Tubulointerstitial nephritis in children and adolescents.

The tubulointerstitial compartment comprises most of the kidney parenchyma. Inflammation in this compartment (tubulointerstitial nephritis-TIN) can be acute and resolves if the offending factor is withdrawn or may enter a chronic process leading to irreversible kidney damage. Etiologic factors differ, including different exposures, infections, and autoimmune and genetic tendency, and the initial damage can be acute, recurrent, or permanent, determining whether the acute inflammatory process will lead to complete healing or to a chronic course of inflammation leading to fibrosis. Clinical and laboratory findings of TIN are often nonspecific, which may lead to delayed diagnosis and a poorer clinical outcome. We provide a general review of TIN, with special mention of the molecular pathophysiological mechanisms of the associated kidney damage.

Glucocorticoid does not improve the renal prognosis of patients with diabetic nephropathy combined with acute tubulointerstitial nephritis: a retrospective analysis.

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.

Two acute kidney injury episodes after ICI therapy: a case report.

A 74-year-old Japanese male with lung squamous cell carcinoma received his first dose of immune checkpoint inhibitors (ICIs): ipilimumab and nivolumab. He developed acute kidney injury (AKI) and was admitted to our department. We diagnosed kidney immune-related adverse effects (irAE), and a kidney biopsy revealed acute tubulointerstitial nephritis. We started oral prednisolone (PSL) and his AKI immediately improved. The patient maintained stable findings after PSL was tapered off. However, seven months after the ICI administration, he developed rapid progressive glomerular nephritis and was admitted to our department again. The second kidney biopsy showed findings consistent with anti-glomerular basement membrane glomerulonephritis. Although the patient was treated with pulse methylprednisolone followed by oral PSL and plasma exchange, he became dependent on maintenance hemodialysis. To our knowledge, no case report has described two different types of biopsy-proven nephritis. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered.

Acute Tubulointerstitial Nephritis due to Human Papillomavirus Vaccination.

Acute tubulointerstitial nephritis (ATIN), a rare cause of acute kidney injury in children, is caused by various factors such as drugs, infection, and systemic inflammation. We herein present a case of ATIN with mild encephalitis/encephalopathy with reversible splenial lesion (MERS)-like findings on head magnetic resonance imaging (MRI), which was associated with human papillomavirus (HPV) vaccination. A 14-year-old girl presented to our hospital with a high fever for 5 days. Results of common laboratory tests were normal except for increased C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR). Antibiotics were administered, and the fever promptly resolved after admission. After 7 weeks, she was readmitted due to a high fever for 4 days. In addition to increased CRP levels and ESR, urine test revealed high urine N-acetyl-ß-D-glucosaminidase and ß-2-microglobulin levels, and a renal scintigram showed mild bilateral uptake of 67Ga-citrate, consistent with the pathology of ATIN. Furthermore, head MRI, which was performed because the patient experienced prolonged headaches, revealed MERS-like lesions, although she did not have other neurological symptoms. Detailed examination of her medical records revealed that she had developed high fever 10 days after the third HPV vaccination and another previous episode of high fever 12 weeks after the second HPV vaccination. Based on these findings, we concluded that the ATIN and MERS-like lesions could have been associated with HPV vaccination. Although HPV vaccination is important for preventing uterine cancer, physicians must be vigilant about its various potential adverse effects, including ATIN.

Clinical Features, Outcomes, and Response to Corticosteroid Treatment of Acute Tubulointerstitial Nephritis: A Single-Centre Retrospective Cohort Study in the Czech Republic.

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.

Renal Immune-related Adverse Event of Pembrolizumab Masked by Pemetrexed.

A Japanese woman in her 60s developed a kidney injury 9 weeks after treatment with pemetrexed, carboplatin, and pembrolizumab for stage IV lung adenocarcinoma. A renal biopsy showed chronic tubulointerstitial damage with minimal focal interstitial inflammation, consistent with pemetrexed-induced nephropathy; thus, pemetrexed was withdrawn. However, the kidney injury continued to worsen. A repeated biopsy showed severe acute tubulointerstitial nephritis, suggestive of a pembrolizumab-induced immune-related adverse event (irAE). The worsening after pemetrexed discontinuation suggested that the irAE had already begun, as the first biopsy showed focal inflammation. This case suggests thatcombining immune checkpoints and chemotherapy requires considering concurrent drug-induced nephrotoxicity.

Biopsy-proven acute tubulointerstitial nephritis in patients treated with immune checkpoint inhibitors: a pooled analysis of case reports.

