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Renal fibrosis is an outcome of chronic kidney disease, independent of the underlying etiology. Renal fibrosis is caused primarily by oxidative stress and inflammation. We identified the components of Plantaginis semen and elucidated their anti-fibrotic and anti-inflammatory mechanisms. The renoprotective components and underlying molecular mechanisms of P. semen were investigated in rats with adenine-induced chronic tubulointerstitial nephropathy (TIN) and in idole-3-acetic acid (IAA)-stimulated NRK-52E cells. Acetate and n-butanol extracts were found to be the bioactive fractions of P. semen. A total of 65 compounds including geniposidic acid (GPA), apigenin (APG), and acteoside (ATS) were isolated and identified. Among the seven main extract components, treatment with GPA, APG, and ATS reduced the serum levels of creatinine and urea in TIN rats. Mechanistically, GPA ameliorated renal fibrosis through repressing aryl hydrocarbon receptor (AHR) signaling and regulating redox signaling including inhibiting proinflammatory nuclear factor kappa B (NF-ƙB) and its target gene products as well as activated antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream target gene products in both TIN rats and IAA-stimulated NRK-52E cells. The inhibitory effect of GPA on AHR, NF-Ƙb, and Nrf2 signaling were partially abolished in IAA-stimulated NRK-52E cells treated with CH223191 compared with untreated IAA-stimulated NRK-52E cells. These data demonstrated that GPA alleviates oxidative stress and inflammation partly by suppressing AHR signaling., (© 2024 John Wiley & Sons Ltd.)

Interstitial nephritis is the primary cause of mortality in IBV-infected chickens. Our previous research has demonstrated that Radix Isatidis polysaccharide (RIP) could alleviate this form of interstitial nephritis. To explore the mechanism, SPF chickens and chicken embryonic kidney cells (CEKs) were pre-treated with RIP and subsequently infected with QX-genotype IBV strain. Kidneys were sampled for transcriptomic and metabolomic analyses, and the cecum contents were collected for 16S rRNA gene sequencing. Results showed that pre-treatment with RIP led to a 50 % morbidity reduction in infected-chickens, along with decreased tissue lesion and viral load in the kidneys. Multi-omics analysis indicated three possible pathways (including antioxidant, anti-inflammatory and anti-apoptosis) which associated with RIP's efficacy against interstitial nephritis. Following further validation both in vivo and in vitro, the results showed that pre-treatment with RIP could activate the antioxidant transcription factor Nrf2, stimulate antioxidant enzyme expression, and consequently inhibit oxidative stress. Pre-treatment with RIP could also significantly reduce the expression of NLRP3 inflammasome and apoptosis-associated proteins (including Bax, Caspase-3, and Caspase-9). Additionally, RIP was also observed to promote the growth of beneficial bacteria in the intestine. Overall, pretreatment with RIP can alleviate QX-genotype IBV-induced interstitial nephritis via the Nrf2/NLRP3/Caspase-3 signaling pathway. This study lays the groundwork for the potential use of RIP in controlling avian infectious bronchitis (IB)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: The authors have no conflicts of interest to declare.

Post-infectious glomerulonephritis (PIGN), an uncommon variety of glomerulonephritis (GN), is characterized by emergence of nephritic syndrome within a few weeks following an infectious event. PIGN typically presents as a mild condition and tends to resolve by the time of diagnosis for GN. Aggregatibacter actinomycetemcomitans belongs to the HACEK group of bacteria, which constitutes less than 3% of bacteria responsible for community-acquired infective endocarditis. We present a case of 29-year-old man suspected of lymphoma with B-symptoms along with severe splenomegaly and nephromegaly. Shortly after, he developed an episode of nephritic syndrome accompanied by acute kidney injury (AKI) and high titers of cytoplasmic ANCA (c-ANCA)-positivity. Kidney biopsy revealed PIGN with tubulointerstitial nephritis. Despite treatment with antibiotics and corticosteroid, he visited the emergency room due to worsening dyspnea and multi-organ failure. An echocardiogram showed a bicuspid aortic valve with vegetation unseen on previous echocardiogram. He underwent aortic valve replacement immediately without adverse events. Four months after valve replacement, his renal function and cardiac performance have remained stable. We report a case of PIGN with AKI and high titers of c-ANCA appearing later as an infective endocarditis due to Aggregatibacter actinomycetemcomitans. With careful clinical observation and appropriate and timely management, satisfactory outcomes for patient health are possible., (© 2024 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

We report a 67-year-old man who presented with poor dietary intake and fatigue. Laboratory tests showed leukopenia, antinuclear antibody (ANA) positivity, anti-dsDNA antibody (A-dsDNA) and anti-Smith antibody (anti-Sm) negativity, decreased C3 and C4, elevated serum immunoglobulin G (IgG), IgG4, and creatinine, and 1.25 g urinary protein at 24 hours. As his condition worsened, re-examination showed thrombocytopenia and A-dsDNA positivity, and renal biopsy pathology showed IgG4-related tubulointerstitial nephritis. The final diagnosis was IgG4-related disease (IgG4-RD) with systemic lupus erythematosus (SLE). His condition improved with glucocorticoid (GC) combined with hydroxychloroquine (HCQ) and mycophenolate mofetil (MMF) treatment. This case highlights that IgG4-RD and SLE may occur successively or co-exist and may convert into each other.

Background and Objectives: In clinical practice, some patients are diagnosed with diabetic nephropathy (DN) combined with acute tubulointerstitial nephritis (ATIN) through renal biopsy. There is relatively little research on the treatment and prognosis of such patients, and no consensus exists on the use of glucocorticoid for treatment. Therefore, our study explores the progression of DN combined with ATIN and the renal outcomes after treatment with glucocorticoid., Methods: This study retrospectively analyzed patients diagnosed with DN combined with ATIN through renal biopsy at our center from January 1, 2015, to December 31, 2021. We collected general patient information, laboratory indicators, renal pathology indicators, and the glucocorticoid usage after kidney biopsy. Follow-up data were collected from medical records. Statistical analysis methods included t-tests, non-parametric tests, and chi-square tests. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for renal endpoint events in patients. Statistical significance was defined as p -values < 0.05., Results: In this study, a total of 67 patients were included. The subjects were divided into two groups based on whether they received glucocorticoid treatment: 33 patients in the steroid group and 34 in the non-steroid group. In the steroid group, 19 patients reached the renal endpoint event, which was significantly higher than in the non-steroid group (57.58% vs. 29.41%, p  = 0.038). Univariate Cox regression analysis showed that serum creatinine (HR = 1.008, p  < 0.001), albumin (HR = 0.919, p  < 0.001), 24-h urinary protein (HR = 1.093, p  = 0.002), hemoglobin (HR = 0.964, p  = 0.001), triglycerides (HR = 1.12, p  = 0.04), and the use of glucocorticoid (HR = 2.507, p  = 0.019) were influencing factors for renal endpoint events in patients with DN combined with ATIN. Multivariate Cox regression analysis showed that albumin (HR = 0.863, p  = 0.003) was an independent risk factor for renal endpoint events in patients with DN combined with ATIN., Conclusions: The use of glucocorticoid in treatment does not improve renal prognosis in patients with DN combined with ATIN. Lower levels of albumin are associated with a worse renal prognosis.

