Fanconi syndrome with karyomegalic interstitial nephritis after ifosfamide treatment for osteosarcoma: a case report.

Patients with ifosfamide-induced renal damage present with Fanconi syndrome. Karyomegalic nephropathy/interstitial nephritis (KNIN) is a rare form of chronic tubulo-interstitial nephritis that was initially considered a type of familial nephropathy. However, several reports of drug-induced KNIN, i.e., KNIN-like nephropathy, have been reported in recent years. We present the case of an 18-year-old man who presented with Fanconi syndrome and progressive renal dysfunction after receiving chemotherapy including ifosfamide and cisplatin for right femoral osteosarcoma. Renal biopsy revealed numerous atrophied tubular epithelial cells with large, polymorphic nuclei, and the definitive diagnosis was KNIN. Most patients with KNIN-like nephropathy who receive ifosfamide are concomitantly treated with cisplatin, indicating that ifosfamide and cisplatin might act synergistically to increase the risk for KNIN-like nephropathy. Further investigation in case series is warranted to reveal potential treatment approaches and to evaluate prognosis.

Antibrush Border Antibody Disease: A Case Series.

Antibrush border antibody (ABBA) disease is a rare cause of kidney disease characterized by progressive renal tubular injury associated with immune complex deposition along the basement membranes of the proximal tubule and circulating autoantibodies to brush border antigens. Several antigens have been identified as targets of autoantibodies in this disease, including low-density lipoprotein receptor related protein 2 (LRP2), cubilin, and amnionless proteins. We present 9 patients from 2 academic medical centers and describe the clinicopathologic characteristics and outcome data. All patients presented with acute kidney injury and proteinuria. Pathology confirmed immune complex deposition along proximal tubular basement membranes in all patients, but the majority (6/8) also showed segmental glomerular subepithelial immune complexes. Two of 3 patients treated with rituximab demonstrated stabilization of kidney function; 1 of these patients had mantle cell lymphoma. One patient with lung cancer showed stabilization of disease after treatment of the malignancy. The remaining patients progressed to end-stage kidney disease with either conservative therapy (3 patients) or immunosuppression with glucocorticoids (2 patients). This series highlights the poor prognosis of ABBA disease, but a potential benefit of anti-B cell therapy or treatment of an underlying malignancy in some cases.

Tubulointerstitial nephritis with storiform fibrosis in a patient with angioimmunoblastic T-cell lymphoma.

We present a case of an angioimmunoblastic T-cell lymphoma (AITL) and tubulointerstitial nephritis with storiform fibrosis in a 76-year-old man. The patient exhibited lymphadenopathy, polyclonal hypergammaglobulinemia, and renal dysfunction and was diagnosed with AITL on the basis of lymph node biopsy findings. The serum IgG4 level was highly elevated. Renal biopsy revealed IgG4-positive plasma cells and storiform fibrosis without infiltration of AITL, and the findings indicated IgG4-related kidney disease (IgG4-RKD). Following THPCOP therapy for AITL, the renal function improved. While diagnosing IgG4-RKD in a patient with AITL poses challenges, follicular helper T cell involvement appeared crucial in AITL and renal tubulointerstitial lesions in this case.

Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family.

Pathogenic variants in the FAN1 gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic-genotypic features of a FAN1 mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney disease of unknown cause treated with renal replacement therapy and elevated liver enzymes. Short stature, emaciation, latte-colored skin, freckles, and a hawk-like nose in four patients, a limited intellect in two patients, and chronic restrictive lung disease in one patient completed the phenotype. Severe infections occurred in four patients. All five patients had ceased. Four patients underwent autopsy. KIN and extrarenal karyomegaly were observed histologically; the livers showed no specific abnormality. The genotyping using formalin-fixed tissue samples detected a hitherto undescribed homozygous FAN1 mutation (c.1673_1674insT/p.Met558lfs*4; exon 5) in three of these patients and a heterozygous FAN1 mutation in one patient. The reason for the heterozygosity is discussed. In addition, 56 family members consented to the screening for FAN1 mutation from which 17 individuals proved to be heterozygous carriers; a blood chemistry evaluation of their kidney and liver function did not find any abnormality. The clinical presentation of FAN1-related disease was multifaceted, and not yet described manifestations were observed besides kidney and liver disease. Mutation in this gene should be suspected in adults with small kidneys of unknown cause, elevated liver enzymes, and recurrent infections, even without a family history.