Introduction: Acute kidney injury (AKI) in cancer patients receiving immune checkpoint inhibitors (ICIs) may recognize multiple causes. Here, we reviewed cases of biopsy-proven acute tubulointerstitial nephritis (ATIN) to describe the clinical characteristics and outcomes of this condition. Method: We conducted a pooled analysis of clinical cases of ICI-related biopsy-proven ATIN up to 1 May 2022. We collected data on clinical characteristics, AKI, biopsy findings, laboratory examinations, and renal outcomes. Results: Eighty-five patients (61.4 ± 19 years, 56 male) were evaluated. Melanoma was the most prevalent diagnosis (51%), followed by non-small cell lung cancer (30%). ICI treatment consisted of PD-1, PDL-1 (nivolumab, pembrolizumab, atezolizumab), and CTLA-4 inhibitors (i) (ipilimumab) or combination PD-1i+CTLA4i. Renal toxicity developed after a median of four cycles of therapy. Fifty-one patients (65.5%) developed the most severe form of AKI- stage 3, including five patients requiring dialysis. All the 19 patients treated with dual ICI blockade developed AKI-stage 3, compared with 29 patients out of the 60 receiving a single agent (p<0.001). Most events were managed with corticosteroids associated with ICI withdrawal. In 15 patients ICI was restarted, but in six (40%) AKI recurred. Overall, 32 patients (40%) presented a complete renal recovery, which chance was inversely associated with dual ICI blockade (OR 0.15, 95CI 0.03-0.7, p=0.01). Conclusion: ICI-related ATIN may develop late after the therapy initiation, presenting as severe AKI, particularly in patients with dual ICI blockade. Although this complication may be partially reversible, concerns remain about the renal function sequelae and the possibility of restarting ICI treatment.

Improvement in Tubulointerstitial Nephritis With Glucocorticoid Therapy in an Anorexia Nervosa Patient.

Anorexia nervosa is a psychiatric disorder that is often diagnosed in adolescents and young adults. Renal-related complications of anorexia nervosa include abnormal water metabolism, electrolyte abnormalities, and nephrocalcinosis, which may lead to irreversible renal damage. Furthermore, tubulointerstitial nephritis has been reported as a renal pathological feature of anorexia nervosa. Immunosuppressive therapy, such as with glucocorticoids, has been recommended for idiopathic interstitial nephritis treatment; however, the effectiveness of immunosuppressive therapy for interstitial nephritis in patients with anorexia nervosa remains unestablished. Here, we report a case of interstitial nephritis in a patient with anorexia nervosa whose renal function was successfully improved with glucocorticoid therapy. The patient was a 38-year-old woman who was referred for renal dysfunction (estimated glomerular filtration rate: 7.6 mL/min/1.73 m2). She had anorexia nervosa and repeated episodes of vomiting. Hypokalemia (K: 2.1 mEq/L) and metabolic alkalosis (HCO3-: 54.2 mEq/L) were observed. Fluid therapy and potassium supplementation did not improve renal function; therefore, a percutaneous renal biopsy was performed. The renal pathology results revealed interstitial fibrosis, inflammatory cell infiltration in the interstitium, and tubulitis, suggesting a diagnosis of tubulointerstitial nephritis. Glucocorticoid therapy improved the patient's renal function to an estimated glomerular filtration rate of 19.91 mL/min/1.73 m2, and the renal function remained stable thereafter. This case suggests that glucocorticoid therapy may be considered for the treatment of interstitial nephritis in patients with anorexia.

Rifampicin-induced acute tubulointerstitial nephritis during pulmonary tuberculosis treatment: A case report.

Drug-induced tubulointerstitial nephritis is an uncommon complication in patients on anti-tuberculosis therapy that can lead to permanent kidney damage. Rifampicin is the most offending drug. We report a case of a 41-years old man being treated for pulmonary tuberculosis and presenting with tubulointerstitial nephritis associated with rifampicin. We focus on diagnosis features and therapeutic challenges.

Favorable course of leptospirosis and hantavirus-induced acute tubulointerstitial nephritis under corticosteroid treatment.

BACKGROUND: We present two children with acute tubulointerstitial nephritis (ATIN) caused by leptospirosis in a 12-year-old boy and hantavirus in a 10-year-old girl. The role of glucocorticoids in the management of ATIN triggered by infectious agents is unclear. CASE-DIAGNOSIS/TREATMENT: Both children were hospitalized with jaundice, elevated serum creatinine, and thrombocytopenia. There was no oliguria or hypertension. Urine analysis revealed tubular proteinuria. Kidney biopsy was performed on one patient and showed tubulointerstitial inflammation with mild mesangial proliferation. Both patients were treated with glucocorticoids in view of deteriorating kidney function with respective serum creatinine values of 5.2 and 4.1 mg/dl. Both children exhibited an excellent clinical and biochemical response to treatment. Neither of the patients required dialysis. Positive serology test results indicated a recent leptospirosis and hantavirus infection. CONCLUSIONS: Leptospirosis and hantavirus associated ATIN share common clinical and biochemical features. Due to the low incidence in Europe these infectious causes of kidney dysfunction may be overlooked. Glucocorticoids may be considered in the management of ATIN.

