Drug-induced Acute Tubulointerstitial Nephritis Research Articles

Acute kidney injury in a child treated with cisplatin and amphotericin B.

Cisplatin and amphotericin B are both known to be potentially nephrotoxic. We describe acute kidney injury due to the combination of Liposomal amphotericin B and cisplatin in an adolescent with osteosarcoma. Acute kidney injury (peak creatinine 431 µmol/L) consistent with drug-induced acute tubulointerstitial nephritis was observed a few days after concomitant administration of cisplatin and amphotericin B. Kidney function nearly normalised during follow-up. The timing of the concomitant administration of amphotericin B and cisplatin led us to presume that the combination was the cause of renal failure, and we conclude that concurrent administration of cisplatin and amphotericin B should be avoided.

Global burden of anticancer drug-induced acute kidney injury and tubulointerstitial nephritis from 1967 to 2023

This study aims to figure out the worldwide prevalence of anticancer therapy-associated acute kidney injury (AKI) and tubulointerstitial nephritis (TIN) and the relative risk of each cancer drug. We conducted an analysis of VigiBase, the World Health Organization pharmacovigilance database, 1967–2023 via disproportionate Bayesian reporting method. We further categorized the anticancer drugs into four groups: cytotoxic therapy, hormone therapy, immunotherapy, and targeted therapy. Reporting odds ratio (ROR) and information component (IC) compares observed and expected values to investigate the associations of each category of anticancer drugs with AKI and TIN. We identified 32,722 and 2056 reports (male, n = 17,829 and 1,293) of anticancer therapy-associated AKI and TIN, respectively, among 4,592,036 reports of all-drug caused AKI and TIN. There has been a significant increase in reports since 2010, primarily due to increased reports of targeted therapy and immunotherapy. Immunotherapy exhibited a significant association with both AKI (ROR: 8.92; IC0.25: 3.06) and TIN (21.74; 4.24), followed by cytotoxic therapy (7.14; 2.68), targeted therapy (5.83; 2.40), and hormone therapy (2.59; 1.24) for AKI, and by cytotoxic therapy (2.60; 1.21) and targeted therapy (1.54; 0.61) for TIN. AKI and TIN were more prevalent among individuals under 45 years of age, with a female preponderance for AKI and males for TIN. These events were reported in close temporal relationship after initiation of the respective drug (16.53 days for AKI and 27.97 days for TIN), and exhibited a high fatality rate, with 23.6% for AKI and 16.3% for TIN. These findings underscore that kidney-related adverse drug reactions are of prognostic significance and strategies to mitigate such side effects are required to optimize anticancer therapy.

Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes

Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes

POS-022 ACUTE TUBULO-INTERSTITIAL NEPHRITIS WITH EOSINOPHILS, SUSPECTED TO BE DRUG-INDUCED, AS SEEN ON NATIVE KIDNEY BIOPSIES: 10-YEAR EXPERIENCE FROM AN INDEPENDENT CENTRAL PATHOLOGY LABORATORY IN KENYA