We report a case of IgG4-related disease (IgG4-RD) with marked eosinophilia. A 79-year-old woman was admitted due to diarrhoea and weight loss. Cervical lymphadenopathy, bilateral submandibular glands swelling, anaemia (Hb8.5 g/dl), hypereosinophilia (9750/μl), elevated serum creatinine (1.57 mg/dl), pancreatic amylase (191 IU/l), and IgG4 (3380 mg/dl) were found. Diffusion-weighted image on magnetic resonance imaging showed high-intensity signals inside both the pancreas and the kidneys. The echogram of submandibular glands revealed cobblestone pattern. Kidney biopsy revealed acute tubulointerstitial nephritis. Biopsies of lip, gastrointestinal tract, and bone marrow showed infiltration of lymphoplasmacytic cells and IgG4-positive plasma cells (30-67/HPF). Gastrointestinal and bone marrow biopsies also showed eosinophilic infiltration. Adrenal insufficiency, rheumatic disease, tuberculosis, parasite infection, drug-induced eosinophilia, and eosinophilic leukaemia were all ruled out. We started treatment with 40 mg of prednisolone (PSL) and her general condition rapidly improved. The eosinophil count, serum IgG4, and serum creatinine decreased. We gradually tapered PSL and maintained 5 mg/day. During the 5 years of treatment, she had no recurrence of the symptom. According to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD, eosinophils >3000/μl is one of the exclusion criteria. If we comply with this criterion, the diagnosis of IgG4-RD should be avoided. However, our case fit the diagnostic criteria of type I autoimmune pancreatitis, IgG4-related sialadenitis, and global diagnosis of IgG4-RD. We finally diagnosed our case as IgG4-RD with secondary hypereosinophilic syndrome. This case suggests that IgG4-RD with eosinophils >3000/μl does exist in the real world., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Purpose: To report the first series of tubulointerstitial nephritis (TINU) syndrome from the Middle East., Methods: We retrospectively included patients with elevated urine beta-2 microglobulin, and a diagnosis of TINU based on anterior uveitis with or without posterior involvement. Multimodal imaging, duration of follow-up, local and systemic treatment used were recorded., Results: 24 eyes of 12 patients (8 male, mean age 20.3 years) met the criteria for TINU. The most common posterior segment clinical finding was optic nerve head edema (41.7%), while on fluorescein angiography 58.3% and 75% of eyes had peripheral vascular and optic disc leakage, respectively. The mean follow-up was 2.5 years and all patients required immunomodulatory treatment., Conclusions: Middle Eastern patients with TINU seem to have a male predominance, a bimodal distribution in terms of age, and present with ocular involvement first. Multimodal imaging is paramount in detecting subclinical inflammation and tailoring immunomodulatory treatment.

Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1 high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4 + and CD8 + T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1 +/+ mice than in the kidneys of TIN-induced Eprs1 +/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1 +/- mice. TIN-induced fibrosis was also reduced in Rag1 -/- mice adoptively transferred with Eprs1 +/- T cells compared to the Rag1 -/- mice transferred with Eprs1 +/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Immunoglobulin G4-related disease is an inflammatory disease affecting multiple organs including the kidney. Immunoglobulin G4-related kidney disease most commonly manifests as a tubulointerstitial nephritis and is associated with glomerular disease in a proportion of cases. Membranous nephropathy is the most frequent glomerular lesion. Herein, we report the first documented case of immunoglobulin G4-related disease presenting with nephrotic syndrome owing to minimal change disease., Case Presentation: A 67-year-old South Asian male presented to our service with systemic upset and leg swelling. He had heavy proteinuria (urine protein:creatinine ratio 1042 mg/mmol) and was hypoalbuminemic (17 g/L) and hypercholersterolemic (9.3 mmol/L), consistent with the nephrotic syndrome. His serum creatinine was 140 μmol/L, and he was hypocomplementemic (C3 0.59 g/L, C4 < 0.02 g/L) with raised immunoglobulin G4 subclass levels (5.29 g/L). Kidney biopsy demonstrated minimal change disease alongside a plasma-cell-rich tubulointerstitial nephritis with strong positive staining for immunoglobulin G4. A diagnosis of minimal change disease in the setting of immunoglobulin G4-related disease was made. He was commenced on oral prednisolone at 60 mg daily but suffered infectious complications, including necrotizing fasciitis within 3 weeks of starting treatment, ultimately resulting in his death 52 days after initial presentation., Conclusion: This case highlights the potential for immunoglobulin G4-related disease to be associated with a spectrum of glomerular pathologies including minimal change disease. It adds to the differential diagnosis of secondary causes of minimal change disease, and moreover, aids as an important reminder of the potential complications of high-dose steroids used in its treatment., (© 2024. The Author(s).)

Purpose: Tubulointerstitial nephritis and uveitis (TINU) syndrome is an uncommon disease. We present a confirmed case of TINU syndrome, and a systematic review of epidemiological characteristics, clinical manifestations, management, and outcomes in Chinese patients., Methods: A systematic search was carried out using defined terms and updated up to September 2022, in PubMed, Web of Science, Wanfang, CNKI, and VIP, to identify reported cases of TINU in China, according to PRISMA guidelines., Results: An 18-year-old boy presented with elevated serum creatinine and 24-h urine protein level of > 2 g. Inspection result revealed acute tubulointerstitial nephritis, and bilateral uveitis. The patient was diagnosed with TINU syndrome and received treatment with methylprednisolone sodium succinate, which resulted in a significant decrease in creatinine and urinary protein levels. Systematic review identified 35 publications that met the inclusion criteria. A total of 71 cases were included in this article, of which 70 were from publications and 1 was from our hospital. The median age at onset was 42 years and was significantly lower in males than females (P < 0.05). The symptoms of uveitis often occurred after kidney injury (54%) and most uveitis was anterior (55%) and bilateral (75%). Among the 51 patients who were followed up for more than 6 months, 24 had recurrent ocular symptoms or progression to chronic uveitis. Twenty patients experienced chronic or progressive kidney disease., Conclusion: TINU syndrome is prone to misdiagnosis because kidney damage may not occur simultaneously with uveitis. The incidence of kidney sequelae in children is lower than that in adults, and glucocorticoids are the preferred treatment., Inplasy Registration Number: INPLASY202350050., (© 2023. The Author(s).)

Pembrolizumab, an immune checkpoint inhibitor, is used to treat a variety of refractory malignancies. However, these agents are sometimes associated with immune-related adverse events. A 71-year-old woman received pembrolizumab-integrated chemotherapy to treat her recurrent mandibular gingival cancer. Five months after stopping pembrolizumab, she developed acute tubulointerstitial nephritis associated with Fanconi syndrome and type 1 renal tubular acidosis, which resolved with steroid therapy. We experienced a case of pembrolizumab-induced Fanconi syndrome and type 1 renal acidosis. We recommend follow-up of the tubular function in addition to the renal function even after discontinuation of pembrolizumab.

Purpose: To describe the various ocular clinical features and visual outcomes in Tubulointerstitial Nephritis and Uveitis Syndrome (TINU)., Methods: The medical records of 13 patients (26 eyes) diagnosed with TINU were reviewed., Results: Twenty-six (26) eyes of 13 patients with TINU were reviewed in this study. The median age at onset of uveitis was 14 (range, 9-45). Eight (61.5%) subjects were female. The median follow-up of patients was 30 months (range, 6-89 months). Posterior segment findings were seen in 18 eyes of 9 patients (69.2%). The most common posterior findings were optic nerve head inflammation (16 eyes, 88.8%) and retinal vasculitis (13 eyes, 72.2%). Other posterior findings included vitritis (8 eyes, 44.4%), macular edema (6 eyes, 33.3%), snowball (4 eyes, 22.2%), and chorioretinal lesions (2 eye, 11.1%). Eight patients had fluorescein angiography (FA) data available and most eyes had retinal capillary leakage (13 eyes, 81.2%) followed by optic disc staining/leakage (12 eyes, 75%). Twelve (12) patients (92.3%) were treated with immunomodulatory treatment (IMT) and/or biologics. Five patients (%38.4) required biologics to control intraocular inflammation., Conclusion: Posterior segment involvement may be common in patients with TINU syndrome. FA provides significant information for detecting posterior segment involvement and disease activity in TINU. The majority of patients required systemic treatment in order to control intraocular inflammation and prevent relapses., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Anti-tubular basement membrane (anti-TBM) antibody nephritis is a rare type of tubulointerstitial nephritis associated with progressive decline in kidney function. It is characterized histopathologically by tubular atrophy and dilation, interstitial fibrosis, lymphocyte and macrophage-predominant cellular infiltration, and linear deposition of IgG and complement along the tubular basement membrane. We herein present a case of a 69-year-old male who was recently diagnosed with chronic lymphocytic leukemia (CLL) and was referred for evaluation of kidney failure, ultimately diagnosed as anti-TBM antibody nephritis progressing into end-stage kidney disease (ESKD). This case report highlights the management challenges of anti-TBM antibody nephritis as a rare kidney disorder., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SN has received payments from Caliditas, Travere, Boehringer Ingelheim, and Otsuka in the past. The remaining authors declare that they have no relevant financial interests.