Clinical Characteristics of Children With Acute Tubulointerstitial Nephritis: A Single-Center Experience.

OBJECTIVE: Acute tubulointerstitial nephritis (ATIN) is an infiltration of the kidney interstitium with inflammatory cells. Medications are most frequently blamed for the etiology. Patients may present with non-specific signs and symptoms. Therefore, the diagnosis of ATIN is often delayed. In this study, clinical characteristics, treatment protocols, and outcomes of children diagnosed with ATIN were presented. METHODS: This is a retrospective study based on the data of 18 patients diagnosed with ATIN between 2017 and 2022 at Gazi University. Patients were divided into two groups: steroid-treated (n=13) and non-steroid-treated (n=5). Clinical features and laboratory evaluations were compared between the groups. RESULTS: The mean age of the patients was 14.4±2.6 years, and the great majority were girls (88.9%, n=16). ATIN was mostly medication-related (n=17, 94.4%). Steroids were started in one-third of patients using non-steroidal anti-inflammatory drugs. Steroids were started in 45.4% of the patients with eosinophilia, 75% of those with pyuria, 66.6% of those with hematuria, and half of the patients with increased kidney echogenicity. The kidney functions returned to normal ranges in all patients. In steroid-treated patients, although recovery times for serum creatinine were longer (7.2±2.5 vs. 71.2±100.7 days), blood eosinophil count reached normal values more rapidly (5.4±2.3 vs. 3.1±1.0 days). CONCLUSION: ATIN can be associated with diverse clinical presentations. The first and most important step of treatment is to discontinue the medication responsible for the etiology. Steroid treatment improves eosinophilia more rapidly. However, randomized controlled studies are needed to determine further treatment steps and establish a more definite treatment protocol.

IgA-dominant infection-related glomerulonephritis with NAPlr-positive tubulointerstitial nephritis.

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.

'Prevention is better than cure': warning for comedications in patients receiving immune checkpoint inhibitors to avoid acute kidney injury.

The introduction of immune checkpoint inhibitors (ICI) has resulted in significant improvement in cancer care, but has been accompanied by the occurrence of immune-related adverse events (irAEs). Also, kidney irAEs have been reported, and the most frequent one is acute tubulointerstitial disease which impacts renal and overall prognosis. There is an unmet need to stratify renal risk in oncologic patients, to allow individualized monitoring and therefore, early detection of ICI-related acute kidney injury (ICI-AKI). Although risk factors for ICI-AKI have been described in previous case-control studies, where 'cases' were ICI-AKI patients and 'controls' ICI-treated patients without AKI, there is limited epidemiologic knowledge concerning patients developing different irAEs. In this issue of the Clinical Kidney Journal, Gerard et al. describe five factors that were associated with the development of ICI-AKI: older age, previous chronic kidney disease, and concomitant use of fluindione, non-steroidal anti-inflammatory drugs and proton pump inhibitors. These findings suggest that ICI may be a 'second hit' that precipitates AKI caused by a concomitant drug. These results urge an increased focus to prevent the prescription of potential nephrotoxic drugs in ICI-treated patients, avoiding iatrogenic events.

The systemic immune response due to cholesterol crystal embolization syndrome: a case report.

BACKGROUND: Cholesterol crystal embolization syndrome (CES) occurs when an atherosclerotic plaque causes small-vessel embolization, resulting in multi-organ damage. Although CES is pathologically characterized by an infiltration of eosinophils, the implication of the systemic inflammatory response represented by hypereosinophilia is unclear in clinical practice. Herein we present the case of a patient diagnosed with CES who developed multiple allergic organ injuries, including daptomycin-related dermatitis and later vancomycin-induced acute tubulointerstitial nephritis, which was successfully treated by the withdrawal of each medicine with or without corticosteroid therapy, one by one. CASE PRESENTATION: A 76-year-old Japanese man diagnosed with thoracic aneurysm rupture underwent total arch replacement through the open stent graft technique. Postoperatively, he developed methicillin-resistant Staphylococcus epidermidis bacteremia, which was treated with daptomycin. Subsequently, he presented with palpable purpura on both dorsal feet, erythema around his body, and hypereosinophilia. Daptomycin was replaced with vancomycin due to suspicion of drug-induced erythema. The erythema gradually faded. On nine days after vancomycin therapy, the systemic erythema rapidly reappeared followed by acute renal failure. The renal function decline prompted hemodialysis. A skin biopsy revealed cholesterol embolization, whereas a kidney biopsy revealed acute tubulointerstitial nephritis. After vancomycin discontinuation and initiation of systemic corticosteroid treatment, his kidney function was restored to the baseline level. CONCLUSIONS: The present case highlights cholesterol embolization can cause allergic complications in addition to direct organ damage.