Drug-induced acute tubulointerstitial nephritis (ATIN) is a well-recognised cause of unexplained AKI that can lead to CKD. The presence of eosinophils in the tubulo-interstitial inflammation associated with ATI is considered a hallmark of the diagnosis. There is scarcity of data on biopsy-proven drug-induced ATIN in Africa. The author set out to establish the extent of biopsy-proven drug-induced ATIN in native kidney biopsies a 10-year period from his experience at a pathology central referral laboratory that handles the highest number of kidney biopsies in the region. Histopathology reports in text form were searched for key words “tubulo-interstitial nephritis” and respective cases identified were further examined to confirm those that were acute or active tubule-interstitial nephritis with eosinophils present, which were deemed to be in keeping with a diagnosis of drug-induced acute tubulo-interstitial nephritis. Associated pathological findings present in the biopsies were also recorded. The results were tabulated and tallied on Excel spreadsheet to obtain the summary statistics. A total of 34 cases of suspected drug-induced ATIN were identified representing 3.2% of all native kidney biopsies in the 10-year period. The cases were reported in each year except for 2014, with 2011-2013 having a case each, 2015 had 4 cases, 2016 had 5 cases, while 2017-2019 had 6 cases each and 2020 had 4 cases. An equal gender distribution was noted with ½ the cases being males and ½ being females. The youngest patient was 15 years old and the oldest 69 years old, the mean age at 39.2 years and median of 40 years. The degree of inflammation and acute kidney injury was mild in 14 cases (41%), similarly moderate in 14 cases (41%) and severe in 6 cases (18%), while concurrent chronic kidney damage was minimal in 16 cases (47%), mild in 5 cases (15%), moderate in 12 cases (35%) and severe in 1 case (3%). All but 4 cases (12%) had an associated pathological diagnostic finding, of which the commonest associated pathological finding was hypertensive changes of benign nephrosclerosis in 6 cases (18%), membranous glomerulopathy 6 cases (18%), diabetic nephropathy 4 cases (12%), lupus nephritis 4 cases (12%), two cases each of AL amyloidosis, HIVAN and IgA nephropathy, and a case each of AA amyloidosis, primary FSGS, ascending infection and malignancy. The majority of biopsy-proven cases of drug-induced ATIN seen at this independent central laboratory in Kenya are associated with other renal pathologies on the same respective biopsies, and only 12% had no related renal pathologies on the biopsies thus only a minority of cases were 'purely' drug-induced ATIN as the primary pathology. The exact medication linked to the drug-induced ATIN was not indicated in the clinical details. Interestingly, none of the cases was actually clinically suspected pre-biopsy to be drug-induced ATIN. Although rare, biopsy-proven drug-induced ATIN is a significant cause of AKI, and based on this analysis, it appears that most cases of drug-induced ATIN compound or exacerbate other underlying renal pathologies with underlying hypertensive kidney disease, membranous nephropathy and diabetic nephropathy as the commonest associated pathologies. ATIN needs to be born in mind by nephrologists when working up patients for AKI, and also born in mind by pathologists when examining kidney biopsies.

Acute tubulointerstitial nephritis associated with antineutrophil cytoplasmic antibody following cimetidine treatment: a case report

BackgroundAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis usually induces rapidly progressive glomerulonephritis, including pauci-immune necrotizing crescentic glomerulonephritis. Acute tubulointerstitial nephritis (ATIN), which is often drug-induced, is a frequent cause of kidney injury. However, ATIN associated with ANCA without any glomerular lesions has been rarely reported, and drug-induced ATIN associated with ANCA is not well recognized. Here we present a case of an older woman with ATIN associated with myeloperoxidase-ANCA (MPO-ANCA) following cimetidine treatment.Case presentationA 70-year-old woman was admitted to our hospital due to acute kidney injury and mild proteinuria. She had a one-year history of chronic thyroiditis and dyslipidemia, for which she was taking levothyroxine sodium and atorvastatin, respectively. Two weeks before admission she had started cimetidine, methylmethionine sulfonium chloride, and itopride hydrochloride for gastric discomfort persistent since a month. She had experienced fatigue for two weeks and later appetite loss. The patient demonstrated a positive titer for MPO-ANCA (192 IU/mL) and a positive drug-induced lymphocyte stimulation test for cimetidine. She underwent two kidney biopsies that revealed ATIN without any glomerular lesions. Despite discontinuation of cimetidine on admission, renal injury continued with the presence of high MPO-ANCA titer. Oral steroid treatment was closely related with the recovery of her renal function and disappearance of MPO-ANCA.ConclusionsIn this case, ATIN presented as sustained renal insufficiency and high MPO-ANCA titer despite withdrawal of cimetidine. Therefore, we reason that the development of ANCA-associated ATIN was caused by cimetidine. Serologic follow-up with measurement of MPO-ANCA titers and renal biopsy are recommended when the clinical history is inconsistent with the relatively benign course of drug-induced ATIN.