Objectives: We investigated the efficacy of a predetermined protocol that consisted of immunosuppressive drug reduction/withdrawal and intravenous immunoglobulin administration for the treatment of polyoma BK virus nephropathy., Materials and Methods: Patients with biopsy-proven polyoma BK virus nephropathy received a treatment regimen based on discontinuation of both calcineurin inhibitors and antiproliferative agents and switching to mTOR inhibitors accompanied by intravenous immunoglobulin administration., Results: Our study included 508 patients, with polyoma BK viremia detected in 80 patients. The mean age was 45.3 ± 9.5 years (range, 18-71 y), 64% were male, and mean follow-up was 37 ± 21 months (6-94 mo). All 16 patients who developed polyoma BK virus nephropathy and 9 patients who had highgrade polyoma BK viremia without nephropathy received intravenous immunoglobulin treatment. Compared with patients with viremia, patients with polyoma BK virus nephropathy had significantly higher rates of graft loss due to rejection (18.8% vs 1.6%; P = .024) and all-cause graft loss (31.2% vs 6.3%; P = .014). Histopathologically, viral inclusion bodies disappeared and SV40 became negative after treatment in all 13 patients who underwent protocol biopsies. Unfortunately, histopathologically complete recovery without chronic tubular and interstitial tissue damage was achieved in only 4 patients after treatment. In addition, 3 patients lost their grafts due to acute antibody-mediated or mixed-type rejection (18.8%)., Conclusions: In patients with polyoma BK virus nephropathy, clearance of viremia and SV40 should not be the sole outcomes to obtain. Aggressive reductions in maintenance immunosuppression and switching to double-drug therapy combined with high-dose intravenous immunoglobulin leads to high rates of graft loss/rejection and sequalae of chronic histological changes.

Introduction: Acute tubulointerstitial nephritis (ATIN) is a well-recognized cause of acute kidney injury (AKI) due to the tubulointerstitial inflammation. The aim of this study was to explore the clinical features, outcomes, and responses to corticosteroid treatment in patients with ATIN., Methods: Patients with biopsy-proven ATIN, who were diagnosed between 1994 and 2016 at the Department of Nephrology, Charles University, First Faculty of Medicine, and General University Hospital in Prague, were included in the study. Patient demographics, the aetiological and clinical features, the treatment given, and the outcome at 1 year of follow-up were extracted from patient records., Results: A total of 103 ATIN patients were analysed, of which 68 had been treated with corticosteroids. There was no significant difference in the median serum creatinine 280 (169-569) µmol/L in the conservatively managed group versus 374 (249-558) µmol/L in the corticosteroid-treated group, p = 0.18, and dependence on dialysis treatment at baseline at the time of biopsy (10.3 vs. 8.6%). During the 1 year of follow-up, those ATIN patients who had been treated with corticosteroids did better and showed greater improvement in kidney function, determined as serum creatinine difference from baseline and from 1 month over 1-year period (p = 0.001)., Conclusions: This single-centre retrospective cohort study supports the beneficial role of the administration of corticosteroid therapy in the management of ATIN., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Sarcoidosis affects multiple organs and exhibits diverse clinical manifestations. Although tubulointerstitial nephritis is a known feature of renal involvement, necrotizing vasculitis is rare. Furthermore, prostate involvement with urinary retention is unusual in patients with sarcoidosis. Here, we report a case of systemic sarcoidosis with a rare combination of manifestations and different acute kidney injuries., Case Presentation: A 66-year-old man developed sudden urinary retention and fever. He was diagnosed with prostatitis and admitted to our hospital. An indwelling urethral catheter was inserted, and antimicrobial therapy was initiated; however, the prostatitis was refractory. Computed tomography revealed enlarged mediastinal lymph nodes. Analysis of transbronchoscopic lymph node and prostate biopsies showed epithelioid cell granulomas, suggesting systemic sarcoidosis. During the clinical course, the serum creatinine level rapidly increased to 2.36 mg/dL without oliguria. A kidney biopsy revealed tubulointerstitial injury with moderate lymphohistiocytic infiltration and small-vessel vasculitis in the interstitium. Following oral administration of 60 mg/day prednisolone, the patient's renal function immediately improved, and urinary retention did not recur., Conclusions: To the best of our knowledge, this is the first reported case of sarcoidosis with two unusual complications. Given its clinical course and pathology, this case is clinically valuable., (© 2023. The Author(s).)

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a disorder that was originally described in 1975. The syndrome, although diagnosed in all age ranges, is more frequently reported in pediatric patients. Diagnosis can be difficult, and its clinical spectrum is still being defined. In this article, we review the epidemiology, diagnosis, pathogenesis, clinical findings, prognosis, and treatment of both the ocular and renal disease. We comment on the current difficulties in diagnosis and study of the disease, its expanding clinical spectrum, and treatment strategies in pediatric patients.

Background: Despite recent well-established kidney tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), usually presenting as acute kidney injury (AKI), there are few published cases with SARS-CoV-2-related tubulointerstitial nephritis (TIN). We report an adolescent with TIN and delayed association with uveitis (TINU syndrome), where SARS-CoV-2 spike protein was identified in kidney biopsy., Case-Diagnosis/treatment: A 12-year-old girl was assessed for a mild elevation of serum creatinine detected during the evaluation of systemic manifestations including asthenia, anorexia, abdominal pain, vomiting, and weight loss. Data of incomplete proximal tubular dysfunction (hypophosphatemia and hypouricemia with inappropriate urinary losses, low molecular weight proteinuria, and glucosuria) were also associated. Symptoms had initiated after a febrile respiratory infection with no known infectious cause. After 8 weeks, the patient tested positive in PCR for SARS-CoV-2 (Omicron variant). A subsequent percutaneous kidney biopsy revealed TIN and immunofluorescence staining with confocal microscopy detected the presence of SARS-CoV-2 protein S within the kidney interstitium. Steroid therapy was started with gradual tapering. Ten months after onset of clinical manifestations, as serum creatinine remained slightly elevated and kidney ultrasound showed mild bilateral parenchymal cortical thinning, a second percutaneous kidney biopsy was performed, without demonstrating acute inflammation or chronic changes, but SARS-CoV-2 protein S within the kidney tissue was again detected. At that moment, simultaneous routine ophthalmological examination revealed an asymptomatic bilateral anterior uveitis., Conclusions: We present a patient who was found to have SARS-CoV-2 in kidney tissue several weeks following onset of TINU syndrome. Although simultaneous infection by SARS-CoV-2 could not be demonstrated at onset of symptoms, since no other etiological cause was identified, we hypothesize that SARS-CoV-2 might have been involved in triggering the patient's illness., (© 2023. The Author(s).)

