Acute tubulointerstitial nephritis in adults: A retrospective case series from a nephrology center in Tunisia and literature review

Acute tubulointerstitial nephritis in adults: A retrospective case series from a nephrology center in Tunisia and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Acute tubulointerstitial nephritis in adults: A retrospective case series from a nephrology center in Tunisia and literature review Sanda Mrabet, Nermine Ben Achour, Raja Boukadida, Nihed Abdessaied, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4535564/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Acute interstitial nephritis (AIN) is a leading cause of acute kidney injury that shows variability in incidence and etiology based on geography. In recent years, there have been significant changes in its diagnostic and therapeutic approach. The study aimed to offer an understanding of the characteristics and root causes of AIN, its diagnosis methods, treatment strategies, and results within a Tunisian population. Method We retrospectively gathered data on biopsy proven AIN from a Nephrology center over a 16-year period. The collected data consisted of demographic information, initial clinical and biochemical findings, renal biopsy results, treatment approaches, and follow-up details. Results We gathered 36 confirmed cases of biopsy proven AIN with an annual incidence rate of 2.5 cases. The average age of the patients was 50.58 years, with a male-to-female ratio of 0.71. The predominant clinical signs were fatigue (58%) and fever (22%). The mean levels of creatinine and eosinophils were 691.58 µmol/l and 481.66 10^9/L, respectively. On kidney biopsy, interstitial infiltrate was significant in 52.77% of cases, with eosinophils present in only 5.55% of cases and fibrosis noted in 27.77% of cases. Drug-related causes accounted for 46.66% of AIN cases, while infections and systemic diseases were responsible for 16.66% and 11.11% of cases, respectively. We have identified two exceptional causes of AIN, one associated with treatment with Rituximab and the other with a triple parasitic infection. AIN associated with malignancies were seen in 2.77% of cases, with some cases (25%) lacking an identifiable cause. Corticosteroid treatment was recommended for 93.33% of cases presenting with immune allergic AIN and those associated with systemic diseases. The median follow-up duration was 2.2 years. Seven patients required hemodialysis during the acute phase, and 71.42% showed recovery in renal function. The presence of interstitial fibrosis correlated with the progression to chronic kidney disease. Conclusion Acute Interstitial Nephritis (AIN) is a leading cause of acute kidney injury that can progress to chronicity. Interstitial fibrosis is associated with the progression to chronic kidney failure. The primary etiology is drug intake, and some causes are yet to be identified. Nephritis Acute kidney injury Drug Fibrosis Acute interstitial nephritis Figures Figure 1 BACKGROUND Acute interstitial nephritis (AIN), characterized by inflammatory infiltrates and edema within the interstitium, is one of the major etiologies of acute kidney injury (AKI) with diagnosis-specific treatment options [ 1 ]. AIN accounts for 2–3% of renal biopsies and up to 27% of biopsies for AKI diagnosis [ 2 – 4 ] . Delays in diagnosing AIN are common due to nonspecific symptoms, potentially leading to severe consequences [ 5 , 6 ]. Biologically, AIN manifests as AKI, often accompanied by eosinophilia, hematuria, leukocyturia, and proteinuria [ 7 ]. Histopathological confirmation is often necessary [ 8 ]. Drug-related factors are the primary cause (70% of cases), with increasing prevalence linked to antibiotics, nonsteroidal anti-inflammatory drug (NSAID), proton pump inhibitors (PPI), and other medications triggering renal hypersensitivity reactions [ 7 , 9 ]. AIN can also stem from infections, autoimmune conditions, or infiltrative diseases, rarely being idiopathic [ 10 ]. Several studies have demonstrated regional variations in the causes of AIN, possibly influenced by differences in infection rates and medication usage [ 1 ]. Additionally, an increasing number of cases among the elderly have been reported [ 11 ]. with notable changes in clinical manifestations and treatment approaches [ 12 – 14 ]. To address the lack of data on AIN in Tunisian adults, this study was conducted to provide insights into its characteristics, underlying causes, diagnostic processes, treatment approaches, and outcomes in a Tunisian population. METHODS This study was a retrospective observational and analytic review conducted at a single Nephrology center. We investigated patients aged 15 years and above diagnosed with AIN based on renal biopsies of native kidneys spanning from January 1, 2006, to December 31, 2021, covering a 16-year period. The study involved gathering epidemiological, clinical, biological, and histological data, as well as details on treatment and patient outcomes. Information was obtained from patient records and the Pathology department's database, excluding cases with incomplete records. Glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula [15], while acute kidney injury was determined based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria [16]. Recovery of renal function after an episode of AKI was assessed based on the eGFR. It could be complete, partial, or absent. Proteinuria was considered positive at a level of 200 mg/d and nephrotic syndrome (NS) was defined as proteinuria was ≥ 3.5 g/day/1.73 m2. The diagnosis of AIN relied on the presence of cellular infiltrate in histological analysis [17]. Statistical analyses were conducted using SPSS (Statistical Package for Social Sciences) software version 23. Qualitative variables were presented in frequencies and percentages. We analyzed quantitative variables by calculating their means, medians, standard deviations, and identifying extreme values. The analytical study was conducted using the Chi-square test for comparing two percentages and the Student's t-test for comparing two means. The significance level was set at 5%. For multivariate analysis, we included in the binary logistic regression the variables with a p-value < 0.2 in the univariate analysis. We retained the variables that were statistically significantly associated with a 5% error risk. RESULTS A total of 40 cases of biopsy- proven AIN were collected between 2006 and 2021, representing 2.84% of all renal biopsies performed during this period, or a total of 1407 cases. In consideration of the inclusion and exclusion criteria, 36 cases of AIN were included in this study. The mean incidence was 2.25 cases per year. In our series, the incidence exhibited a variable pattern over time. The incidence reached its maximum during the period from 2010 to 2013, with 13 cases (36.11%). The study population consisted of 21 females and 15 males, resulting in a sex ratio of 0.71. The mean age of the patients was 50.58 ± 17.76 years, with a range of 15 to 78 years. The median age was 50 years. The age group between 61 and 75 was the most prevalent. Hypertension was the most common comorbidity among the patients. Fatigue was the predominant symptom reported at the initial presentation, while fever was the most frequently observed clinical sign during examination (see table 1). Table1: Patients' clinical data Number, % Comorbidities HTN (n=11, 30.55%), diabetes mellitus (n=5, 13.88%), atopy (n=4, 11.11%), peripheral hypothyroidism (n=4, 11.11%), CKD (n=2, 5.55%), systemic sclerosis (n=1, 2.77%), mantle cell lymphoma (n=1, 2.77%), and IgA nephropathy (n=1, 2.77%) Initial clinical presentation Symptoms : fatigue (n=21, 58%), inflammatory polyarthralgia of the large joints (n=14, 38.9%), abdominal pain (n=12, 33.3%), anorexia (n=19, 52.8%), nausea and vomiting (n=13, 36.1%), dry cough (n=7, 22.2%), and xerostomia (n=6, 16.6%). Examination signs : acute lung edema (n=1, 2.77%), hypertension (n=3, 8.33%), fever (8, 22%), urticaria (7, 19%), maculopapular lesions (1, 2.77 %), bilateral anterior uveitis (2, 