Vancomycin-Associated Tubular Casts and Vancomycin Nephrotoxicity

IntroductionVancomycin nephrotoxicity is frequent and may be due to drug-induced acute tubular necrosis (ATN) or tubulointerstitial nephritis (TIN). Vancomycin-associated tubular cast (VTC) was recently described and may represent a novel cause of vancomycin nephrotoxicity. However, much is still unknown about VTC.Materials and MethodsThirty-seven kidney biopsy specimens from patients who were treated with vancomycin and developed acute kidney injury (AKI) were found among a total of 4673 biopsy samples between 2010 and 2019. These biopsy specimens were subjected to light microscopy, immunofluorescence, electron microscopy, and immunolocalization for vancomycin, uromodulin, myoglobin, tubular segment–specific markers, and examined for VTCs. The findings were correlated with the clinical course.ResultsVTCs displayed precipitated vancomycin casts in a background of uromodulin; the casts were limited to the distal tubules, and always associated with a background of more diffuse renal injury (ATN or TIN). The diagnosis of vancomycin nephrotoxicity was made in in 28 of 37 patients. VTC was noted in 25 of 28 biopsy samples from patients diagnosed with vancomycin nephrotoxicity and in one of nine biopsy samples from patients without this diagnosis. Vancomycin nephrotoxicity was diagnosed in 25 of 26 patients whose biopsy specimens showed VTC, but in only 3 of 11 patients without VTC in the biopsy samples.ConclusionsVTC displays a characteristic morphologic profile amenable to ready recognition in biopsy specimens. It results from coprecipitation of vancomycin and uromodulin. It facilitates the biopsy diagnosis of vancomycin nephrotoxicity. It may have a nephrotoxic effect superimposing on and independent from the ATN or interstitial nephritis in the pathogenesis of vancomycin nephrotoxicity.

Elevation of erythrocyte sedimentation rate and C-reactive protein levels reflects renal interstitial inflammation in drug-induced acute tubulointerstitial nephritis

BackgroundA renal biopsy is needed to define active inflammatory infiltration and guide therapeutic management in drug-induced acute tubulointerstitial nephritis (D-ATIN). However, factors such as various contraindications, refusal of informed consent and limited technical support may stop the biopsy process. It is thus of great importance to explore approaches that could deduce probable pathologic changes.MethodsA total of 81 biopsy-proven D-ATIN patients were enrolled from a prospective cohort of ATIN patients at Peking University First Hospital. The systemic inflammation score (SIS) was developed based on the CRP and ESR levels at biopsy, and patients were divided into high-SIS, median-SIS, and low-SIS groups. The demographic data, clinicopathologic features, and renal outcomes were compared.ResultsThe SIS was positively correlated with inflammatory cell infiltration and was inversely correlated with interstitial fibrosis. The number of interstitial inflammatory cells increased significantly with increasing SISs. The proportions of neutrophils and plasma cells were the highest in the high-SIS group compared with the other two groups. Prednisone (30–40 mg/day) was prescribed in all patients. The high-SIS group tended to have more favorable renal restoration than the other two groups. By 12 months postbiopsy, a decreased eGFR (< 60 mL/min/1.73 m2) was observed in 66.7% of medium-SIS patients, 32.4% of high-SIS patients, and 30.4% of low-SIS patients.ConclusionThe SIS was positively correlated with active tubulointerstitial inflammation and therefore could help to aid therapeutic decisions in D-ATIN.