Tofacitinib for the treatment of refractory immune checkpoint inhibitor-associated immune nephritis.

Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines recommend treatment of ICI-associated AIN with steroids, then TNF-alpha inhibitor infliximab. However, some cases are refractory to these therapies, potentially due to insufficient cytokine blockade. This is the first case where a 65-year-old female with metastatic lung adenocarcinoma, requiring high maintenance doses of steroids for immune nephritis was treated with tofacitinib, an oral Janus kinase (JAK) inhibitor. Tofacitinib enabled successful steroid tapering and might be a therapy option for refractory immune nephritis.

Immune checkpoint inhibitors induce acute interstitial nephritis in mice with increased urinary MCP1 and PD-1 glomerular expression.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) induce acute interstitial nephritis (AIN) in 2-5% of patients, with a clearly higher incidence when they are combined with platinum derivatives. Unfortunately, suitable disease models and non-invasive biomarkers are lacking. To fill this gap in our understanding, we investigated the renal effects of cisplatin and anti-PD-L1 antibodies in mice, assessing PD-1 renal expression and cytokine levels in mice with AIN, and then we compared these findings with those in AIN-diagnosed cancer patients. METHODS: Twenty C57BL6J mice received 200 µg of anti-PD-L1 antibody and 5 mg/kg cisplatin intraperitoneally and were compared with those receiving cisplatin (n = 6), anti-PD-L1 (n = 7), or saline (n = 6). After 7 days, the mice were euthanized. Serum and urinary concentrations of TNFα, CXCL10, IL-6, and MCP-1 were measured by Luminex. The kidney sections were stained to determine PD-1 tissue expression. Thirty-nine cancer patients with AKI were enrolled (AIN n = 33, acute tubular necrosis (ATN) n = 6), urine MCP-1 (uMCP-1) was measured, and kidney sections were stained to assess PD-1 expression. RESULTS: Cisplatin and anti PD-L1 treatment led to 40% AIN development (p = 0.03) in mice, accompanied by elevated serum creatinine and uMCP1. AIN-diagnosed cancer patients also had higher uMCP1 levels than ATN-diagnosed patients, confirming our previous findings. Mice with AIN exhibited interstitial PD-1 staining and stronger glomerular PD-1 expression, especially with combination treatment. Conversely, human AIN patients only showed interstitial PD-1 positivity. CONCLUSIONS: Only mice receiving cisplatin and anti-PDL1 concomitantly developed AIN, accompanied with a more severe kidney injury. AIN induced by this drug combination was linked to elevated uMCP1, consistently with human AIN, suggesting that uMCP1 can be potentially used as an AIN biomarker.

Diagnosis, management, and outcomes of immune checkpoint inhibitor induced acute interstitial nephritis: A single-center experience.