5.54%), unilateral anterior uveitis (n=1, 2.77%), scleritis (n=1, 2.77%), hepatomegaly and splenomegaly (n=3, 8.33%), oligoanuria (n=5, 13.88%), polyuria (n=2, 5.54%) and peripheral edema (n=5, 13.88%) CKD: chronic kidney disease, HTN: arterial hypertension, HSM Hepatosplenomegaly In the context of our series, previous renal function was known in two cases, with one patient exhibiting CKD stage 2 and the other exhibiting CKD stage 3a. At presentation, the serum creatinine level was, on average, 691.583 ± 456.043 µmol/L. Hyperkalemia was noted in three cases (8.33%), anemia in 30 (83.33%), eosinophilia in 14 (38.88%), biological inflammatory syndrome in 12 (33.33%), hepatic cytolysis in four (11.11%), leukocyturia in 21 (58.33%), and microscopic hematuria in nine (25%). Urine culture was positive in four patients and NS was defined in one patient. Refer to Table 2 for a detailed overview of the biochemical features observed at the time of initial presentation. Table 2: Biochemical features at presentation of patients with biopsy proven AIN Parameter Average Range Plasma Creatinine 691,58± 456,04 [141 ; 1949] 49-90 µmol/L Urea 22,01 ± 10,84 2.8-7.2 mmol/L Hemoglobin 10 ±1,89 12-16 g/dL Eosinophils 481,66 ± 375,83 [20 ; 2160] 0,1-0,5 × 10 9 /L Plasma protein 70,18±11,27 [33 ; 88] 66-83 g/L Plasma albumin 32,26±6,62 [10.5 ; 41.8] 35-52 g/L C-reactive protein 66,51 [1 ; 218] ≤ 5 mg/L Urinary albumin 1,02 ±1,17 [0,13 ; 5,2] <0.3g/ d Urinary leukocytes 113,13 [0 ; 1600] < 10 mm 3 Urinary red blood cells 73 [0; 1400] < 10 mm 3 Table 1 exposes the clinical para-clinical characteristics of the 15 patients. Table 1 exposes the clinical para-clinical characteristics of the 15 patients. Table 1 exposes the clinical para-clinical characteristics of the 15 patien The presence of antinuclear antibodies was evaluated in 22 patients, with positive results observed in three individuals (8.33%). Anti-SSA and anti-SSB antibodies were tested in four patients, with positive results observed in two cases (5.55%). Total immunoglobulin E (IgE) level was quantified in 10 patients, with elevated level observed in four of them. One patient underwent IgG level measurement, which returned elevated with a high IgG4. Renal ultrasound revealed that four patients (11.11%) exhibited enlarged kidneys, while the remaining patients exhibited normal renal ultrasound findings. The diagnosis of AIN was based on the results of a renal biopsy. The histological findings are detailed in Table 3. Table 3: Histological findings in biopsy proven AIN Number, % Interstitial lesions Infiltrate: -Intensity: Significant (n=19, 52.77%), moderate (n=16, 44.44%), discreet (1, 2.77%). -Cells: EOS (2, 5.55%), NEUT (n=20, 55.55%, LYMPH (N=5, 13.88%), plasma cells (n=15, 44.66%), histiocytes (n=4, 11.11%), polymorph (n=10, 27.77%) - Granulomatous (n=5, 13.88%) Oedema (n=25, 69.44%) Fibrosis: discreet (n=2, 5.55 %), moderate (n=6, 16.66%) , significant (n=2, 5.55) Tubular lesions ATN (n=4, 11.11%), tubulitis (n=4, 11.11%), tubular atrophy (n=8, 22.22%) Glomerular lesions Mesangial proliferation (n=1, 2.77%) Vascular lesions fibrous endarteritis (n=3, 8.33%) Immunofluorescence examination Immunohistochemistry examination IgA (n=1, 2.77%) IgG4 (n=1, 2.77%) EOS: eosinophils, NEUT: neutrophils, LYMPH: lymphocytes, IgA: Immunoglobulin A, IgG4: Immunoglobulin G4 The final clinical and histological diagnoses were primarily drug-induced AIN, observed in 15 patients (41.66%). Among the cases, one was identified as a non-immune-allergic drug reaction due to rituximab (anti-CD20 monoclonal antibody) in one patient. This was a sarcoidosis-like reaction, which was treated with r-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) for mantle cell lymphoma. Infection was identified in 16.66% of cases. In addition to acute bacterial pyelonephritis, AIN was para-infectious following a multiple parasitic infection. The patient was a 61-year-old individual who presented with a fever, a diffuse pruritic maculopapular rash, purpura in the lower extremities, and watery diarrhea. A stool parasitological examination revealed the presence of Giardia lamblia, Entamoeba coli, and Endolimax nana. The various causes of AIN encountered in our series are presented in Table 4. Table 4 : Etiology of biopsy-proven AIN Drugs (41.66%) Immune allergic pathway (14 ): NSAID (6), Amoxicillin-clavulanic acid (2), Amoxicillin (1), Cefixime (1), Gentamicin + NSAIDs (1), NSAIDs + Macrolide (1), Captoril (1), Acetaminophen (1) Non immune-allergic pathway (1): Rituximab (anti-CD20 monoclonal antibody) Infections (16.66%) Associated with systemic disease (11.11%) Bacterial acute pyelonephritis (5): Escherichia coli (3) , Klebsiella pneumoniae (1), and Pseudomonas aeruginosa (1). para-infectious parasitic AIN (1): Giardia lamblia + Entamoeba coli + Endolimax nana. primary Sjögren's syndrome (1), SLE (1), systemic sarcoidosis (1), IgG4-related disease (1) Paraneoplastic interstitial nephropathy (2.77%) pancreatic neuroendocrine tumor (1) TINU (2.77%) Idiopathic (25%) NSAID: nonsteroidal anti-inflammatory drug,SLE:Systemic lupus erythematosus,TINU tubulointerstitial nephritis and uveitis syndrome A review of the clinical and paraclinical presentations of patients with AIN based on the etiology revealed that fever was present in five patients with drug-induced immune-allergic AIN, one patient with an infectious cause, one patient with sarcoidosis, and one patient with idiopathic AIN. In all cases, urticaria was drug-induced immune-allergic, while the maculopapular rash was linked to a triple parasitic infection. The patient who had a NS had an NSAID-induced AIN. Enlarged kidneys were associated with infectious AIN, paraneoplastic AIN, and drug-induced immune-allergic AIN due to beta-lactam antibiotics. Patients with significant interstitial fibrosis had a known CKD. Given that immune-allergic AIN was the most incriminated cause in AIN, we compared the epidemiological, clinical, biological, and anatomopathological data of patients with immune-allergic AIN with those of the rest of the patients. This comparison revealed that cutaneous signs, microscopic hematuria, and hypereosinophilia were significantly higher in patients with immune-allergic AIN with p-values of 0.002, 0.02, and 0.04, respectively. There was no significant difference for the remaining parameters. A total of seven cases (19.44%) required hemodialysis sessions during the acute phase of the disease. For patients with drug-induced AIN, it was recommended that all patients discontinue any suspected medication. Corticosteroid therapy was indicated in 14 cases of them (93.33%), on average 10 days after the diagnosis of AIN, using oral prednisolone at a dose of 0.5 to 1 mg/kg/day for one month, followed by gradual tapering. In the case of the patient with drug-induced AIN and a sarcoid-like reaction, oral corticosteroid therapy was initiated at a dose of 1 mg/kg/day. Patients with AIN associated with systemic diseases and those of undetermined origin received oral corticosteroid therapy at a dose of 1 mg/kg/day and 0.5 mg/kg/day, respectively. The patient with IgG4-related AIN was administered 0.6 mg/kg/day of prednisone. Patients with infectious AIN were administered appropriate antibiotic therapy. Infections were observed in two patients receiving corticosteroid therapy. One patient developed herpetic uveitis, while the other developed a common bacterial pneumonia. The median follow-up duration was 2.2 years. A total of five patients were lost to follow-up, representing 16.66% of the total number of patients. One patient died at home, the cause of death being undetermined. The evolution of renal function was assessed according to eGFR in patients, after excluding known chronic renal failure patients, those lost to follow-up, and those who died. The mean creatinine level at the conclusion of the follow-up period was 176.77 µmol/l (range: 64–1000), with a median eGFR of 57.62 ml/min/1.73m2 (range: 4.1–124.6). At the conclusion of the follow-up period in our study, 20 patients (71.42% of the total) demonstrated a recovery of renal