Infection-related glomerulonephritis (IRGN) is one of the most common causes of acute kidney injury (AKI). Positive glomerular staining of the nephritis-associated plasmin receptor (NAPlr) has been reported as a useful biomarker of IRGN. Although the infection can provoke acute tubulointerstitial nephritis (AIN), there are few reports of positive staining for NAPlr with AIN. We report a case of methicillin-sensitive Staphylococcus aureus (MSSA) infection-related nephritis complicated with AIN, which showed positive staining for tubulointerstitial NAPlr. The patient developed AKI and nephrotic syndrome during an intraperitoneal MSSA infection. A diagnosis of IRGN complicated by infection-related acute tubulointerstitial nephritis (IRAIN) was made based on glomerular endocapillary proliferation with tubulointerstitial infiltrating cells and tubular atrophy. Tubulointerstitial infiltrating cells were positive for NAPlr staining and plasmin activity. Treatment of the infection by antibiotics and drainage did not improve the AKI, but steroid administration improved that. NAPlr evaluation is a helpful tool for identifying causes of AIN during infection., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Background: Tubulointerstitial nephritis and uveitis (TINU) syndrome is an uveits characterized by complications of idiopathic acute tubulointerstitial nephritis, and most cases present only anterior uveitis. We report a case of TINU syndrome in which the presence of choroiditis was revealed by multimodal imaging., Case Presentation: A 12-year-old male visited our hospital with a 6-day history of ocular pain and hyperemia. Conjunctival and ciliary injections, 1 + flare and 3 + cells of anterior chamber inflammation with mutton fat keratic precipitates were observed in both eyes (OU), together with redness and swelling of the optic disc OU. Laboratory tests showed slightly high levels of soluble IL-2R and serum β2 microglobulin and markedly high levels of urinary β2 microglobulin. The diagnosis of probable TINU syndrome was established on the basis of bilateral uveitis and urinalysis results in accordance with a clinical criteria of tubulointerstitial nephritis. With treatment with oral prednisolone (PSL) at 20 mg/day, ocular findings improved, and the dose of PSL was gradually reduced and withdrawn 6 months later. However, 1 month later from the withdrawal, ocular inflammation recurred with the presence of retinal exudates and snowball vitreous opacities in the peripheral retina OU. Fluorescein angiography showed leakages from peripheral retinal vessels and staining corresponding to retinal exudates. Indocyanine green angiography showed hypofluorescent dots scattered over the ocular fundus. Optical coherence tomography revealed the presence of choroidal thickening. Laser speckle flowgraphy color map showed a relatively cooler color. Findings from these multimodal images indicated the presence of subclinical choroiditis; therefore, oral PSL was administered again, and ocular inflammatory findings were improved., Conclusions: TINU syndrome can exhibit subclinical choroiditis detected with multimodal imaging. Further studies are necessary to determine the frequency of subclinical choroiditis in TINU syndrome., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: Nephropathy due to BK virus infection is a major cause of graft dysfunction and loss. No specific treatment has been developed for the BK virus. Here, we compared the combination of intravenous immunoglobulin and leflunomide versus intravenous immunoglobulin to treat BK virus nephropathy after renal transplant., Materials and Methods: This study was a randomized controlled clinical trial. Sixteen kidney transplant patients with BK virus infection were randomly divided into 2 groups; 1 group received intravenous immunoglobulin, and another group received leflunomide and intravenous immunoglobulin. P < .05 was considered statistically significant., Results: Results of a polymerase chain reaction test for BK virus after 2 months of treatment were negative in 3 patients in the intravenous immunoglobulin group and in 7 patients in the intravenous immunoglobulin + leflunomide group. The amount of BK virus decreased significantly in each group, and a significant difference was observed between the 2 groups after 3 months (P = .014). The average level of creatinine in the intravenous immunoglobulin group at 1, 2, and 3 months after treatment was 1.7 ± 0.23, 1.8 ± 0.5, and 1.5 ± 0.3, respectively, and in the intravenous immunoglobulin + leflunomide group was 2.1 ± 0.75, 1.76 ± 0.37, and 1.4 ± 0.18, respectively (P > .05)., Conclusions: Although BK viral load decreased significantly in both groups, there was a significant difference between patients who received intravenous immunoglobulin versus those who received the combination of intravenous immunoglobulin + leflunomide after 3 months. The addition of leflunomide to the intravenous immunoglobulin treatment seems to have a better effect in reducing BK viral load. However, further studies with a larger sample and longer duration are needed.

Because of their broad-spectrum bactericidal activity, amoxicillin (AMX) and third-generation cephalosporins (TGC) are widely used for the prophylaxis and treatment of established infections. They are considered relatively safe, but several recent reports have suggested substantial nephrotoxicity, especially with AMX use. Considering the importance of AMX and TGC for clinical practice, we conducted this up-to-date review, using the PubMed database, which focuses specifically on the nephrotoxicity of these molecules. We also briefly review the pharmacology of AMX and TGC. Nephrotoxicity of AMX may be driven by several pathophysiological mechanisms, such as a type IV hypersensitivity reaction, anaphylaxis, or intratubular and/or urinary tract drug precipitation. In this review, we focused on the two main renal adverse effects of AMX, namely acute interstitial nephritis and crystal nephropathy. We summarize the current knowledge in terms of incidence, pathogenesis, factors, clinical features, and diagnosis. The purpose of this review is also to underline the probable underestimation of AMX nephrotoxicity and to educate clinicians about the recent increased incidence and severe renal prognosis associated with crystal nephropathy. We also suggest some key elements on the management of these complications to avoid inappropriate use and to limit the risk of nephrotoxicity. While renal injury appears to be rarer with TGC, several patterns of nephrotoxicity have been reported in the literature, such as nephrolithiasis, immune-mediated hemolytic anemia, or acute interstitial nephropathy, which we detail in the second part of this review., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) is a newer disease about which there are many unclear points. Glucocorticoid therapy is effective in many cases of IgMPC-TIN; however, relapse during glucocorticoid tapering has been reported. Relapse and its treatment are poorly defined., Case Presentation: Case 1 was a 61-year-old man with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. He was diagnosed with IgMPC-TIN accompanied by Fanconi syndrome and distal renal tubular acidosis (d-RTA). Prednisolone (PSL; 30 mg daily, 0.45 mg/kg/day) treatment was highly effective, and PSL was gradually tapered and discontinued after 1 year. However, 1 month after PSL discontinuation, therapeutic markers were elevated. Therefore, PSL (10 mg daily, 0.15 mg/kg/day) was administered, and the markers indicated improvement. Case 2 was a 43-year-old woman referred for renal dysfunction and proteinuria. Laboratory data revealed that she had primary biliary cholangitis (PBC), d-RTA, and Fanconi syndrome. A renal biopsy showed accumulation of IgM-positive plasma cells in the tubulointerstitium without any glomerular changes. A diagnosis of IgMPC-TIN was made and the patient was started on PSL (35 mg daily, 0.6 mg/kg/day). Therapeutic markers decreased immediately and PSL was discontinued after 1 year. Three months later, the proteinuria and Fanconi syndrome worsened. PSL treatment was restarted (20 mg daily, 0.35 mg/kg/day) and markers indicated improvement. Case 3 was a 45-year-old woman with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. The patient had PBC, Sjögren syndrome, d-RTA, and Fanconi syndrome, and the diagnosis of IgMPC-TIN was made. The patient was started on PSL (30 mg daily, 0.4 mg/kg/day) and disease markers decreased immediately. However, when PSL was tapered to 15 mg daily (0.2 mg/kg/day), the patient's serum IgM levels increased; therefore, we maintained the PSL at 15 mg daily (0.2 mg/kg/day)., Conclusion: We report three cases of relapsed IgMPC-TIN associated with reduction or discontinuation of glucocorticoid therapy. In these cases, elevation of serum IgM preceded that of other markers such as urinary β 2 -microglobulin, proteinuria, and glycosuria. We recommend monitoring serum IgM levels while tapering glucocorticoids; a maintenance dose of glucocorticoid should be considered if relapse is suspected or anticipated., (© 2023. The Author(s).)