BACKGROUND: Immune checkpoint inhibitor (ICI)-associated acute interstitial nephritis (AIN) is a recognized complication of immunotherapy (IO), but literature on its management and outcomes is limited. METHODS: We retrospectively reviewed patients who received ICIs and developed biopsy-proven or clinically-suspected ICI-associated AIN at the University of Virginia Comprehensive Cancer Center from 2012-2023. We analyzed baseline characteristics and clinical outcomes, including treatment interruption and rechallenge rates. Acute kidney injury (AKI) was defined as a ≥ 1.5-fold increase in baseline creatinine under seven days, a two-fold increase above the upper limit of normal, or an increase by ≥0.3 mg/dL. Kidney function returning to within 0.3 mg/dL or less than twice baseline was considered complete (CRc) and partial (PRc) recovery, respectively. RESULTS: We identified 12 cases of ICI-AIN: four by biopsy (33%) and eight (67%) by clinical suspicion. Two patients received anti-CTLA-4 and anti-PD1, six received anti-PD1 alone, and four received chemo-immunotherapy. The majority (58%) of patients developed AIN within the first 5 cycles. Eight patients developed ≥ Grade 3 AKI, and six developed multiple irAEs. ICI was permanently discontinued in seven patients (58%) and temporarily interrupted in four (30%). The CRc and PRc rates were 67% and 8%, respectively. Upon AIN onset, the best disease response was stable disease in five patients, partial response in three, and progressive disease in three. Median overall survival was 4.87 years, and progression-free survival was 1.5 years. CONCLUSIONS: Rechallenge with IO after kidney irAE may be possible in some patients but requires careful evaluation on an individual basis.

Acute Interstitial Nephritis and Oxalate Nephropathy After Rapid Pasireotide Response in Treatment-resistant Acromegaly.

We report a case of interstitial nephritis, likely secondary to oxalate nephropathy, due to the development of pancreatic exocrine dysfunction after commencement of pasireotide for acromegaly. Pasireotide is known to impair insulin secretion but can also impair pancreatic exocrine function, hypothezised to result from high-affinity binding of somatostatin receptors 1, 2, 3, and 5. This has been an advantage in postoperative tissue anastomoses after pancreatic surgery, but exocrine insufficiency has not been reported when used for the treatment of acromegaly. A 73-year-old woman, diagnosed with acromegaly, was unable to achieve biochemical control despite 2 surgical resections of an invasive mammosomatotroph pituitary tumor and treatment with cabergoline and maximal-dose lanreotide. The tumor expressed somatostatin receptor type 5 but not somatostatin receptor type 2, predicting good response from pasireotide, which was commenced at 40 mg every 4 weeks. IGF-1 rapidly normalized, but the patient presented with nausea, anorexia, and acute kidney injury. Renal biopsy revealed acute-on-chronic interstitial nephritis, with numerous oxalate crystals. Increased fecal fat globules were noted on fat stain (3+), supporting malabsorption as an etiology of secondary enteric hyperoxaluria. Renal function recovered to near baseline over months following pasireotide withdrawal and high-dose glucocorticoids.

Acute kidney injury in lamotrigine-induced DRESS syndrome.

We present a case of lamotrigine-triggered DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome with acute kidney injury stage 3. A 17-year-old girl with known epilepsy treated with lamotrigine presented with acute kidney injury as well as skin eruption, fever, and apathy. Extended diagnostics, considering infectious and autoimmune diseases, remained unremarkable. Lamotrigine blood levels were within the target range. Kidney biopsy showed acute interstitial nephritis with tubular necrosis. Methylprednisolone pulse therapy led to an improvement in kidney function; skin eruption and neurological symptoms resolved. During the hospital stay, the girl admitted to inconsistent and variable intake of lamotrigine, occasionally resulting in notable overdosing. This report demonstrates that acute kidney injury in lamotrigine-induced DRESS syndrome is an acute interstitial nephritis with tubular necrosis, an aspect that has not been deeply characterized so far. Additionally, we aim to elevate awareness towards non-adherence as cause of disease, especially among the adolescent population.

Dapagliflozin-induced drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Followed By Acute Interstitial Nephritis (AIN): A Case Report.

A 78-year-old male was admitted to the hospital with acute renal failure and generalized erythema after starting dapagliflozin 10 mg/day for chronic kidney disease (CKD). A skin biopsy revealed superficial perivascular dermatitis with eosinophils. A renal biopsy revealed lymphocytic and eosinophilic infiltration of the interstitium, and focal tubulitis. The patient was diagnosed with a dapagliflozin-induced drug reaction with eosinophilia and systemic symptoms (DRESS), followed by acute interstitial nephritis (AIN), and prednisolone therapy was therefore initiated. The patient's renal function improved, and erythema disappeared. To our knowledge, this is the first report of DRESS caused by dapagliflozin, and the patient was successfully treated with prednisolone.