function, with eGFR of at least 90 ml/min/1.73 m2 for 13 patients (46.42%) and an eGFR between 60 and 90 ml/min/1.73 m2 for seven patients (25%). Eight patients (28.57%) did not regain normal renal function and progressed to chronic kidney disease (CKD). The distribution of these patients was as follows: Two patients exhibited CKD stage 3a, one patient exhibited CKD stage 3b, two patients exhibited CKD stage 4, and one patient exhibited CKD stage 5. Two patients required chronic hemodialysis (7.14%). Figure 3 presents a summary of the changes in renal function observed at the end of the follow-up period, stratified by the patients' previous eGFR. The predictive factors for progression CKD were determined using a univariate statistical study. We identified the interstitial fibrosis as the only predictor of progression to CKD (p=0.004). Multivariate analysis showed that interstitial fibrosis was an independent factor associated with CKD progression (OR=14.27; 95% CI=1.1-170.3; p=0.036). DISCUSSION In this study, we reviewed all patients with biopsy-proven AIN followed at a single Tunisian adult Nephrology center to identify the clinical, laboratory, etiological, and evolutionary characteristics. In studies, AIN accounts for 0.5–6% of all renal biopsies. This prevalence ranges from 5–27% in biopsies conducted for investigating AKI. Our research found an overall prevalence of 2.84%, suggesting that AIN is less frequent in our center. The incidence of AIN varies from year to year, experiencing a resurgence over the last decade [ 14 , 18 – 20 ]. Some authors attribute the increased incidence of AIN to the rising number of biopsies performed in recent years and the increasing prescription of drugs that can cause immune-allergic interstitial damage [ 14 , 21 ]. In our study, the peak incidence of AIN was observed between 2010 and 2013, subsequently decreasing over the past decade. The mean age of our patients was 50.58 years. Our results are consistent with those documented in various studies, which show an average age range of 40 to 65 years [ 11 , 13 , 22 , 23 ]. When examining the age groups, it was observed that the adult population, especially those aged 61 to 75 years, were most affected. This is consistent with similar observations in other studies [ 24 , 25 ]. This pattern may be related to the higher medication use of these patients and their increased life expectancy. In our study, 22.2% of patients experienced fever, with a notable link to drug-induced causes. Existing literature reports fever occurrence in 20–42% of cases and commonly link it to drug-induced AIN. The exact cause remains unidentified, emphasizing its nature as an epidemiological observation. A skin rash was observed in 19.4% of our patients, in 85.71% of cases, it was associated with immune-allergic AIN. This finding is consistent with other studies where the rate varies between 8% and 23% of cases [ 6 , 25 – 30 ]. Only 13.88% of patients had oligoanuria at the time of nephropathy diagnosis. In the literature, the reported proportions of oligoanuria varied from 12–30%. In the series by Clarkson et al., oliguria was more common with a prevalence of 51%. Polyuria is not common in AIN; it is rather associated with chronic tubulointerstitial nephropathies. Its prevalence in our series was 5.54%, possibly explained by a urine concentration defect due to an associated tubular impairment. Proteinuria during AIN is usually low, ranging from 0.4 g/d to 1.4 g/d [ 31 – 35 ], because interstitial nephropathy spares the glomeruli. Our results confirm this. Leukocyturia was present in 58.33% of our patients, it was aseptic in 80.95% of cases and indicative of infectious origin in 10% of patients. Our results align closely with the literature, where this rate ranges from 50% [ 36 ] to 85% [ 13 , 32 ]. Among our patients, 25% exhibited microscopic hematuria during urine analysis. The prevalence of this condition varies, ranging from 30–70% across different studies [ 27 , 33 , 37 ]. Formerly, the presence of red blood cell casts was considered a specific indicator of glomerular disease [ 38 ]. Nevertheless, up to one-third of patients with AIN may display red blood cell casts, potentially due to interstitial blood vessel damage leading to erythrocyte leakage into the tubular lumen [ 38 ]. The gold standard for establishing a definitive diagnosis of AIN is renal biopsy [ 39 – 40 ]. However, in certain cases of immune-allergic AIN, this invasive procedure can be avoided and only recommended in the presence of an atypical presentation or lack of improvement after removal of the causal agent [ 21 ]. Several studies in the literature have demonstrated the diagnostic value of renal biopsy in cases of unknown origin of acute kidney injury [ 11 , 24 ] Recently, the urinary level of CXCL9 has been validated as a biomarker for the diagnosis of AIN [ 1 ] and it has also shown that some AIN etiologies can be detected by Positron-Emission Tomography-Computed Tomography Imaging [ 41 – 43 ]. An inflammatory infiltrate in the renal interstitium is a key indicator of this kidney disease, predominantly located in the renal cortex [ 9 , 44 ]. It consists mainly of T lymphocytes, monocytes, eosinophils, and other plasma cells [ 18 , 45 ]. The distribution of the infiltrate and the dominant cell type varied in our study. Eosinophils (EOS) were found in only 5.55% of all biopsies in our study, they were associated with an immune-allergic etiology in 50% of cases. In the literature, the presence of EOS in histology ranges from 18% in Muriithi's series [ 13 ] to 94% in Clarkson's series [ 36 ], where the drug etiology was dominant. The presence of EOS in the inflammatory infiltrate in immune-allergic AIN suggests the involvement of allergic hypersensitivity mechanisms [ 46 ]. Histologic examination revealed interstitial fibrosis in 27.77% of patients. In fact, kidney damage during AIN progresses to fibrosis and this progression typically occurs within 7 to 10 days following the onset of the acute inflammatory process [ 18 ]. The development towards interstitial fibrosis and tubular atrophy can be prevented by avoiding the offending agent or promptly initiating steroid treatment [ 47 ]. Review of the histologic features of AIN in our series, led us to believe that renal biopsy remains an important tool in cases of AIN, because even if the diagnosis can be made by other means [ 1 , 41 – 43 ], evaluation of the renal parenchyma remains important for prognostic purposes, given the high number of biopsies containing interstitial fibrosis and the high number of associated tubular lesions found in our patients. Over the years, there has been a shift in etiology from the original description of AIN when infections were predominantly the main cause [ 48 , 49 ]. At present, drugs are the main culprits in the majority of cases [ 4 , 21 , 50 , 51 ]. Between 70 and 90% of all diagnosed cases of AIN are of immune-allergic origin [ 2 , 4 , 13 , 21 , 36 , 52 ]. In our series, 41.66% of all patients had immune-allergic AIN. This scenario is further complicated by the increasing use of over-the-counter drugs such as NSAID or PPI [ 53 ]. Patients often perceive these drugs to be safe with minimal side effects and may use them for chronic conditions for extended periods, thereby increasing the risk of adverse effects [ 5 , 36 , 54 – 56 ]. Several studies suggest that the use of antibiotics is the main cause of immune-allergic AIN [ 14 , 23 , 33 , 57 , 58 ]. In our series, antibiotics were the second most common cause, accounting for 28.56% of cases, and NSAID were the most common cause of immune-allergic AIN. However, other authors reported that NSAID were the second most common cause after antibiotics in the etiology of immune-allergic AIN [ 13 , 23 , 25 , 47 , 59 ]. Apart from the immune-allergic mechanism of drug-associated AIN, our series included one patient who presented with an unusual drug-associated AIN. This was a renal sarcoid-like reaction associated with rituximab after r-CHOP treatment for mantle cell lymphoma [ 60 ]. In different studies, the frequency of