The field of nephrology has been slow in moving beyond the utilization of creatinine as an indicator for chronic kidney disease and acute kidney injury (AKI). Early diagnosis and establishment of etiology, in particular, are important for treatment of AKI. In the setting of hospital-acquired AKI, tubular injury is more common, but acute interstitial nephritis (AIN) has a more treatable etiology. However, it is likely that AIN is under- or misdiagnosed due to current strategies that largely rely on clinical gestalt. In this issue of the JCI, Moledina and colleagues made an elegant case for the chemokine called C-X-C motif ligand 9 (CXCL9) as a biomarker of AIN. The authors used urine proteomics and tissue transcriptomics in patients with and without AIN to identify CXCL9 as a promising, noninvasive, diagnostic biomarker of AIN. These results have clinical implications that should catalyze future research and clinical trials in this space.

Introduction: The introduction of BRAF/MEK inhibitors has significantly improved overall survival of patients with BRAF V600-mutant advanced or metastatic melanoma. Most patients treated with BRAF/MEK inhibitors will experience adverse events during the course of their treatment. Kidney impairment, however, was rarely reported in the pivotal trials. To date, there are only three cases of biopsy-proven acute interstitial nephritis associated with dabrafenib and trametinib reported in the literature., Case Report: A 50-year-old man diagnosed with metastatic melanoma was hospitalized in August 2021, 5 months after treatment initiation with dabrafenib and trametinib. He presented with acute kidney injury, with serum creatinine of 3.34 mg/dL and eGFR of 20.3 mL/min/m². Kidney biopsy revealed acute interstitial nephritis., Management & Outcome: He was treated with methylprednisolone 16 mg qd, and both dabrafenib and trametinib were permanently discontinued, with recuperation of his kidney function. Another BRAF/MEK inhibitor combination, encorafenib and binimetinib, was introduced, with preserved kidney function and excellent disease control., Discussion: We report the first case of biopsy-proven interstitial nephritis in a patient treated with dabrafenib and trametinib, with successful introduction of another BRAF/MEK inhibitor combination. Although rare, clinicians should be aware of the risk of renal adverse events associated with BRAF/MEK inhibitors. Renal biopsy is mandatory in the absence of a clear explanation or rapid recovery of renal failure. In case of proven interstitial nephritis, corticosteroids should be initiated. Switching to another BRAF/MEK inhibitor combination can be considered for patients with complete recovery of renal function and limited treatment options.

Tubulointerstitial nephritis and uveitis (TINU) is a rare autoimmune disorder often triggered by drugs and infections. Since the onset of the COVID-19 pandemic, we have observed an unusual cluster of paediatric cases. Four children (3 females) were diagnosed with TINU (median age 13 years) following a kidney biopsy and ophthalmologic assessment. Presenting symptoms included abdominal pain (3 cases), fatigue, weight loss and vomiting (2 cases). At presentation, median eGFR was 50.3 ml/min/1.73m 2 (range 19.2-69.3). Anaemia was common (3 cases) with median haemoglobin of 10.45 g/dL (range 8.4-12.1). Two patients were hypokalaemic and 3 had non-hyperglycaemic glycosuria. Median urine protein:creatinine ratio was 117 mg/mmol (range 68-167). SARS-CoV-2 antibodies were detected in 3 cases at presentation. All were asymptomatic for COVID-19 with a negative PCR. Kidney function improved following high-dose steroids. However, disease relapse was observed during steroid tapering (2 cases) and upon discontinuation (2 cases). All patients responded well to further high dose steroids. Mycophenolate mofetil was introduced as a steroid-sparing agent. At latest follow up (range 11-16 months), median eGFR was 109.8 ml/min/1.73m 2 . All four patients continue on mycophenolate mofetil, with 2 patients applying topical steroids for uveitis. Our data suggest that SARS-CoV-2 infection might be a trigger for TINU., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Because of some similarities in organ involvement, clinical manifestations, and histopathological features, IgG4-related disease (IgG4-RD) may occur concurrently with some clinicopathologic variants of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). An overlap syndrome of IgG4-RD and AAV has recently been proposed in clinical and/or histopathological studies, indicating that there may be some potential pathophysiological associations between the two disease entities; however, the mechanisms underlying these are incompletely understood. Here, we describe a rare case of a 63-year-old man with IgG4-related tubulointerstitial nephritis (IgG4-TIN) and microscopic polyangiitis-associated glomerulonephritis (MPA-GN) overlap syndrome. The clinical diagnosis of MPA was based on the 2022 American College of Rheumatology (ACR)/European League Against Rheumatology (EULAR) classification criteria. Remission induction therapy with intravenous methylprednisolone was initiated, followed by oral prednisone maintenance therapy with gradual tapering. The patient remained asymptomatic and his renal function was essentially normalized within 3.5 months of follow-up. The serum IgG4 levels decreased to 5 g/L. We also conducted a literature review to identify clinical findings, treatment options, and outcomes of patients with concurrent IgG4-RD and MPA and briefly discussed the potential pathophysiological association between IgG4-RD and MPA. Our findings enrich the database of this rare overlap syndrome and provide a basis for the diagnosis and early intervention in both diseases. These results provide some insights for clinicians to recognize and treat this overlap syndrome., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Purpose: To report sarcoid-like uveitis with or without tubulointerstitial nephritis (TIN) during coronavirus disease 2019 (COVID-19) and to discuss diagnostic evaluation and treatment., Methods: Detailed information on the subject's demographics, medical history, ophthalmic examination findings, and laboratory results were obtained from medical records. Fluorescein angiography (FA) and indocyanine green angiography (ICGA) images were evaluated., Results: All seven patients aged between 8 and 17 had bilateral granulomatous panuveitis. TIN preceded in four patients. Thorax computed tomography of patient 1 was found to be compatible with COVID-19, patients 2 and 3 were in contact with Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive parents, patients 4 and 5 were found to be SARS-CoV-2 PCR positive, and patients 6 and 7 were positive for SARS-CoV-2 IgG antibodies. ICGA revealed hypofluorescent dots in six patients. Intraocular inflammation was controlled with corticosteroid and/or immunomodulatory therapy. Visual acuity was maintained or improved in all., Conclusion: SARS-CoV-2 infection may be related to sarcoid-like uveitis and acute tubulointerstitial nephritis.