COVID-19 infection and renal injury: where is the place for acute interstitial nephritis disease?

Novel coronavirus disease infection (coronavirus disease 2019, COVID-19) was declared a global pandemic in March 2020 and since then has become a major public health problem. The prevalence of COVID-19 infection and acute kidney injury (AKI) is variable depending on several factors such as race/ethnicity and severity of illness. The pathophysiology of renal involvement in COVID-19 infection is not entirely clear, but it could be in part explained by the viral tropism in the kidney parenchyma. AKI in COVID-19 infection can be either by direct invasion of the virus or as a consequence of immunologic response. Diverse studies have focused on the effect of COVID-19 on glomerulonephritis (GN) patients or the 'novo' GN; however, the effect of COVID-19 in acute tubulointerstitial nephritis (ATIN) has been scarcely studied. In this article, we present five cases with different spectrums of COVID-19 infection and ATIN that may suggest that recent diagnosis of ATIN is accompanied by a worse clinical prognosis in comparison with long-term diagnosed ATIN.

Immune checkpoint inhibitors in patients with chronic kidney disease: Assessing their ability to cause acute kidney injury and informing their proper use.

Immune check point inhibitors (ICI) have secured regulatory approvals across the world for the treatment of various types of cancers. Though not as frequent as immune-related adverse events (AEs) involving other organs, a considerable number of ICI-related renal AE have also been reported and predicting such events has become important. We provide an updated review on possible mechanisms of ICI-related acute kidney injury (AKI), related risk factors, and the use of ICIs in patients with chronic kidney diseases (CKD). A systematic search for related articles was conducted. Acute tubulointerstitial nephritis (ATIN) is known to be the main cause of ICI-related AKI, with glomerulonephritis also a significant cause. Factors including use of concurrent medications, extra-renal immune related AEs, and combination of two or more immunotherapy drugs are possible risk factors. Use of ICI in patients with CKD may be related to increased occurrence of overall immune related AEs. If the diagnosis of ICI related renal AEs is confirmed, prompt use of steroids is recommended, and in severe cases of AKI, discontinuation of ICI should be considered.

Vancomycin-Associated Acute Kidney Injury: A Narrative Review from Pathophysiology to Clinical Application.

Vancomycin is the most frequently used antibiotic, accounting for up to 35% of hospitalized patients with infection, because of its optimal bactericidal effectiveness and relatively low price. Vancomycin-associated AKI (VA-AKI) is a clinically relevant but not yet clearly understood entity in critically ill patients. The current review comprehensively summarizes the pathophysiological mechanisms of, biomarkers for, preventive strategies for, and some crucial issues with VA-AKI. The pathological manifestations of VA-AKI include acute tubular necrosis, acute tubulointerstitial nephritis (ATIN), and intratubular crystal obstruction. The proposed pathological mechanisms of VA-AKI include oxidative stress and allergic reactions induced by vancomycin and vancomycin-associated tubular casts. Concomitant administration with other nephrotoxic antibiotics, such as piperacillin-tazobactam, high vancomycin doses, and intermittent infusion strategies compared to the continuous infusion are associated with a higher risk of VA-AKI. Several biomarkers could be applied to predict and diagnose VA-AKI. To date, no promising therapy is available. Oral steroids could be considered for patients with ATIN, whereas hemodialysis might be applied to remove vancomycin from the patient. In the future, disclosing more promising biomarkers that could precisely identify populations susceptible to VA-AKI and detect VA-AKI occurrence early on, and developing pharmacological agents that could prevent or treat VA-AKI, are the keys to improve the prognoses of patients with severe infection who probably need vancomycin therapy.

The Shifting Landscape of Lupus Nephritis Management: A Review.

Systemic lupus erythematosus (SLE) is commonly the first autoimmune disease that comes to mind for most people when rheumatology is mentioned. It remains an enigma that many of us, including patients and healthcare providers, do not fully understand. Although an ancient disease, it still remains difficult to both diagnose and treat. Historically, there has always been a paucity of therapeutic interventions for SLE as a whole. One of the most distressing manifestations for the patient and diagnostic and therapeutically challenging aspects of SLE is lupus nephritis (LN). There has historically been some difficultly in the development of LN drugs that provide significant therapeutic benefits while having an acceptable side-effect profile. This difficulty led to decades in which no drugs were approved for LN. With a better understanding of the pathogenesis of SLE and LN and improvement in trial design, great therapeutic strides have recently been made. The immunosuppressive landscape of LN has changed recently with the approval of two newer agents as well as a number of promising trials in LN. With the increased number of therapeutic agents (both immunosuppressive and non-immunosuppressive), the clinical question is how and when to use these medications, and, more importantly, which agents to use first. With the increased number of agents, the answers to these questions are becoming more difficult to answer. The purpose of the paper is to review updates in LN diagnosis and management.