infectious interstitial nephritis (IIN) ranged from 3–15% [ 24 , 52 , 61 , 62 ]. In our study, IIN accounted for 13.88% of cases. It can occur as a result of direct renal invasion by microorganisms or the release of pro-inflammatory cytokines from a primary site of infection [ 14 ]. Bacterial pyelonephritis is the most common form and involves organisms such as Streptococcus, Staphylococcus, Salmonella and Brucella [ 3 , 63 ]. Parasitic IIN associated with giardiasis has been reported [ 64 ] and we observed a severe case associated with dermatitis and hemolytic anemia in a patient with a triple parasitic infection, a first reported case [ 46 ]. In our series, 13.88% of patients had AIN secondary to systemic disease. The frequency of this etiology varies between studies from 1–24% [ 13 , 26 , 33 , 52 ]. TINU, with a prevalence of 3.5 cases/million population [ 65 ], was diagnosed in only one patient in our series, whereas AIN was classified as idiopathic in 25% of cases. In the literature, idiopathic AIN represents 4% (6,21) to 20% [ 32 ]of AIN cases. Idiopathic cases in our series had no relevant known drug exposures and were classified as idiopathic after an investigative work-up. However, we believe that some of the idiopathic cases of AIN in our series are actually cases of TINU, since ocular abnormalities may appear later than renal damage [ 66 ]. Hence the importance of ophthalmological follow-up of patients with idiopathic AIN. Concerning therapeutic management, there is a general agreement that discontinuation of the suspected causative medication is the primary approach in treating drug induced AIN [ 9 , 19 ]. If kidney function does not show signs of recovery within 5–7 days after discontinuing the suspected medication, studies recommend initiating treatment with steroids [ 9 ]. Prednisolone is consistently described as the reference molecule. The initial dose varies from 0.5 mg/kg/day to 1 mg/kg/day depending on the series [ 23 , 25 , 33 , 67 – 69 ]. However, intravenous methylprednisolone therapy at a dose of 500 mg/day for 3 days followed by oral corticosteroid therapy may be proposed [ 18 , 47 ]. From another perspective, some studies suggest the use of other immunosuppressive agents such as mycophenolate mofetil, especially in the setting of corticosteroid failure [ 70 ]. In view of the rapid onset of interstitial fibrosis in AIN, as demonstrated in this series, we recommend early initiation of corticosteroid therapy in this etiology of AIN within no more than 7 days of diagnosis, since discontinuation of the drug alone would not be sufficient to repair the histological damage. Our management aligns with the literature data where corticosteroid therapy represents the primary treatment for idiopathic interstitial nephritis [ 6 , 33 , 71 ]. Few studies suggest immunosuppressants as the first alternative [ 70 ]. The standard protocol for TINU involves systemic corticosteroid therapy, typically using prednisolone at a dosage of 1 to 1.5 mg/kg/day for a 4-week period, with possible extensions based on the patient's initial response. Specialized management of ophthalmological complications is also essential for cases that are recurrent or refractory [ 34 , 72 , 73 ]. Corticosteroid therapy is the mainstay treatment for interstitial nephritis associated with systemic diseases, supported by evidence of its effectiveness in managing the condition [ 13 , 34 , 71 ]. In cases of resistance to corticosteroids, alternative immunosuppressive treatments like rituximab or mycophenolate mofetil may be considered. In our series, the median follow-up was 2.2 years, in line with the median follow-up found in the literature, which varies between two and three years in the majority of studies [ 13 , 23 , 26 , 32 , 33 , 47 , 71 ]. The course of renal function in AIN is often favorable. The time to renal recovery in AIN is often described in the literature as highly variable. Indeed, recovery can take from two weeks to three months. In our series, the evolution of renal function was generally favorable. Twenty patients, or 71.42% of cases, achieved renal recovery. Our results are similar to those reported in the literature (Table 5 ). Table 5 Renal recovery in the literature and in our series Series Total recovery of renal function Partial recovery of renal function No recovery of renal function Fernandez et al. (28) 41,2% 45,6% 13,2% Muriithi et al. (13) 47% 38% 14% Tao Su et al. (26) 45,9% 22,9% 29,2% Yun et al. (71) 41,1% 10,8% 45,1% Hadded (37) 64% 10% 26% Our serie 46,42% 25% 28,57% At the end of follow-up in our series, two of our patients were on end-stage hemodialysis. This result is comparable with those published in the literature, with a rate varying between 4% and 14% in the majority of studies [ 13 , 23 , 33 , 47 , 52 ]. In AIN, mortality is rarely related to renal damage per se [ 27 ]. Rather, it is the consequence of infectious complications and cardiovascular and neoplastic comorbidities. Indeed, the mortality rate in AIN described in the literature varies from 4% in Chabchoub's study to 17% in Clackson's and Yun's series [ 33 , 36 , 71 ]. There were no deaths in the acute phase of AIN in our study. The only death was of undetermined cause remote from the AIN episode. Strengths and limitations of the study The limitations of our study were primarily the number of cases and the retrospective nature of our research. However, in the literature, most studies on AKI were retrospective and based on data from renal biopsy registries. The main strengths were the diversity of pathological conditions associated with AIN including some exceptional causes. CONCLUSION This study has presented a case series of biopsy-proven AIN in Tunisian adults confirming that AIN is a common cause of AKI and also a significant contributor to CKD. Our findings also confirmed that the clinical presentation of AIN can be misleading with nonspecific symptoms at times. In this study, the etiology of AIN was predominantly drug-induced immune-allergic; however, a significant rate of idiopathic AIN was identified, suggesting potentially undiagnosed cases of NITU and highlighting the need for ophthalmological follow-up. The etiological spectrum of AIN remains broad, including rare and likely still unrecognized causes. The anatomoclinical correlation in AIN in this series underscores the crucial role of renal biopsy in diagnosis and prognostication of the disease. Management depends on the etiology, thus initiating treatment promptly is advisable to improve prognosis and limit progression of histological lesions towards chronicity. Abbreviations AIN : Acute interstitial nephritis AKI : Acute kidney injury CKD : Chronic kidney disease eGFR : Gomerular filtartion rate EOS : Eosinophils HTN: arterial hypertension HSM : Hepatosplenomegaly IgA: Immunoglobulin A IgG4: Immunoglobulin G4 IIN: Infectious interstitial nephritis LYMPH: lymphocytes NEUT: neutrophils NSAID: Nonsteroidal anti-inflammatory drug NS : Nephrotic syndrome PPI: Proton pump inhibitors SLE: Systemic Lupus Erythematosus, TINU : Tubulointerstitial Nephritis and Uveitis Syndrome Declarations Acknowledgements : Not applicable. Authors’ contributions : Both SM, NBA and DZ were major contributors in writing the manuscript. RB, AF, WS,AA,N BA and NT, analyzed and interpreted the patients data and contributed to the manuscript, NA and MM performed the histological examination of the kidney, and contributed to the manuscript . All authors read and approved the final manuscript. Funding : No funds to declare. Availability of data and materials : The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate : The study was approved by the ethics committee of the faculty of medicine of Sousse Reference number : CEFMS 105/2022. Consent for publication : Not applicable. Competing interests :The authors declare that they have no competing interests. References Moledina DG, Obeid W, Smith RN, Rosales I, Sise ME, Moeckel G, et al. Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis. J Clin Invest. 