Karyomegalic Interstitial Nephritis in the Allograft Kidney - A Case Report.

Karyomegalic interstitial nephritis is a rare progressive renal disease. We report a 36-year-old male patient who developed kidney failure due to this condition, underwent kidney transplantation from his sister, and developed the same condition in the graft. Genetic testing of the donor revealed autosomal recessive compound heterozygous mutation of Fanconi anemia-associated nuclease1 (FAN1) gene. Karyomegalic interstitial nephritis is most probably donor derived in our patient. It should not be mislabeled as viral nephropathy.

The diagnosis of acute interstitial nephritis caused by infection versus antibiotic-induced interstitial nephritis: a narrative review.

Acute interstitial nephritis (AIN) is a significant contributor to acute kidney injury and can be attributed to a variety of factors, including but not limited to allergens or drugs, infections, autoimmune or systemic diseases, and idiopathic forms of the disease. In some cases, AIN requires a therapeutic action according to a single specific etiology by handling the offending agent and applying an immunosuppressant. Although AIN can be diagnosed through renal biopsy, it is not able to pinpoint the precise cause when multiple causes are suspected to be present simultaneously. Such situations arise when a patient suffering from infection develops AIN during antibiotic therapy, the exact causative factor of which becomes a challenge for the clinicians to determine. This is attributed to the different approaches employed in different etiologies, wherein clinicians are required to maintain the current antibiotic therapy or augment the dose in cases of infection as AIN etiology, without resorting to immunosuppressant therapy as the primary objective is infection killing. In contrast, antibiotics as an etiology for AIN require an alternative drug from the antibiotics group, along with an immunosuppressant. In the interim, delaying the identification of the precise cause may result in interstitial fibrosis and chronic kidney disease. This narrative review highlights certain findings that can be typical of infection-associated ATIN compared with antibiotic-associated ATIN based on clinical history and physical examination, clinical presentation of different antibiotic drug classes, histopathological features, classical and novel biomarkers, serum and urine cytokines and chemokines, cellular biomarkers, and genetic biomarkers. Although these findings cannot provide conclusive and clear recommendations that can be useful in the clinical practice, they can entice researchers to conduct original research on these features to discover clear recommendations.

Severe acute interstitial nephritis induced by α-glucosidase inhibitor miglitol in an elderly patient with type 2 diabetic nephropathy.

A 79-year-old male patient with type 2 diabetic nephropathy and hypertension was admitted to our hospital because of acute kidney injury with significantly elevated serum creatinine (8.12 mg/dL) and urinary ß2-microglobulin (ß2MG, 31,748 µg/L) levels. α-Glucosidase inhibitor (α-GI) miglitol, started two weeks prior to presentation, was discontinued because drug-induced acute interstitial nephritis (AIN) was suspected. Renal biopsy revealed AIN and diabetic nephropathy. The drug-induced lymphocyte stimulation test for miglitol was also positive. After the discontinuation of miglitol, the urinary ß2MG levels decreased to the normal range. This case raises the possibility that α-GI miglitol can worsen the renal function in patients with underlying renal dysfunction.

Evidence of tosufloxacin deposition in the kidneys of a patient presenting with crystal nephropathy.

Tosufloxacin tosilate is classified as a new quinolone antibacterial agent, which has been reported to cause crystal nephropathy. However, the origin of these crystal deposits has not yet been elucidated. We encountered a case of renal failure that progressed slowly owing to crystal-forming interstitial nephritis after long-term exposure to tosufloxacin. Mass spectrometry of the renal specimens revealed that tosufloxacin was deposited in the kidneys. The patient's renal function improved slowly with the withdrawal of tosufloxacin and steroid therapy. This is the first case to demonstrate the presence of crystal deposits consisting of tosufloxacin.