Drug-Induced Acute Tubulointerstitial Nephritis

Abstract Nowadays, incidence of drug-induced acute tubulointerstitial nephritis is on the rise due to increased access of the patients to a variety of both prescribed and over-the-counter drugs. Acute kidney injury and hypersensitivity manifestations are the main features of acute tubulointerstitial nephritis. Classically considered reversible after prompt withdrawal of the offending medication, recent decades revealed potential for evolution to chronic kidney disease. This article presents the challenges in the diagnosis and treatment and also evolutive features of allergic acute tubulointerstitial nephritis induced by drugs.

P0441CONCOMITANT MEDICATIONS OR IMMUNE CHECHKPOINT INHIBITOR, WHO IS THE CAUSE OF ACUTE TUBULOINTERSTITIAL NEPHRITIS IN IMMUNOTHERAPY?

Abstract Background and Aims During the last decades, the incidence of drug-associated acute tubulointerstitial nephritis (ATIN) has markedly increased. In the recent years, immune checkpoint inhibitors (ICI) have shown promising results in the treatment of malignancies such as melanoma or lung cancer. Immune mediated adverse events are frequent during the use of these drugs as a result of their mechanism of action. The most common kidney lesion in ICI-treated patients who present acute kidney injury (AKI) is ATIN. It is well established that classical drug-induced ATIN is an allergic drug hypersensitivity reaction mediated by T lymphocytes that occurs 7-10 days after exposure. On the contrary, the pathomechanism of ICI-related ATIN remains controversial. Together with the hypothesis that ATIN is a hypersensitivity reaction against ICI itself, other authors propose that loss of inhibition of T cells may facilitate hypersensitivity reactions to previously tolerated drugs or kidney antigens. Method We reviewed 3 cases of ICI-associated ATIN diagnosed in our nephrology unit with known concomitant medications associated to ATIN. The main demographical, clinical and analytical variables such as gender, age, type of malignancy and oncological treatment were recorded. Results: Patient 1 A 70 year-old man was diagnosed with a non-small-cell lung carcinoma in June 2018. He was treated with carboplatin, paclitaxel and nivolumab (first cycle 21st June 2018), and underwent lobectomy. NSAIDs were prescribed on September 2018 after surgery. Creatinine was normal at baseline. On September 2018 (110 days after nivolumab initiation and 7 days after NSAIDs prescription) he was admitted to the nephrology unit due to AKI, and the kidney biopsy revealed ATIN. ICI and NSAIDs were discontinued. He was treated with steroids with partial renal recovery. Patient 2 An 82 year-old man was diagnosed with a locally advanced nasal melanoma. He was treated with pembrolizumab. He was referred to the emergency room 73 days after pembrolizumab initiation presenting acute renal failure. Immunological tests were negative and ultrasonography was normal. No other ATIN-related drugs were identified. The final diagnostic was ATIN confirmed by kidney biopsy and the patient was treated with steroids. ICI was discontinued and the recovery of the kidney function was partial. Six months later he was diagnosed with septic arthritis on his right wrist due to Pseudomonas aeruginosa. 7 days after ciprofloxacin prescription he presented AKI. The diagnosis was a flare of interstitial nephritis, thus oral steroids were re-initiated. Kidney function partially recovered. Patient 3 A 63-year-old woman was diagnosed of renal cancer diagnosed in 2014. She was initially treated with Sunitinib, but it was discontinued due to hypothyroidism. She initiated second-line treatment with Nivolumab 7 months before referral to our nephrology unit. Baseline creatinine was normal. 5 days before referral, she took 3 pills of ibuprofen 600mg during three days due to knee pain. The final diagnostic according to kidney biopsy was ATIN. ICI and NSAIDs were discontinued and she was treated with steroids. Kidney function was totally recovered. Conclusion ICI associated ATIN present scarce temporal association with the initiation of ICI. High prevalence of use of other ATIN-related drugs has been noticed among these patients. Herein, we report 3 cases of ATIN in the setting of the treatment with ICI. The temporal association of the first episode with other drugs rather than ICI, and the relapse after the rechallenge with a drug classically associated with ATIN suggests that it might be caused by these drugs rather than by ICI itself, that actually may facilitate the drug hypersensitivity reaction. Research in the pathomechanisms of ATIN in ICI patients is required in order to anticipate, prevent and treat this adverse effect.