Background: We determine the benefit of pulsed methylprednisolone for improving kidney function in patients with sarcoidosis tubulointerstitial nephritis., Methods: We conducted a multicenter, prospective, randomized, open-label, controlled trial in patients with biopsy-proven acute tubulointerstitial nephritis caused by sarcoidosis at 21 sites in France. Patients were randomly assigned to receive a methylprednisolone pulse 15 mg/kg/day for 3 days, then oral prednisone (MP group) or oral prednisone 1 mg/kg/day alone (PRD group). The primary end point was a positive response at 3 months, defined as a doubling of estimated glomerular filtration rate (eGFR) compared with the eGFR before randomization., Results: We randomized 40 participants. Baseline eGFR before PRD was 22 mL/min/1.73m2 {interquartile range [IQR], 16-44} and before MP was 25 mL/min/1.73m2 (IQR, 22-36) (P = .3). The two groups did not differ in underlying pathological lesions, including mean percentage of interstitial fibrosis and intensity of interstitial infiltrate. In the intent-to-treat population, the median eGFR at 3 months did not significantly differ between the PRD and MP groups: 45 (IQR, 34-74) and 46 (IQR, 39-65) mL/min/1.73m2. The primary end point at 3 months was achieved in 16 of 20 (80%) PRD patients and 10 of 20 (50%) MP patients (P = .0467). The eGFR was similar between the two groups after 1, 3, 6, and 12 months of treatment. For both groups, eGFR at 1 month was strongly correlated with eGFR at 12 months (P < .0001). The two groups did not differ in severe adverse events., Conclusion: Compared with a standard oral steroid regimen, intravenous MP may have no supplemental benefit for renal function in patients with tubulointerstitial nephritis caused by sarcoidosis.Trial Registration: ClinicalTrials.gov: NCT01652417; EudraCT: 2012-000149-11., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare condition characterised by bilateral uveitis and interstitial nephritis. There is no nationally, or internationally agreed upon treatment regimen. A systematic review was undertaken to report the renal outcomes in TINU, and treatments used., Methods: Medline (1969-2021) and EMBASE (1988-2021) databases were searched for primary studies, clinical practice guidelines and case reports of adult and paediatric TINU cases, as defined by Mandeville criteria. Two reviewers identified articles meeting inclusion criteria (registered with PROSPERO). Data were extracted into a synthesis table and meta-analysis performed. Quality of case series was also assessed., Results: One hundred twenty-two articles were identified, totalling 257 cases included in the meta-analysis. Females were more commonly affected than males (2:1), and median age was 19 years. GFR at follow-up correlated with nadir GFR, and the proportion with GFR <90 ml/min/1.73 m 2 was statistically different between adult and paediatric groups. Of the entire cohort, 40% had GFR <90 ml/min/1.73 m 2 at follow-up. Glucocorticoid monotherapy was the most common treatment (70%); other strategies included no treatment (9%) and immunosuppressant drugs (e.g. azathioprine), mostly in steroid-resistant cases, or as 'steroid-sparing' alternatives., Conclusions: The majority of literature regarding TINU is limited to case reports and case series. There are no prospective trials assessing the effects of different treatments on renal outcomes, and currently employed treatment strategies are physician-specific without a reliable evidence-base. Prospective data collection as part of multicentre trials should be a research focus to improve the evidence-base., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Purpose: To assess the clinical features, management and prognosis of patients diagnosed with tubulointerstitial nephritis and uveitis (TINU) syndrome in Spain and Portugal., Methods: Retrospective multicenter study, which included all patients diagnosed with TINU syndrome managed in 15 uveitis referral centers from Spain and Portugal., Results: Forty-eight subjects with a mean age at diagnosis of 25.0 [14.8; 49.5] years were included. Both eyes were affected in 43 patients (89.6%). The visual outcome was favorable, but immunosuppressive systemic therapy (IST) was needed in 26 (54.16%) due to relapses. Renal function normalized in 35 patients (72.9%). HLA-DQB1*05 was the most common genetic typing (57.1%). The mean follow-up time was 22.5 [11.0; 48.0] months., Conclusions: Both visual and renal outcomes were favorable, although IST was frequently used. TINU is under- diagnosed, so further prospective studies would provide more knowledge about its recognition and management., Expert Opinion: TINU Syndrome is underdiagnosed because ocular and renal disease are asynchronous. Outcomes are favorable so it has to be highly suspected in cases of bilateral anterior uveitis. According to literature and our experience, systemic immunosuppressive therapy is often required because of ocular relapses.This study adds to the previous knowledge that HLA-DQB1*05 could be an important HLA type amongst the TINU Syndrome Iberian population. HLA typing should be assessed in these patients in order to describe its phenotype-genotype relationship better. A considerable number of patients in our series were diagnosed in their sixties, so TINU Syndrome should also be suspected in elderly patients.

Background: Patients presenting with acute interstitial nephritis (AIN) of unknown aetiology, probably the earliest presentation of chronic kidney disease of unknown aetiology (CKDu), have been treated with oral prednisolone and doxycycline by physicians in Sri Lanka. This trial assessed the effectiveness of prednisolone and doxycycline based on eGFR changes at 6 months in patients with AIN of unknown aetiology., Method: A randomized clinical trial with a 2 × 2 factorial design for patients presenting with AIN of unknown aetiology (n = 59) was enacted to compare treatments with; A-prednisolone, B-doxycycline, C-both treatments together, and D-neither. The primary outcome was a recovery of patients' presenting renal function to eGFR categories: 61-90 ml/min/1.73m 2 (complete remission- CR) to 31-60 ml/min/1.73m 2 (partial remission- PR) and 0-30 ml/min/1.73m 2 no remission (NR) by 6 months. A secondary outcome was progression-free survival (not reaching < 30 ml/min/1.73m 2 eGFR), by 6-36 months. Analysis was by intention to treat., Results: Seventy patients compatible with a clinical diagnosis of AIN were biopsied for eligibility; 59 AIN of unknown aetiology were enrolled, A = 15, B = 15, C = 14 and D = 15 randomly allocated to each group. Baseline characteristics were similar between groups. The number of patients with CR, PR and NR, respectively, by 6 months, in group A 3:8:2, group B 2:8:3 and group C 8:5:0 was compared with group D 8:6:1. There were no significant differences found between groups A vs. D (p = 0.2), B vs. D (p = 0.1) and C vs. D (p = 0.4). In an exploratory analysis, progression-free survival in prednisolone-treated (A + C) arms was 0/29 (100%) in comparison to 25/30 (83%) in those not so treated (B + D) arms, and the log-rank test was p = 0.02, whereas no such difference found (p = 0.60) between doxycycline-treated (B + C) arms 27/29 (93%) vs those not so treated (A + D) arms 27/30 (90%)., Conclusion: Prednisolone and doxycycline were not beneficial for the earliest presentation of CKDu at 6 months. However, there is a potential benefit of prednisolone on the long-term outcome of CKDu. An adequately powered steroid trial using patients reaching < 30 ml/min/1.73m 2 eGFR by 3 years, as an outcome is warranted for AIN of unknown aetiology., Trial Registration: Sri Lanka Clinical Trial Registry SLCTR/2014/007, Registered on the 31st of March 2014., (© 2023. The Author(s).)