Kidney manifestations of sarcoidosis.

Renal involvement is a clinically relevant organ manifestation of sarcoidosis, leading to increased morbidity and complications. Although the exact incidence remains unknown, renal disease is likely to occur in up to one third of all sarcoidosis patients. Every patient with newly diagnosed sarcoidosis should receive a renal work-up and screening for disrupted calcium metabolism. Amid various forms of glomerulonephritis, granulomatous interstitial nephritis is the most common one, but it rarely leads to renal impairment. Histologically, granulomas can be absent. Nephrocalcinosis and nephrolithiasis are frequent forms when hypercalcaemia or hypercalciuria occur. Drugs used for treatment of systemic sarcoidosis can also cause renal damage. Due to its high heterogeneity, renal sarcoidosis can be difficult to treat. Glucocorticoids and various immunosuppressive treatments have been proven to be effective based on case series, but clinical trials are lacking. A treatment guideline for renal sarcoidosis is urgently needed. In this review article, we present an overview of the different forms of renal sarcoidosis and the diagnostic steps to confirm renal involvement; in addition, we provide insights on the management and available treatments. A better understanding regarding the pathogenesis of sarcoidosis is the key for the development of more specific, targeted therapies.

A Case of Omeprazole-Associated Acute Interstitial Nephritis.

Acute interstitial nephritis (AIN) is characterized by an inflammatory infiltrate of the interstitium of the kidney, typically causing a decline in kidney function. Drug-induced AIN (also called allergic AIN) is a type of AIN. Common drugs associated with AIN are antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (PPIs). A 59-year-old male with a history of recent laparoscopic robotic sleeve gastrectomy presented to the emergency department with five weeks of progressively worsening fatigue, nausea, and lightheadedness. Postoperatively, he was prescribed omeprazole 20 mg daily for gastric ulcer prophylaxis. His other home medications were amlodipine, atorvastatin, ursodiol, and budesonide-formoterol fumarate nebulizer. His physical examination was normal. Laboratory studies revealed elevated creatinine of 4.19 mg/dL from a baseline of 0.9 mg/dL two months ago and the presence of urine eosinophils. The etiology of this elevated creatinine was unclear, prompting CT-guided left renal biopsy. The biopsy showed diffuse interstitial inflammatory infiltration with numerous lymphocytes, a large number of neutrophils, and scattered eosinophils, consistent with the allergic type of AIN. Omeprazole was discontinued and the patient received a seven-day course of prednisone. Despite treatment, permanent renal damage occurred, and the patient's new baseline creatinine was 2.3 mg/dL. AIN caused by PPIs should be considered in the differential diagnosis of acute kidney injury (AKI). AIN can be difficult to diagnose, presenting with nonspecific symptoms, such as oliguria, malaise, nausea, and vomiting. An accurate and timely diagnosis can help prevent and treat worsening renal failure.

Renal dysfunction in routine proton-pump inhibitor use may be linked to comorbidities: A real-world observational study.

INTRODUCTION: The use of proton-pump inhibitors (PPI) is linked with infrequent but serious adverse events, including acute kidney injury, chronic kidney disease (CKD) and progression of CKD. Data on renal safety in routine use of PPI are more relevant to clinical practice. We studied whether such use of PPI is associated with renal dysfunction. METHODS: Patients taking PPI for at least six weeks had serum creatinine tested pre (n = 200) and post (n = 180) recruitment. These patients were then advised to follow-up: those taking PPI for at least 90 days in the next six months (n = 77) and at least another 90 days in the following six months (n = 50), had serum creatinine tested at such follow-up. Renal dysfunction was defined as any increase in serum creatinine level above baseline. RESULTS: The 200 patients recruited had mean age 39.6 (SD 9.2) years. Ninety-eight (49%) patients had a history of previous PPI use (median six months; interquartile range [IQR] 3-24). Only 20 (11.1%) patients at six weeks, 11 (14.3%) at six months and six (12%) at one year had increase in creatinine level; a majority of them had less than 0.3 mg/dL increase. Ten of these 20 (six weeks), five of 11 (six months) and five of six (one year) had other risk factors for renal dysfunction. No patient developed CKD during the study period. CONCLUSIONS: Mild and non-progressive increase in serum creatinine occurred in 10% to 15% of patients on routine PPI use. A majority of them had other risk factors. Small sample size and short follow-up duration are a few limitations of this study.