The Role of PET Scanning in the Evaluation of Patients With Kidney Disease.

Patients with underlying kidney disease are often required to undergo imaging for a variety of purposes including diagnosis and prognosis. A test that is being increasingly used with for this group of patients is the positron emission test (PET) scan. In addition, combining the nuclear medicine technique (PET) with computed tomography scan allows additional imaging advantages over either alone. These imaging modalities are commonly used for a number of extrarenal indications (ie, cancer, coronary artery disease, central nervous system disease, infectious diseases, and others). They have also been used for diagnosis of acute tubulointerstitial nephritis, evaluation and management of retroperitoneal fibrosis, identifying infection within kidney and liver cysts, and distinguishing complex kidney cysts from kidney cancer in patients with underlying CKD. We will review PET scan utility in patients with kidney disease.

RENAL SAFETY OF PROTON PUMP INHIBITORS

Proton pump inhibitors are a widely used in clinical practice, and are taken by millions of patients around the world for a long time. While proton pump inhibitors are well-tolerated class of drugs, the number of publications has been raised about adverse renal effects, specially their association with acute tubulointerstitial nephritis. It is one of the leading causes of acute renal injury and have catastrophic long-term consequences called chronic kidney disease. In this review, we consider epidemiology, pathogenesis, diagnostic criteria (including biopsy and morphological pattern), clinical manifestations and treatment of proton pump inhibitors-induced acute tubulointerstitial nephritis. A subclinical course without classical manifestations of a cell-mediated hypersensitivity reaction (fever, skin rash, eosinophilia, arthralgia) is characteristic of acute tubulointerstitial nephritis. Increased serum creatinine, decreased glomerular filtration rate, electrolyte disorders, pathological changes in urine tests are not highly specific indicators, but allow to suspect the development of acute tubulointerstitial nephritis. The “gold” standard of diagnosis is the intravital morphological examination of the kidney tissue. Timely diagnosis and immediate discontinuation of the potentially causative drug is the mainstay of therapy and the first necessary step in the early management of suspected or biopsy-proven drug-induced acute tubulointerstitial nephritis. The usage of proton pump inhibitors should be performed only on strict indications with optimal duration of treatment and careful monitoring of kidney function. Multiple comorbidities (older age, heart failure, diabetes, cirrhosis, chronic kidney disease, hypovolemia) increase potential nephrotoxicity. Awareness of this iatrogenic complication will improve diagnosis of proton pump inhibitors-induced acute tubulointerstitial nephritis by multidisciplinary specialists and increase the possibility of successful treatment.

Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI isa new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.

Acute tubulointerstitial nephritis in Scotland.

Acute tubulointerstitial nephritis (ATIN) is a potentially reversible cause of acute kidney injury with the majority of cases drug related. Our aims were to examine the incidence profile of patients with ATIN in Scotland and to assess the impact of corticosteroid treatment. All adult patients with biopsy-proven ATIN, diagnosed between 2000 and 2012, presenting to renal units serving 1.9 of Scotland's 5 million population were included. Patient demographics, presenting, aetiologic and pathologic features, treatment given and outcome were extracted from patient records. In total, 171 cases representing 4.7% of native renal biopsies were identified. Median serum creatinine (sCr) was 327 μmol/l at biopsy (106 μmol/l at baseline). Eosinophilia, fever or rash was present in 57% with all 3 in only 1.1%. Active urinary sediment was found in 68%. Aetiology appeared drug induced in 73%. Proton pump inhibitors (PPIs) were likely causative in almost as many cases as antibiotics (35% each) and were more frequently implicated than non-steroidal anti-inflammatory drugs (20%). Number of PPI-related cases paralleled the rising prescription of these drugs. Corticosteroids were prescribed in 59% of drug-induced ATIN (median sCr at biopsy: 356 μmol/l vs. 280 μmol/l in those managed conservatively). There was no difference in sCr at 1, 6 and 12 months, with similar proportions of both groups experiencing complete renal recovery (48% vs. 41%) and becoming dialysis dependent (10% in both). Incidence of biopsy-proven ATIN in Scotland has been rising over the past decade with the majority of cases drug induced. Evidence supporting corticosteroid treatment is lacking.