Background: Renal sarcoidosis is a rare cause of tubulointerstitial nephritits (TIN). The clinical and pathological characteristics, as well as outcomes, of renal sarcoidosis remain unclear., Methods: This single-center study retrospectively analyzed 18 patients affected by sarcoidosis with tubulointerstitial nephritis (TIN) and 53 patients with tubulointerstitial nephritis  not related to sarcoidosis. Patients were further stratified into the granulomatous (12 sarcoidosis and 6 non-sarcoidosis) and non-granulomatous (6 sarcoidosis and 47 non-sarcoidosis) TIN groups., Results: Half of the patients with renal sarcoidosis had signs of acute kidney injury at kidney biopsy, 94% of whom presented with extra-renal involvement. The prevalence of hypercalcemia, hypercalciuria, and elevated serum angiotensin-converting enzyme levels was 27.6%, 33.3%, and 31.3%, respectively. Renal sarcoidosis patients with eGFR < 30 mL/min/1.73 m 2 scored higher for total chronic tubulointerstitial injury (p = 0.044) and glomerular sclerosis (p = 0.027). Compared to non-sarcoidosis patients, higher urinary calcium levels (for patients with GFR [Formula: see text] 40 mL/min/1.73 m 2 , p = 0.034), lower scores of acute tubular injury (p = 0.008), and more prominent glomerular sclerosis were observed in renal sarcoidosis. Similar characteristics of chronicity and hypercalciuria were also identified in granulomatous interstitial nephritis; however, interstitial inflammation was obvious (p = 0.001). Patients with renal sarcoidosis were initially treated with corticosteroids. Five patients receiving immunosuppressive agents showed better long-term renal recovery. High 24-h urine calcium (adjusted by weight) was identified as a factor associated with long-term remission., Conclusion: Renal sarcoidosis is a systemic disease of insidious onset and chronic progression, sharing similar features of chronicity and hypercalciuria with granulomatous interstitial nephritis of other cause. Hypercalciuria may predict a better response to immunosuppressive therapy, presumably indicating active interstitial inflammation; thus, strengthened immunosuppression might be considered., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Objectives: The combination of immune-checkpoint inhibitors (ICI) and platinum-pemetrexed chemotherapy (CT) in first-line setting improved survival outcomes of advanced non-small cell lung cancer (NSCLC) patients. Among the various adverse events, renal toxicity can be a relevant safety issue., Materials and Methods: We conducted a single-center, observational retrospective study including consecutive patients treated with upfront CT-ICI for advanced nonsquamous NSCLC to investigate incidence and clinical characteristics of acute kidney injury (AKI) using 'Acute Kidney Injury Working Group of Kidney Disease: Improving Global Outcomes' (KDIGO) definition., Results: A total of 89 patients received a first-line CT/ICI. The median age was 69 years. 60.7 % were male, and 87.6 % had an ECOG PS of 0-1. 92.1 % had a baseline glomerular filtration rate of at least 60 ml/min. According to KDIGO criteria, 25 (28 %) patients developed AKI. Considering risk factors for AKI onset, patients receiving >10 cycles of CT/ICI were more likely to experience AKI (p < 0.001). No other associations were found with other variables, including concomitant medications. Any component of the treatment was discontinued (pemetrexed pembrolizumab or both) in 10 (40 %) patients, and 9 patients (36 %) were addressed to nephrological consultation. These patients had higher mean creatinine variation from baseline (1 vs 0.6 mg/dl, p = 0.025) and creatine level (1.8 vs 1.4 mg/dl, p = 0.015), but lower eGFR (35.7 vs 54.2 ml/min, p = 0.011) in comparison to patients not addressed. No patients had microscopic hematuria or pyuria, but mild proteinuria (<0.8 g/24 h) was found in 4 patients. A renal biopsy was performed on 3 patients, revealing acute tubule interstitial nephritis (ATIN), karyomegalic interstitial nephritis, and acute tubular necrosis (ATN)., Conclusion: Renal toxicity represents a challenging adverse event that could negatively impact outcomes of metastatic nonsquamous NSCLC patients receiving CT/ICI demanding a multidisciplinary approach., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential inhibitory regulator of immune activation. CTLA-4 haploinsufficiency is known to be associated with dysregulation of FOXP3 + regulatory T cells, hyperactivation of effector T cells, and lymphocytic infiltration of multiple organs. However, there have only been a few reports of renal involvement with CTLA-4. Herein, we present a case of acute granulomatous tubulointerstitial nephritis (TIN) in a patient with CTLA-4 haploinsufficiency., Case Presentation: A 44-year-old man presented with a 3-week history of fever and malaise, and subsequently developed acute kidney injury (AKI) a few days after treatment with levofloxacin (LVFX). A kidney biopsy and immunohistochemical staining revealed granulomatous TIN with dominantly infiltrating CD4 + T cells. General symptoms and renal impairment showed improvement after discontinuation of LVFX and initiation of oral steroids. However, they worsened following steroid tapering. Further, a colon biopsy analysis showed similar findings to the renal tissue analysis. We suspected that granulomatous TIN was possibly associated with CTLA-4 haploinsufficiency. Therefore, the patient was transferred to another hospital for further treatment of CTLA-4 haploinsufficiency using immunosuppressive agents., Conclusions: There have been few reports regarding renal involvement of CTLA-4 haploinsufficiency. In the present case, granulomatous TIN could have arisen due to instability of immune regulatory functions, such as CTLA-4 haploinsufficiency, and treatment with LVFX could have triggered immunologic activation and severe inflammation as well as renal dysfunction., (© 2022. The Author(s).)

AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal syndrome type 1, also referred to as hepatorenal syndrome-AKI, is the most salient and unique etiology. Patients with cirrhosis are vulnerable to traditional causes of AKI, such as prerenal azotemia, acute tubular injury, and acute interstitial nephritis. In addition, other less common etiologies of AKI specifically related to chronic liver disease should be considered, including abdominal compartment syndrome, cardiorenal processes linked to cirrhotic cardiomyopathy and portopulmonary hypertension, and cholemic nephropathy. Furthermore, certain types of GN can cause AKI in cirrhosis, such as IgA nephropathy or viral hepatitis related. Therefore, a comprehensive diagnostic approach is needed to evaluate patients with cirrhosis presenting with AKI. Management should be tailored to the specific underlying etiology. Albumin-based volume resuscitation is recommended in prerenal AKI. Acute tubular injury and acute interstitial nephritis are managed with supportive care, withdrawal of the offending agent, and, potentially, corticosteroids in acute interstitial nephritis. Short of liver transplantation, vasoconstrictor therapy is the primary treatment for hepatorenal syndrome type 1. Timing of initiation of vasoconstrictors, the rise in mean arterial pressure, and the degree of cholestasis are among the factors that determine vasoconstrictor responsiveness. Large-volume paracentesis and diuretics are indicated to relieve intra-abdominal hypertension and renal vein congestion. Direct-acting antivirals with or without immunosuppression are used to treat hepatitis B/C-associated GN. In summary, AKI in cirrhosis requires careful consideration of multiple potentially pathogenic factors and the implementation of targeted therapeutic interventions., (Copyright © 2022 by the American Society of Nephrology.)

Background: Patients with acute interstitial nephritis (AIN) can present without typical clinical features, leading to a delay in diagnosis and treatment. We therefore developed and validated a diagnostic model to identify patients at risk of AIN using variables from the electronic health record., Methods: In patients who underwent a kidney biopsy at Yale University between 2013 and 2018, we tested the association of &gt;150 variables with AIN, including demographics, comorbidities, vital signs and laboratory tests (training set 70%). We used least absolute shrinkage and selection operator methodology to select prebiopsy features associated with AIN. We performed area under the receiver operating characteristics curve (AUC) analysis with internal (held-out test set 30%) and external validation (Biopsy Biobank Cohort of Indiana). We tested the change in model performance after the addition of urine biomarkers in the Yale AIN study., Results: We included 393 patients (AIN 22%) in the training set, 158 patients (AIN 27%) in the test set, 1118 patients (AIN 11%) in the validation set and 265 patients (AIN 11%) in the Yale AIN study. Variables in the selected model included serum creatinine {adjusted odds ratio [aOR] 2.31 [95% confidence interval (CI) 1.42-3.76]}, blood urea nitrogen:creatinine ratio [aOR 0.40 (95% CI 0.20-0.78)] and urine dipstick specific gravity [aOR 0.95 (95% CI 0.91-0.99)] and protein [aOR 0.39 (95% CI 0.23-0.68)]. This model showed an AUC of 0.73 (95% CI 0.64-0.81) in the test set, which was similar to the AUC in the external validation cohort [0.74 (95% CI 0.69-0.79)]. The AUC improved to 0.84 (95% CI 0.76-0.91) upon the addition of urine interleukin-9 and tumor necrosis factor-α., Conclusions: We developed and validated a statistical model that showed a modest AUC for AIN diagnosis, which improved upon the addition of urine biomarkers. Future studies could evaluate this model and biomarkers to identify unrecognized cases of AIN., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Renal sarcoidosis frequently causes granulomatous interstitial nephritis, but clinically relevant nephritis is uncommon. IgA nephropathy caused by sarcoidosis is usually associated with milder stages of renal dysfunction, and only one case of rapidly progressive IgAN has been reported to date. We present an interesting case of a patient with a rapidly progressive form of IgA nephropathy caused by sarcoidosis that was successfully treated.  DOI: 10.52547/ijkd.7027.

