. The clinical implications of ABS in patients with EE should be investigated further.

Background and study aims Recurrence of common bile duct stones (CBDS) in patients treated with endoscopic sphincterotomy (ES) can lead to deterioration in their quality of life. Although the pathology and related factors are unclear, we speculated that proton pump inhibiter (PPI) administration increases the risk of CBDS recurrence by altering the bacterial mixture in the bile duct. Patients and methods The primary endpoint of this retrospective study was recurrence-free period. Several independent variables considered to have a relationship with CBDS recurrence including PPI use were analyzed using a COX proportional hazard model, with potential risk factors then evaluated by propensity score matching analysis. Results A total of 219 patients were analyzed, with CBDS recurrence found in 44. Analysis of variables using a COX proportional hazard model demonstrated that use of PPIs and ursodeoxycholic acid (UDCA), as well as the presence of periampullary diverticula (PD) each had a hazard ratio (HR) value greater than 1 (HR 2.2, P = 0.007; HR 2.0, P = 0.02; HR 1.9, P = 0.07; respectively). Furthermore, propensity score matching analysis revealed that the mean recurrence-free period in the oral PPI cohort was significantly shorter as compared with the non-PPI cohort (1613 vs. 2587 days, P = 0.014). In contrast, neither UDCA administration nor PD presence was found to be a significant factor in that analysis (1557 vs. 1654 days, P = 0.508; 1169 vs. 2011 days, P = 0.121; respectively). Conclusion Our results showed that oral PPI administration is a risk factor for CBDS recurrence in patients who undergo ES.

Background and study aims Esophageal mucosal breaks in patients with reflux esophagitis (RE) have a unique circumferential distribution. However, the specific location of mucosal breaks during recurrence of RE remains unclear. We investigated the circumferential distribution of mucosal breaks in patients with recurrent RE and compared their location to that noted at the initial diagnosis. Patients and methods We retrospectively enrolled patients with recurrent RE with Los Angeles (LA) grade A-C who were treated at our University Hospital between July 1996 and June 2014. The circumferential distribution of esophageal mucosal breaks was evaluated at the time of the initial diagnosis and again at the time of recurrence. Information regarding clinical parameters, including proton pump inhibitor administration, presence of hiatal hernia, and mucosal atrophy, was also reviewed. Results A total of 114 patients with recurrent RE were examined during the study period, with a mean duration to recurrence after initial diagnosis of 39.4 months. The majority (72.8 %) had the same LA grade at recurrence. In addition, recurrent mucosal breaks in 96 (84.2 %) patients were observed to have occurred in the same circumferential location as at the initial diagnosis, while those in 18 (15.8 %) were observed in a different location. When recurrent lesions had a different location, the LA grade also tended to be different (P = 0.02). Conclusions We found that most patients with recurrent RE developed lesions in the same circumferential location as noted for the initial lesions. Those in different locations at recurrence were associated with a change in LA grade.

BACKGROUND:CD5+ B cells are a type of regulatory immune cells, though the involvement of this B cell subset in intestinal inflammation and immune regulation is not fully understood. METHODS:We examined the distribution of CD5+ B cells in various mouse organs. Expression levels of CD11b, IgM, and toll-like receptor (TLR)-4 and -9 in B cells were evaluated. In vitro, TLR-stimulated IL-10 production by colonic lamina propria (LP) CD5+ and CD5- B cells was measured. In vivo, mice with acute or chronic dextran sulfate sodium (DSS)-induced colonic injury were examined, and the frequency of colonic LP CD5+ B cells in those was assessed by flow cytometry. RESULTS:The expression level of TLR9 was higher in colonic LP CD5+ B cells as compared to CD5- B cells. Colonic LP CD5+ B cells produced greater amounts of IL-10 following stimulation with TLR ligands, especially TLR9, as compared with the LP CD5- B cells. Acute intestinal inflammation transiently decreased the frequency of colonic LP CD5+ B cells, while chronic inflammation induced a persistent decrease in colonic LP CD5+ B cells and led to a CD5- B cell-dominant condition. CONCLUSION:A persistent altered mucosal B cell population caused by chronic gut inflammation may be involved in the pathogenesis of inflammatory bowel diseases.

Background and study aims: Mallory-Weiss tears (MWTs) are not only a common cause of acute nonvariceal gastrointestinal bleeding but also an iatrogenic adverse event related to endoscopic procedures. However, changes in the clinical characteristics and endoscopic features of MWTs over the past decade have not been reported. The aim of this study was to investigate recent trends in the etiology and endoscopic features of MWTs. Patients and methods: We retrospectively reviewed the medical records of patients with a diagnosis of MWT at our university hospital between August 2003 and September 2013. The information regarding etiology, clinical parameters, endoscopic findings, therapeutic interventions, and outcome was reviewed. Results: A total of 190 patients with MWTs were evaluated. More than half (n = 100) of the cases occurred during endoscopic procedures; cases related to alcohol consumption were less frequent (n = 13). MWTs were most frequently located in the lesser curvature of the stomach and right lateral wall (2 – to 4-o’clock position) of the esophagus, irrespective of the cause. The condition of more than 90 % of the patients (n = 179) was improved by conservative or endoscopic treatment, whereas 11 patients (5.8 %) required blood transfusion. Risk factors for blood transfusion were a longer laceration (odds ratio [OR] 2.3) and a location extending from the esophagus to the stomach (OR 5.3). Conclusions: MWTs were frequently found on the right lateral wall (2 – to 4-o’clock position) of the esophagus aligned with the lesser curvature of the stomach, irrespective of etiology. Longer lacerations extending from the esophagus to the gastric cardia were associated with an elevated risk for bleeding and requirement for blood transfusion.

Introduction: The maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn's disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses. Results and discussion: However, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2) or dendritic cells (Atg16l1ΔCd11c) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7. Conclusion: In conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants. [ABSTRACT FROM AUTHOR]

A major complication of heat-related illness is the development of acute kidney injury (AKI) and damage to kidney tubular cells. Because kidney tubular cells use fatty acids as a major energy source, impaired fatty acid oxidation (FAO) may be associated with kidney injury due to heat stress. Carnitine is essential in the transportation of fatty acid into mitochondria for FAO. To date, there has been little attention given to the role of carnitine in heat-related illness and AKI. To evaluate the relationship between carnitine inadequacy and heat-related illness severity or AKI, we examined serum carnitine levels in patients with heat-related illness. We also used heat-stressed mice to investigate the effect of L-carnitine pretreatment on various kidney functions such as mitochondrial activity, proinflammatory changes in kidney macrophages, and histological damage. We observed an elevation in serum acylcarnitine levels, indicating carnitine insufficiency in patients with severe heat-related illness and/or AKI. L-Carnitine pretreatment ameliorated ATP production in murine tubular cell mitochondria and prevented a change in the kidney macrophage population dynamics observed in AKI: a decrease in tissue-resident macrophages, influx of bone marrow-derived macrophages, and change toward proinflammatory M1 polarization. In conclusion, carnitine insufficiency may be closely associated with severe heat-related illness and related AKI. Enhancement of the FAO pathway by L-carnitine pretreatment may prevent heat stressinduced AKI by restoring mitochondrial function. [ABSTRACT FROM AUTHOR]