Tubulointerstitial Nephritis with Uveitis in Chinese Adults

Tubulointerstitial nephritis and uveitis (TINU) syndrome is considered a rare cause of acute tubulointerstitial nephritis (ATIN) that is usually associated with renal recovery. This study sought to investigate the diagnosis, prognosis, and contributing factors of TINU syndrome using a large cohort of patients with prospective follow-up. This study included patients with TINU syndrome from a prospective cohort of patients with ATIN from 2007 to 2012. Clinical-pathologic data were collected at biopsy and autoantibodies against modified C-reactive protein (mCRP-Ab) were measured. Serum levels and renal tissue expression of Kreb von den Lunge-6 were also detected. Independent risk factors for poor renal outcome at 12 months and late-onset uveitis were analyzed. Thirty-one patients (28%) with biopsy-proven ATIN were classified as having TINU syndrome. Of these patients, 18 (58%) developed late-onset uveitis and were misdiagnosed as having drug-induced ATIN at the time of biopsy. An abnormal level of mCRP-Ab was an independent risk factor for late-onset uveitis (odds ratio, 14.7; 95% confidence interval, 3.4 to 64.0). Patients with TINU syndrome and drug-induced ATIN had comparable levels of Kreb von den Lunge-6 in both serum and renal tissues. Ninety-two percent of patients developed stage 3-4 CKD and/or tubular dysfunction by 12 months postbiopsy. Age, serum creatine level, erythrocyte sedimentation rate, and the presence of concomitant thyroid disease or leukocyturia were related to poor renal outcome. Relapse was seen in 36% (11 of 31) of patients and potentiated poor renal outcome. The diagnosis of TINU syndrome can be missed in a large fraction of patients with ATIN because uveitis can present well after the onset of tubulointerstitial nephritis. Elevated mCRP-Ab levels may be useful in predicting late-onset uveitis TINU syndrome. Unfortunately, patients with TINU tended to have frequent relapses and most patients had incomplete renal recovery. Long-term follow-up is needed to prevent misdiagnosis and properly manage TINU syndrome.

薬剤性急性尿細管間質性腎炎は無尿の原因となり得るか？

薬剤性急性尿細管間質性腎炎は無尿の原因となり得るか？

Giant Cell Tubulitis with Tubular Basement Membrane Immune Deposits

This paper presents two elderly patients who had normal baseline renal function and had stenotic valvular lesions secondary to rheumatic fever and underwent aortic valve replacements with mechanical valves. Both patients developed acute renal failure after cardiac valve replacement procedures. The renal biopsies revealed acute granulomatous tubulointerstitial nephritis. The unique histologic features were tubular basement membrane (TBM) immune complex deposition detected by both immunofluorescence and electron microscopy and prominent multinucleated giant cells surrounding intact TBM. The temporal relationship to the surgical procedure and the subsequent recovery of the patients' renal functions upon therapy suggested that the renal failure may have been due to an allergic drug reaction from the perioperative exposure to unknown agents, such as prophylactic antibiotics and furosemide. The literature on TBM immune complex deposition was reviewed, and the pathophysiologic mechanisms that may account for the similarities between the clinicopathologic features of these two cases were examined. These two cases expand the histopathologic spectrum of previously described cases of putative drug-induced acute tubulointerstitial nephritis.