Acute granulomatous tubulointerstitial nephritis (GTIN) is a rare finding in renal biopsy. Differential diagnosis is facilitated when GTIN is associated with granulomatous bilateral anterior uveitis (GBAU). Nevertheless, differentiation between a rare form of granulomatous tubulointerstitial nephritis and uveitis syndrome (TINU) and sarcoidosis can be challenging. We report a case of biopsy-proven GTIN with concomitant GBAU, leading to a dead-end diagnosis. We discuss workup and propose a diagnostic algorithm based on a literature review. We also report a successful treatment of ophthalmologic and renal relapse using mycophenolate mofetil.

In this case report, we describe the case of a 50-year-old woman referred by her general practitioner to a pulmonologist in order to investigate persistent fever and elevation of C-reactive protein despite antibiotic treatment following a respiratory infection. The patient was examined extensively, during which rheumatology, gastroenterology, nephrology, ophthalmology, laboratory and imaging tests were performed. Due to a rapid progression of renal insufficiency with active urinary sediment, the patient was referred for a renal biopsy, which confirmed tubulointerstitial nephritis, followed by a diagnosis of bilateral anterior uveitis two months later - genetic testing was also conducted, which confirmed the diagnosis of tubulointerstitial nephritis with uveitis syndrome. Steroid treatment brought about a gradual reduction of proteinuria and a stabilisation of renal function.

A woman in her 50s was referred to nephrology clinic due to progressive chronic kidney disease. She exhibited features of proximal renal tubulopathy, namely Fanconi syndrome, including normoglycaemic glycosuria, normal anion gap metabolic acidosis, and intermittent hypouricaemia and hypophosphataemia. Kidney biopsy showed tubulointerstitial inflammation and focal chronic damage. In addition, antimitochondrial antibodies were present and she had abnormal liver blood tests. A unifying diagnosis of primary biliary cholangitis with an associated renal tubulopathy and interstitial nephritis was made. She was commenced on sodium bicarbonate, ursodeoxycholic acid and oral prednisolone, leading to an improvement in liver biochemistry. Kidney function was stabilised, but a sustained improvement was not seen. This case acts as a reminder of the rare association of tubulointerstitial nephritis and Fanconi syndrome with primary biliary cholangitis, which may be an under-recognised phenotype., Competing Interests: Competing interests: JS has received support from Northern Counties Kidney Research Fund and Kidney Research UK for the present manuscript, and speaker honoraria from Sanofi and Takeda. JD has received speaker honararia from Dr Falk Pharma and Intercept, and support for attending meeting from Intercept., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The presented clinical observation reflects the difficulties of differential diagnosis of progressive kidney damage in a patient with sarcoidosis who has undergone a new coronavirus infection. The differential circle included interstitial nephritis as an exacerbation of the underlying disease, acute drug-induced kidney injury, acute glomerulonephritis. Nephrobiopsy confirmed the diagnosis of acute sarcoid tubulointerstitial nephritis with acute tubular necrosis. Timely administration of corticosteroids led to the control of the sarcoidosis process, restoration of kidney function.

Objectives: This paper looks at patients with a diagnosis of tubulointerstitial nephritis and uveitis (TINU) presenting to the Northern Ireland regional adult and paediatric uveitis service in the Belfast Health and Social Care Trust. The demographic distribution, treatment required and the visual and renal outcomes of these patients are documented., Methods: Data were collected retrospectively on 24 patients with TINU using the Northern Ireland Electronic Care Record, central pathology records alongside the adult and paediatric uveitis databases from 2011 to 2021. Patients were categorised into two groups using the Mandeville classification system. Standard Uveitis Nomenclature (SUN) was used to classify the uveitis., Results: The population prevalence is at least 12.6 cases per million based on a population of 1.9 million. Nineteen of 24 cases were definite TINU and five of 24 probable. Seventeen out of 24 had biopsy-positive TIN, all of which met all of the Mandeville clinical diagnostic features required for a definite diagnosis. All but one presented with acute bilateral anterior uveitis. The paediatric cases ranged from age 12 to 18 at age of onset with a mean age of 14. Of the 18 adult onset cases, the age ranged from 20 to 76 years. The mean age of onset for the adult cases was 53 years. Of these patients 71% were female; 42% required second-line immunosuppression for ocular disease. Visual acuity was maintained. Follow-up time ranged from 3 months to 16 years. No patient developed long-term renal impairment., Conclusions: TINU is a cause of uveitis in both the paediatric and adult populations. In Northern Ireland average age with TINU was older than much of the published literature. Long-term immunosuppression for uveitis may be required as ongoing ocular, rather than renal inflammation seemed to require treatment., (© 2021. The Author(s).)

Purpose: To describe subclinical chorioretinal lesions revealed by indocyanine green angiography (ICGA) and their evolution under systemic treatment in tubulointerstitial nephritis and uveitis (TINU) patients., Methods: Retrospective case series of three patients with TINU syndrome. Choroidal and retinal involvement were assessed by fluorescein angiography (FA) and ICGA., Results: Three patients were analyzed. FA demonstrated hot disc, associated in two cases with retinal vascular leakage, and ICGA revealed subclinical chorioretinal dots in all three cases. Given the presence of posterior uveitis and deterioration of kidney function, asystemic treatment by oral methylprednisolone was started. Persistence of retinal and choroidal inflammations under systemic corticosteroids required association with immunosuppressive agent to control the disease activity., Conclusion: Multimodal imaging and more precisely ICGA is useful to assess subclinical choroidal inflammation and monitor treatment response in TINU syndrome. Immunosuppression needs to be revised and adapted when uveitis and/or kidney function are unresponsive to systemic steroids., Abbreviations: TINU: tubulointerstitial nephritis and uveitis; TIN: tubulointerstitial nephritis; ACE: angiotensin-converting enzyme; RF: rheumatoid factor; Uβ2M: urinary β-2microglobulin; AMPPE: acute multifocal placoid pigment epitheliopathy; FA: fluorescein angiography; ICGA: indocyanine green angiography; CT: computed tomography.

Proton pump inhibitors are widely used in the treatment of various acid-related diseases and are among the most commonly used drugs. Studies estimate that 25-70% of proton pump inhibitors are prescribed for inappropriate treatments, doses, and indications, where the benefits of proton pump inhibitor use may be less than the risk of adverse drug reactions for many patients. Acute interstitial nephritis is an immune-mediated atypical kidney injury in the long-term use of proton pump inhibitors that causes problems for clinicians and patients. In this review, we summarize the current knowledge of proton pump inhibitors inducing acute interstitial nephritis, chronic kidney disease, and even end-stage renal disease in terms of incidence, pathogenesis, factors, clinical features, and diagnosis. We discuss how these factors change under conditions of acute interstitial nephritis, chronic kidney disease, and end-stage renal disease. The purpose of this review is to assess the current evidence to help clinicians and patients interpret the potential causal relationship between proton pump inhibitor intake and nephrotoxicity. This prompts clinicians to consider the appropriate dose and duration of proton pump inhibitor therapy to avoid inappropriate use., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)