3 juill 2023;133(13):e168950. Donna, M, Michel, Carolyn, J, Kelly. DISEASE OF THE MONTH Acute Interstitial Nephritis. In 2005 [cité 4 janv 2023]. Disponible sur: https://www.semanticscholar.org/paper/DISEASE-OF-THE-MONTH-Acute-Interstitial-Nephritis-Donna-M./bb845202c6bdbf7440421506399f6cd4ce291348 Joyce E, Glasner P, Ranganathan S, Swiatecka-Urban A. Tubulointerstitial nephritis: diagnosis, treatment, and monitoring. Pediatr Nephrol. avr 2017;32(4):577‑87. Perazella MA, Markowitz GS. Drug-induced acute interstitial nephritis. Nat Rev Nephrol. août 2010;6(8):461‑70. Simpson IJ, Marshall MR, Pilmore H, Manley P, Williams L, Thein H, et al. Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology (Carlton). oct 2006;11(5):381‑5. Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney International. févr 2015;87(2):458‑64. Praga M, González E. 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PET/CT appearance of acute pyelonephritis. Clin Nucl Med. juill 2013;38(7):e299-301. Krishnan N, Perazella MA. The Role of PET Scanning in the Evaluation of Patients With Kidney Disease. Adv Chronic Kidney Dis. mai 2017;24(3):154‑61. Miao J, Alexander MP, Zoghby ZM. Acute Interstitial Nephritis on Positron-Emission Tomography-Computed Tomography Imaging. Kidney Medicine. nov 2022;4(11):100552. Rankin AJ, Cannon E, Gillis K, Crosby J, Mark PB, Geddes CC, et al. Predicting outcome in acute interstitial nephritis: a case–series examining the importance of histological parameters. Histopathology. avr 2020;76(5):698‑706. Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: Acute Interstitial Nephritis. American Journal of Kidney Diseases. juin 2016;67(6):e35‑6. Mrabet S, Romdhane W, Fradi A, Boukadida R, Azzabi A, Guedri Y, et al. Severe Acute Interstitial Nephritis, Dermatitis, and Hemolytic Anemia due to Polyparasitic Infection in an Immunocompetent Male Patient. Am J Mens Health. 2022;16(6):15579883221139914. González E, Gutiérrez E, Galeano C, Chevia C, de Sequera P, Bernis C, et al. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney International. avr 2008;73(8):940‑6. Councilman WT. Acute Interstitial Nephritis. J Boston Soc Med Sci. mai 1898;2(11):189‑92. Councilman WT. ACUTE INTERSTITIAL NEPHRITIS. J Exp Med. 1 juill 1898;3(4‑5):393‑420. Michel DM, Kelly CJ. Acute interstitial nephritis. J Am Soc Nephrol. mars 1998;9(3):506‑15. Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int. mai 1989;35(5):1257‑70. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. janv 2004;19(1):8‑11. Sanchez-Alamo B, Cases-Corona C, Fernandez-Juarez G. Facing the Challenge of Drug-Induced Acute Interstitial Nephritis. Nephron. 2023;147(2):78‑90. Sierra F, Suarez M, Rey M, Vela MF. Systematic review: Proton pump inhibitor-associated acute interstitial nephritis. Aliment Pharmacol Ther. 15 août 2007;26(4):545‑53. Ray S, Delaney M, Muller AF. Proton pump inhibitors and acute interstitial nephritis. BMJ. 22 sept 2010;341:c4412. Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 29 mai 2019;365:l1580. Wilson GJ, Kark AL, Francis LP, Hoy W, Healy HG, Mallett AJ. The increasing rates of acute interstitial nephritis in Australia: a single centre case series. BMC Nephrol. déc 2017;18(1):329. Hiraoka M, Hori C, Tsuchida S, Tsukahara H, Sudo M. Ultrasonographic findings of acute tubulointerstitial nephritis. Am J Nephrol. 1996;16(2):154‑8. Nast CC. Medication-Induced Interstitial Nephritis in the 21st Century. Advances in Chronic Kidney Disease. mars 2017;24(2):72‑9. Mrabet S, Dahmene R, Fradi A, Jaziri A, Boukadida R, Azzebi A, et al. Sarcoid-Like Reaction in the Kidney Following Rituximab for Mantle Lymphoma in a 60-Year-Old Man. Am J Mens Health. mars 2023;17(2):155798832311593. Kopp JB, Falloon J, Filie A, Abati A, King C, Hortin GL, et al. Indinavir‐Associated Interstitial Nephritis and Urothelial Inflammation: Clinical and Cytologic Findings. CLIN INFECT DIS. 15 avr 2002;34(8):1122‑8. Alim N, Peterson L, Zimmerman SW, Updike S. Rofecoxib-induced acute interstitial nephritis. American Journal of Kidney Diseases. mars 2003;41(3):720‑1. Ten RM, Torres VE, Milliner DS, Schwab TR, Holley KE, Gleich GJ. Acute Interstitial Nephritis: Immunologic and Clinical Aspects. Mayo Clinic Proceedings. sept 1988;63(9):921‑30. De Pascalis A, Buongiorno E. Acute Interstitial Nephritis, a Rare Complication of Giardiasis. Clinics and Practice. 30 déc 2011;2(1):e6. Sinnamon KT, Courtney AE, Harron C, O’Rourke DM, Mullan RN. Tubulointerstitial nephritis and uveitis (TINU) syndrome: epidemiology, diagnosis and management. Clinical Kidney Journal. 1 avr 2008;1(2):112‑6. Saarela V, Nuutinen M, Ala-Houhala M, Arikoski P, Rönnholm K, Jahnukainen T. Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study. Ophthalmology. juill 2013;120(7):1476‑81. Pusey CD, Saltissi D, Bloodworth L, Rainford DJ, Christie JL. Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med. 1983;52(206):194‑211. Bomback AS, Markowitz GS. Increased prevalence of acute interstitial nephritis: more disease or simply more detection? Nephrology Dialysis Transplantation. janv 2013;28(1):16‑8. Descamps V, Bouscarat F. Manifestations cutanées de la sarcoïdose. Annales de Dermatologie et de Vénéréologie. janv 2016;143(1):39‑50. Preddie DC, Markowitz GS, Radhakrishnan J, Nickolas TL, D’Agati VD, Schwimmer JA, et al. Mycophenolate Mofetil for the Treatment of Interstitial Nephritis. Clinical Journal of the American Society of Nephrology. juill 2006;1(4):718‑22. Yun D, Jang M jin, An JN, Lee JP, Kim DK, Chin HJ, et al. Effect of steroids and relevant cytokine analysis in acute tubulointerstitial nephritis. BMC Nephrol. déc 2019;20(1):88. Amaro D, Carreño E, Steeples LR, Oliveira-Ramos F, Marques-Neves C, Leal I. Tubulointerstitial nephritis and uveitis (TINU) syndrome: a review. Br J Ophthalmol. juin 2020;104(6):742‑7. Clive DM, Vanguri VK. The Syndrome of Tubulointerstitial Nephritis With Uveitis (TINU). American Journal of Kidney Diseases. juill 2018;72(1):118‑28. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4535564","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":319417268,"identity":"0c2fdc01-d5f3-4800-ab03-68173b7c9347","order_by":0,"name":"Sanda 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Sousse","correspondingAuthor":false,"prefix":"","firstName":"Moncef","middleName":"","lastName":"Mokni","suffix":""}],"badges":[],"createdAt":"2024-06-05 17:03:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4535564/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4535564/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59607634,"identity":"6309e852-086e-47dc-b0d2-915dd07b8f41","added_by":"auto","created_at":"2024-07-03 19:07:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61502,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in renal function at the end of follow-up of patients with biopsy proven AIN,as a function of previous eGFR\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAKI: acute kidney injury, AIN: acute interstitial nephritis, CKD: chronic kidney disease\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4535564/v1/cafdc31bb2af368066b95829.png"},{"id":59609202,"identity":"2c71a09e-4cf0-44f6-b3cb-b4fdba2101f1","added_by":"auto","created_at":"2024-07-03 19:23:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":715476,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4535564/v1/686f9705-f9fb-4271-b32d-24c596be4f6b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Acute tubulointerstitial nephritis in adults: A retrospective case series from a nephrology center in Tunisia and literature review","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eAcute interstitial nephritis (AIN), characterized by inflammatory infiltrates and edema within the interstitium, is one of the major etiologies of acute kidney injury (AKI) with diagnosis-specific treatment options [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. AIN accounts for 2\u0026ndash;3% of renal biopsies and up to 27% of biopsies for AKI diagnosis [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eDelays in diagnosing AIN are common due to nonspecific symptoms, potentially leading to severe consequences [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Biologically, AIN manifests as AKI, often accompanied by eosinophilia, hematuria, leukocyturia, and proteinuria [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Histopathological confirmation is often necessary [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDrug-related factors are the primary cause (70% of cases), with increasing prevalence linked to antibiotics, nonsteroidal anti-inflammatory drug (NSAID), proton pump inhibitors (PPI), and other medications triggering renal hypersensitivity reactions [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. AIN can also stem from infections, autoimmune conditions, or infiltrative diseases, rarely being idiopathic [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies have demonstrated regional variations in the causes of AIN, possibly influenced by differences in infection rates and medication usage [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Additionally, an increasing number of cases among the elderly have been reported [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. with notable changes in clinical manifestations and treatment approaches [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo address the lack of data on AIN in Tunisian adults, this study was conducted to provide insights into its characteristics, underlying causes, diagnostic processes, treatment approaches, and outcomes in a Tunisian population.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis study was a retrospective observational and analytic review conducted at a single Nephrology center. We investigated patients aged 15 years and above diagnosed with AIN based on renal biopsies of native kidneys spanning from January 1, 2006, to December 31, 2021, covering a 16-year period. The study involved gathering epidemiological, clinical, biological, and histological data, as well as details on treatment and patient outcomes. Information was obtained from patient records and the Pathology department\u0026apos;s database, excluding cases with incomplete records.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula [15], while acute kidney injury was determined based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria [16].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecovery of renal function after an episode of AKI was assessed based on the eGFR. It could be complete, partial, or absent.\u003c/p\u003e\n\u003cp\u003eProteinuria was considered positive at a level of 200 mg/d and nephrotic syndrome (NS) was defined as proteinuria was \u0026ge; 3.5 g/day/1.73 m2.\u003c/p\u003e\n\u003cp\u003eThe diagnosis of AIN relied on the presence of cellular infiltrate in histological analysis [17].\u003c/p\u003e\n\u003cp\u003eStatistical analyses were conducted using SPSS (Statistical Package for Social Sciences) software version 23. Qualitative variables were presented in frequencies and percentages. We analyzed quantitative variables by calculating their means, medians, standard deviations, and identifying extreme values.\u003c/p\u003e\n\u003cp\u003eThe analytical study was conducted using the Chi-square test for comparing two percentages and the Student\u0026apos;s t-test for comparing two means. The significance level was set at 5%.\u003cbr\u003e\u0026nbsp;For multivariate analysis, we included in the binary logistic regression the variables with a p-value \u0026lt; 0.2 in the univariate analysis. We retained the variables that were statistically significantly associated with a 5% error risk.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 40 cases of biopsy- proven AIN were collected between 2006 and 2021, representing 2.84% of all renal biopsies performed during this period, or a total of 1407 cases. In consideration of the inclusion and exclusion criteria, 36 cases of AIN were included in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean incidence was 2.25 cases per year. In our series, the incidence exhibited a variable pattern over time. The incidence reached its maximum during the period from 2010 to 2013, with 13 cases (36.11%).\u003c/p\u003e\n\u003cp\u003eThe study population consisted of 21 females and 15 males, resulting in a sex ratio of 0.71. The mean age of the patients was 50.58 \u0026plusmn; 17.76 years, with a range of 15 to 78 years. The median age was 50 years. The age group between 61 and 75 was the most prevalent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHypertension was the most common comorbidity among the patients. Fatigue was the predominant symptom reported at the initial presentation, while fever was the most frequently observed clinical sign during examination (see table 1).\u003c/p\u003e\n\u003cp\u003eTable1: Patients\u0026apos; clinical data\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eHTN (n=11, 30.55%), diabetes mellitus (n=5, 13.88%), atopy (n=4, 11.11%), peripheral hypothyroidism (n=4, 11.11%), CKD (n=2, 5.55%), systemic sclerosis (n=1, 2.77%), mantle cell lymphoma (n=1, 2.77%), and IgA nephropathy (n=1, 2.77%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInitial clinical presentation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSymptoms\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e: fatigue (n=21, 58%), inflammatory polyarthralgia of the large joints (n=14, 38.9%), abdominal pain (n=12, 33.3%), anorexia (n=19, 52.8%), nausea and vomiting (n=13, 36.1%), dry cough (n=7, 22.2%), and xerostomia (n=6, 16.6%).\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eExamination signs\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e: acute lung edema (n=1, 2.77%), hypertension (n=3, 8.33%), fever (8, 22%), urticaria (7, 19%), maculopapular lesions (1, 2.77 %), bilateral anterior uveitis (2, 5.54%), unilateral anterior uveitis (n=1, 2.77%), scleritis (n=1, 2.77%), hepatomegaly and splenomegaly (n=3, 8.33%), oligoanuria (n=5, 13.88%), polyuria (n=2, 5.54%) and peripheral edema (n=5, 13.88%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCKD: chronic kidney disease, HTN: arterial hypertension, \u0026nbsp;HSM Hepatosplenomegaly\u003c/p\u003e\n\u003cp\u003eIn the context of our series, previous renal function was known in two cases, with one patient exhibiting CKD stage 2 and the other exhibiting CKD stage 3a. At presentation, the serum creatinine level was, on average, 691.583 \u0026plusmn; 456.043 \u0026micro;mol/L. Hyperkalemia was noted in three cases (8.33%), anemia in 30 (83.33%), eosinophilia in 14 (38.88%), biological inflammatory syndrome in 12 (33.33%), hepatic cytolysis in four (11.11%), leukocyturia in 21 (58.33%), and microscopic hematuria in nine (25%). \u0026nbsp;Urine culture was positive in four patients and NS was defined in one patient. Refer to Table 2 for a detailed overview of the biochemical features observed at the time of initial presentation.\u003c/p\u003e\n\u003cp\u003eTable 2: Biochemical features at presentation of patients with biopsy proven AIN\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAverage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlasma Creatinine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e691,58\u0026plusmn; 456,04 [141 ; 1949]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e49-90 \u0026micro;mol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e22,01 \u0026plusmn; 10,84\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e2.8-7.2 mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHemoglobin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e10 \u0026plusmn;1,89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e12-16 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEosinophils\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e481,66 \u0026plusmn; 375,83 [20 ; 2160]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e0,1-0,5 \u0026times; 10 \u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlasma protein\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e70,18\u0026plusmn;11,27 [33\u0026nbsp;; 88]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e66-83 g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlasma albumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e32,26\u0026plusmn;6,62 [10.5\u0026nbsp;; 41.