Clarithromycin-induced granulomatous tubulointerstitial nephritis

Acute interstitial nephritis is an important cause of acute renal dysfunction, accounting for up to 15% of patients hospitalized for acute renal dysfunction. Drug-induced interstitial nephritis represents 4% of all cases studied histologically, with an estimated frequency of 8% [1]. We present a case of granulomatous interstitial nephritis in a 38-year-old woman prescribed clarithromycin for pharyngitis. A 38-year-old woman was admitted with a history of abnormal renal function. She was seen by her GP with a history of sore throat and nasal discharge for which she was started on a course of clarithromycin. Whilst on these medications, she developed fever, night sweats, headache, rash and mouth ulcers. A subsequent blood test, done because of her worsening symptoms, revealed deranged renal function, following which she was referred to the hospital. Her past medical history included reactive arthritis requiring a short period of methotrexate more than 2 years previously but this was currently quiescent. She denied any drug allergy but was on clarithromycin and homeopathic medication (transfer factor: an immuno-modulating drug). On examination she was apyrexial, tachycardic (pulse103 bpm) and had a blood pressure of 152/92. General and systemic examination was unremarkable. Investigations revealed: urine analysis pH-5.0, leucocytes<10/mm, and few squamous cells; no blood or protein was detected; haemoglobin 10.2 g/dl, white cell count 9.2 10/l (Neu-8.47, Eos-nil), platelets 513 10/l, erythrocyte Sedimentation Rate (ESR) 136; sodium 137mmol/l, potassium 4.4mmol/l, bicarbonate 20mmol/l, urea 17.3mmol/l, creatinine 654mmol/l, calcium 2.56mmol/l, phosphate 1.38mmol/l, albumin 30 g/l and C-reactive protein (CRP) 84. Autoantibody screen, Anti-glomerular basement membrane (GBM) and anti-neutrophilic Cytoplasmic Antibody (ANCA) were negative. Ultrasound of kidneys was normal. Subsequent renal biopsy showed diffuse inflammatory cell infiltrate within the interstitium, comprising of lymphocytes, plasma cells and numerous eosinophils with non-caseating epitheloid granuloma. A diagnosis of Tubulinointerstitial Nephritis (TIN) was made, all medication was stopped and the patient was started on a short course of oral steroids, following which she made a complete recovery. Drug-induced acute tubulointerstitial nephritis is an inflammatory process involving the tubules, the space between the tubules and the glomeruli. It is mediated by T-cell hypersensitivity reaction and cytotoxic T-cell injury. Renal biopsy is the gold standard for diagnosis. Stopping the suspected medication forms the main component of treatment, with most patients recovering rapidly on withdrawal of the offending drug. Corticosteriod and immunosuppresants, in cases where there is no significant improvement in the renal function, may be of value. Recovery is more rapid in those individuals who have been exposed to the drug for <2 weeks, in comparison to those who have taken the suspected medication for more than 3 weeks. Epithelioid and non-caseating giant-cell granulomas are found in some cases, especially those in which acute interstitial nephritis is secondary to drugs [2]. Granulomatous TIN has been described with drugs like fluoroquinolines and lamotrigine [3,4]. There has been one report of granulomatous reaction in a patient on a combination of dihydrocodeine, amoxicillin, erythromycin and phenylpropanalamine [5]. Other reported cases of granulomatous TIN are seen in infections (tuberculosis), Wegener’s granulomatosis and in sarcoidosis. Idiopathic granulomatous TIN in the absence of features of extra-renal sarcoid has also been described, but these patients may have associated features of hypercalcaemia and raised serum angiotensin converting enzyme [6,7], which were absent in our patient. In our case, the patient was on both clarithromycin and homeopathic medication, which was discontinued immediately after the initial diagnosis was made. Correspondence and offprint requests to: Dr V. K. Audimoolam, 72, Scotney Garden, St Peter Street, Maidstone, Kent, ME16 0GR, UK. Email: vindok@hotmail.com Nephrol Dial Transplant (2006) 21: 2654–2655