Acute interstitial nephritis with acute kidney injury after COVID-19 vaccination: a case report.

In the context of the massive spread of coronavirus disease 2019 (COVID-19), the development of a COVID-19 vaccine is urgently needed. The Pfizer-BioNTech COVID-19 vaccine has been widely applied across global populations. Herein, we report a case of acute interstitial nephritis with acute kidney injury in a young healthy subject after administration of the COVID-19 vaccine. A 20-year-old man was admitted with abdominal discomfort and nausea. He had received the Pfizer-BioNTech COVID-19 vaccine 6 days before. At 9 days after vaccination, his kidney function was decreased, with serum creatinine levels of 1.8 mg/dL. Even with supportive care with hydration, his kidney function worsened, and he underwent a kidney biopsy. The pathology findings revealed diffuse interstitial infiltration of inflammatory cells, predominantly comprising lymphocytes, with preservation of the glomerulus. No abnormal findings were noted by immunofluorescence or electron microscopy. Based on a diagnosis of drug-related acute interstitial nephritis, we treated the patient with high-dose prednisolone. After administration of prednisolone, kidney function slowly improved. A close linkage between COVID-19 vaccination and acute interstitial nephritis should be considered in the clinic, despite the low incidence.

Kidney Diseases Associated With Inflammatory Bowel Disease: Impact of Chronic Histologic Damage, Treatments, and Outcomes.

Introduction: Kidney disease is a well-known extraintestinal manifestation (EIM) associated with inflammatory bowel disease (IBD), with a variety of underlying etiologies. However, little is known about the overall outcomes and predictors. Methods: This is a retrospective, observational cohort study. Patients with IBD in whom a native kidney biopsy was performed at Mayo Clinic (Rochester, MN) between 1994 and 2022, were included. Demographic, clinical, and histologic characteristics of prognostic interest were collected. The main outcomes were kidney failure, disease remission, kidney function changes at last follow-up, and death. Results: From a total cohort of 318 patients, we selected a study group of 111 patients followed-up with at our institution (45 ulcerative colitis [UC] and 66 Crohn's disease [CD]), with a mean age of 48 ± 17 years (40% females). IgA nephropathy (IgAN), chronic interstitial nephritis (CIN), and acute interstitial nephritis (AIN) were the most common diagnoses (22%, 19%, 13%, respectively). Median estimated glomerular filtration rate (eGFR) at presentation was 30 ml/min per 1.73 m2 (interquartile range [IQR]: 17-54) and urinary protein-to-creatinine ratio [UPCR] 0.8 g/g (0.3-3.4), without differences between IBD types. During a median follow-up of 59 months (12-109), 29 patients (26%) reached kidney failure. By multivariable analysis, the main predictors of kidney failure were age (hazard ratio [HR]: 1.04; P = 0.002), baseline eGFR (HR: 0.94; P = 0.003) and histologic chronicity score (HR: 4.01; P < 0.001). Therapeutic management varied according to underlying etiology. Global survival (kidney failure + death) was significantly better in patients who achieved complete or partial remission, or stabilization or improvement of kidney function. Conclusion: One-fourth of patients with IBD with kidney disease may reach kidney failure, and the main determinants of this outcome is age, baseline eGFR, and degree of chronicity in kidney biopsy.