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e35-52 g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eC-reactive protein\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e66,51 [1\u0026nbsp;; 218]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026le; 5 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrinary albumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e1,02 \u0026plusmn;1,17 [0,13 ; 5,2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.3g/ d\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrinary leukocytes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e113,13 [0 ; 1600]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 10 mm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.387622149837135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrinary red blood cells\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.59934853420195%\" valign=\"top\"\u003e\n \u003cp\u003e73\u0026nbsp;[0; 1400]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.01302931596091%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 10 mm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 1 exposes the clinical para-clinical characteristics of the 15 patients.\u003c/p\u003e\n\u003cp\u003eTable 1 exposes the clinical para-clinical characteristics of the 15 patients.\u003c/p\u003e\n\u003cp\u003eTable 1 exposes the clinical para-clinical characteristics of the 15 patien\u003c/p\u003e\n\u003cp\u003eThe presence of antinuclear antibodies was evaluated in 22 patients, with positive results observed in three individuals (8.33%). Anti-SSA and anti-SSB antibodies were tested in four patients, with positive results observed in two cases (5.55%). Total immunoglobulin E (IgE) level was quantified in 10 patients, with elevated level observed in four of them. One patient underwent IgG level measurement, which returned elevated with a high IgG4.\u003c/p\u003e\n\u003cp\u003eRenal ultrasound revealed that four patients (11.11%) exhibited enlarged kidneys, while the remaining patients exhibited normal renal ultrasound findings.\u003c/p\u003e\n\u003cp\u003eThe diagnosis of AIN was based on the results of a renal biopsy. The histological findings are detailed in Table 3.\u003c/p\u003e\n\u003cp\u003eTable 3: Histological findings in biopsy proven AIN\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterstitial lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eInfiltrate:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; -Intensity: Significant (n=19, 52.77%), moderate (n=16, 44.44%), discreet (1, 2.77%).\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;-Cells: EOS (2, 5.55%), NEUT (n=20, 55.55%, LYMPH (N=5, 13.88%), plasma cells (n=15, 44.66%), histiocytes (n=4, 11.11%), polymorph (n=10, 27.77%)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;- Granulomatous (n=5, 13.88%)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eOedema\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;(n=25, 69.44%)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eFibrosis:\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;discreet (n=2, 5.55 %), moderate (n=6, 16.66%) , significant (n=2, 5.55)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTubular lesions\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eATN (n=4, 11.11%), tubulitis (n=4, 11.11%), tubular atrophy (n=8, 22.22%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlomerular lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eMesangial proliferation (n=1, 2.77%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVascular lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003efibrous endarteritis (n=3, 8.33%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunofluorescence examination\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eImmunohistochemistry examination\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eIgA (n=1, 2.77%)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eIgG4 (n=1, 2.77%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eEOS: eosinophils, NEUT: neutrophils, LYMPH: lymphocytes, IgA: Immunoglobulin A, IgG4: Immunoglobulin G4\u003c/p\u003e\n\u003cp\u003eThe final clinical and histological diagnoses were primarily drug-induced AIN, observed in 15 patients (41.66%). Among the cases, one was identified as a non-immune-allergic drug reaction due to rituximab (anti-CD20 monoclonal antibody) in one patient. This was a sarcoidosis-like reaction, which was treated with r-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) for mantle cell lymphoma.\u003c/p\u003e\n\u003cp\u003eInfection was identified in 16.66% of cases. In addition to acute bacterial pyelonephritis, AIN was para-infectious following a multiple parasitic infection. The patient was a 61-year-old individual who presented with a fever, a diffuse pruritic maculopapular rash, purpura in the lower extremities, and watery diarrhea. A stool parasitological examination revealed the presence of Giardia lamblia, Entamoeba coli, and Endolimax nana.\u003c/p\u003e\n\u003cp\u003eThe various causes of AIN encountered in our series are presented in Table 4.\u003c/p\u003e\n\u003cp\u003eTable 4\u0026nbsp;: Etiology of biopsy-proven AIN\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eDrugs (41.66%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eImmune allergic pathway (14\u003cem\u003e): NSAID (6), Amoxicillin-clavulanic acid (2), Amoxicillin (1), Cefixime (1), Gentamicin + NSAIDs (1), NSAIDs + Macrolide (1), Captoril (1), Acetaminophen (1)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNon immune-allergic pathway (1): \u003cem\u003eRituximab\u003c/em\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cem\u003e(anti-CD20 monoclonal antibody)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eInfections (16.66%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAssociated with systemic disease (11.11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eBacterial acute pyelonephritis (5): \u0026nbsp;Escherichia coli (3) , Klebsiella pneumoniae (1), and Pseudomonas aeruginosa (1).\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003epara-infectious parasitic AIN (1): Giardia lamblia + Entamoeba coli + Endolimax nana.\u003cbr\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eprimary Sj\u0026ouml;gren\u0026apos;s syndrome (1), SLE (1), systemic sarcoidosis (1), IgG4-related disease (1)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eParaneoplastic interstitial nephropathy (2.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003epancreatic neuroendocrine tumor (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTINU (2.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eIdiopathic (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNSAID: nonsteroidal anti-inflammatory drug,SLE:Systemic lupus erythematosus,TINU tubulointerstitial nephritis and uveitis syndrome\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA review of the clinical and paraclinical presentations of patients with AIN based on the etiology revealed that fever was present in five patients with drug-induced immune-allergic AIN, one patient with an infectious cause, one patient with sarcoidosis, and one patient with idiopathic AIN. In all cases, urticaria was drug-induced immune-allergic, while the maculopapular rash was linked to a triple parasitic infection. The patient who had a NS had an NSAID-induced AIN. Enlarged kidneys were associated with infectious AIN, paraneoplastic AIN, and drug-induced immune-allergic AIN due to beta-lactam antibiotics. Patients with significant interstitial fibrosis had a known CKD.\u003c/p\u003e\n\u003cp\u003eGiven that immune-allergic AIN was the most incriminated cause in AIN, we compared the epidemiological, clinical, biological, and anatomopathological data of patients with immune-allergic AIN with those of the rest of the patients. This comparison revealed that cutaneous signs, microscopic hematuria, and hypereosinophilia were significantly higher in patients with immune-allergic AIN with p-values of 0.002, 0.02, and 0.04, respectively. There was no significant difference for the remaining parameters.