Acute interstitial nephritis associated with moxifloxacin use

Moxifloxacin is a fluoroquinolone antimicrobial agent with proven efficacy against community-acquired respiratory pathogens. Common adverse effects associated with its use include gastro-intestinal symptoms, but nephrotoxicity has not yet been reported to the manufacturer or in the literature (based on a MEDLINE search [key words: fluoroquinolone, moxifloxacin, kidney, interstitial, and nephritis; years: 1970-2005]). The purpose of this article was to describe a case of nephrotoxicity associated with moxifloxacin use. A 68-year-old woman weighing 65 kg was referred to our nephrology clinic by her general practitioner because of an acute increase in serum creatinine concentration (SCC). In this patient, biopsyproven acute tubulointerstitial nephritis (ATIN) developed approximately 10 days after the end of moxifloxacin therapy for a nonspecific bronchial infection. The patient initially presented with nonspecific clinical symptoms, foaming of her urine, elevated erythrocyte sedimentation rate, and the acute increase in SCC. Urinalysis revealed signs of tubulointerstitial damage, including leukocyturia and proteinuria with a high concentration of alpha(1)-microglobulin. Oral corticosteroid therapy with prednisolone was started approximately 14 days after symptom development, beginning at 1 mg/kg body weight QD. After the initiation of therapy, renal function was gradually restored over 6 months, but mild proteinuria persisted. Although the exact pathogenesis of drug-induced ATIN remains unclear, an immune-mediated hypersensitivity reaction is the assumed mechanism. Fluoroquinolones might have a nephrotoxic effect. In this patient, ATIN was likely associated with moxifloxacin use. Because the course of ATIN is unpredictable and might lead to long-term dialysis, considering ATIN as a possible diagnosis in the scenario of systemic symptoms after moxifloxacin treatment is essential.

Glomerular, tubular and interstitial nephritis associated with non-steroidal antiinflammatory drugs. Evidence of a common mechanism.

To study the mechanisms behind NSAID-associated nephropathy. Analysis of published case reports satisfying strict criteria for NSAID nephropathy. Ninety-seven cases with acute nephritis (AN; 19 patients), minimal change nephropathy (MC; 38 patients), membranous glomerulonephritis (MGN; 19 patients), focal sclerosis (FS; 13 patients) and other glomerulonephritis subgroups (8 patients) were identified. Hypersensitivity reactions were seen in all groups, most often in AN. Proteinuria was more severe in MC and FS than in MGN and unrelated to amount of glomerular deposits. The mean NSAID treatment time was 1.7 months in AN, 8.2 months in MC and 39 months in MGN and associated with amount of glomerular deposits, fusion of podocytes and proteinuria, and inversely associated with hypersensitivity, interstitial damage and renal failure. Rheumatic diseases were common in MGN. At follow-up 68 of 72 patients who had discontinued NSAID treatment had improved, 57 with normal renal function. NSAID nephropathy may be caused by hypersensitivity. The reaction is milder than in drug-induced acute tubulointerstitial nephritis, probably because the offending drug inhibits the inflammatory reaction it has started itself. Heavy proteinuria is probably due to lymphokines produced as a result of the immunological response. If the allergic reaction is strong, AN is produced rapidly with severe renal failure but little proteinuria; if it is less violent, immunocompetent cells may develop to produce lymphokines and proteinuria. Immune complexes may be formed eventually, secondary to the increased glomerular permeability, more easily in patients with a hyperactive immune system and with little consequence for renal function.

Drug-Induced Acute Tubulointerstitial Nephritis: The Clinical Spectrum

Clinical and laboratory findings vary with the drug involved. A definitive diagnosis requires renal biopsy; a gallium scan may be helpful when biopsy is not feasible. Outcome depends on drug withdrawal, but corticosteroids may be beneficial.