\u003c/p\u003e\n\u003cp\u003eA total of seven cases (19.44%) required hemodialysis sessions during the acute phase of the disease.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;For patients with drug-induced AIN, it was recommended that all patients discontinue any suspected medication. Corticosteroid therapy was indicated in 14 cases of them (93.33%), on average 10 days after the diagnosis of AIN, using oral prednisolone at a dose of 0.5 to 1 mg/kg/day for one month, followed by gradual tapering. In the case of the patient with drug-induced AIN and a sarcoid-like reaction, oral corticosteroid therapy was initiated at a dose of 1 mg/kg/day. Patients with AIN associated with systemic diseases and those of undetermined origin received oral corticosteroid therapy at a dose of 1 mg/kg/day and 0.5 mg/kg/day, respectively. The patient with IgG4-related AIN was administered 0.6 mg/kg/day of prednisone. Patients with infectious AIN were administered appropriate antibiotic therapy. Infections were observed in two patients receiving corticosteroid therapy. One patient developed herpetic uveitis, while the other developed a common bacterial pneumonia.\u003c/p\u003e\n\u003cp\u003eThe median follow-up duration was 2.2 years. A total of five patients were lost to follow-up, representing 16.66% of the total number of patients. One patient died at home, the cause of death being undetermined.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe evolution of renal function was assessed according to eGFR in patients, after excluding known chronic renal failure patients, those lost to follow-up, and those who died. The mean creatinine level at the conclusion of the follow-up period was 176.77 \u0026micro;mol/l (range: 64\u0026ndash;1000), with a median eGFR of 57.62 ml/min/1.73m2 (range: 4.1\u0026ndash;124.6).\u003c/p\u003e\n\u003cp\u003eAt the conclusion of the follow-up period in our study, 20 patients (71.42% of the total) demonstrated a recovery of renal function, with eGFR of at least 90 ml/min/1.73 m2 for 13 patients (46.42%) and an eGFR between 60 and 90 ml/min/1.73 m2 for seven patients (25%).\u003c/p\u003e\n\u003cp\u003eEight patients (28.57%) did not regain normal renal function and progressed to chronic kidney disease (CKD). The distribution of these patients was as follows: Two patients exhibited CKD stage 3a, one patient exhibited CKD stage 3b, two patients exhibited CKD stage 4, and one patient exhibited CKD stage 5. Two patients required chronic hemodialysis (7.14%).\u003c/p\u003e\n\u003cp\u003eFigure 3 presents a summary of the changes in renal function observed at the end of the follow-up period, stratified by the patients\u0026apos; previous eGFR.\u003c/p\u003e\n\n\u003cp\u003eThe predictive factors for progression CKD were determined using a univariate statistical study. We identified the interstitial fibrosis as the only predictor of progression to CKD (p=0.004). Multivariate analysis showed that interstitial fibrosis was an independent factor associated with CKD progression (OR=14.27; 95% CI=1.1-170.3; p=0.036).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we reviewed all patients with biopsy-proven AIN followed at a single Tunisian adult Nephrology center to identify the clinical, laboratory, etiological, and evolutionary characteristics.\u003c/p\u003e \u003cp\u003eIn studies, AIN accounts for 0.5\u0026ndash;6% of all renal biopsies. This prevalence ranges from 5\u0026ndash;27% in biopsies conducted for investigating AKI. Our research found an overall prevalence of 2.84%, suggesting that AIN is less frequent in our center.\u003c/p\u003e \u003cp\u003eThe incidence of AIN varies from year to year, experiencing a resurgence over the last decade [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Some authors attribute the increased incidence of AIN to the rising number of biopsies performed in recent years and the increasing prescription of drugs that can cause immune-allergic interstitial damage [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In our study, the peak incidence of AIN was observed between 2010 and 2013, subsequently decreasing over the past decade.\u003c/p\u003e \u003cp\u003eThe mean age of our patients was 50.58 years. Our results are consistent with those documented in various studies, which show an average age range of 40 to 65 years [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. When examining the age groups, it was observed that the adult population, especially those aged 61 to 75 years, were most affected. This is consistent with similar observations in other studies [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This pattern may be related to the higher medication use of these patients and their increased life expectancy.\u003c/p\u003e \u003cp\u003eIn our study, 22.2% of patients experienced fever, with a notable link to drug-induced causes. Existing literature reports fever occurrence in 20\u0026ndash;42% of cases and commonly link it to drug-induced AIN. The exact cause remains unidentified, emphasizing its nature as an epidemiological observation. A skin rash was observed in 19.4% of our patients, in 85.71% of cases, it was associated with immune-allergic AIN. This finding is consistent with other studies where the rate varies between 8% and 23% of cases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Only 13.88% of patients had oligoanuria at the time of nephropathy diagnosis. In the literature, the reported proportions of oligoanuria varied from 12\u0026ndash;30%. In the series by Clarkson et al., oliguria was more common with a prevalence of 51%. Polyuria is not common in AIN; it is rather associated with chronic tubulointerstitial nephropathies. Its prevalence in our series was 5.54%, possibly explained by a urine concentration defect due to an associated tubular impairment.\u003c/p\u003e \u003cp\u003eProteinuria during AIN is usually low, ranging from 0.4 g/d to 1.4 g/d [\u003cspan additionalcitationids=\"CR32 CR33 CR34\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], because interstitial nephropathy spares the glomeruli. Our results confirm this. Leukocyturia was present in 58.33% of our patients, it was aseptic in 80.95% of cases and indicative of infectious origin in 10% of patients. Our results align closely with the literature, where this rate ranges from 50% [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] to 85% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Among our patients, 25% exhibited microscopic hematuria during urine analysis. The prevalence of this condition varies, ranging from 30\u0026ndash;70% across different studies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Formerly, the presence of red blood cell casts was considered a specific indicator of glomerular disease [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Nevertheless, up to one-third of patients with AIN may display red blood cell casts, potentially due to interstitial blood vessel damage leading to erythrocyte leakage into the tubular lumen [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe gold standard for establishing a definitive diagnosis of AIN is renal biopsy [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. However, in certain cases of immune-allergic AIN, this invasive procedure can be avoided and only recommended in the presence of an atypical presentation or lack of improvement after removal of the causal agent [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Several studies in the literature have demonstrated the diagnostic value of renal biopsy in cases of unknown origin of acute kidney injury [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Recently, the urinary level of CXCL9 has been validated as a biomarker for the diagnosis of AIN [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and it has also shown that some AIN etiologies can be detected by Positron-Emission Tomography-Computed Tomography Imaging [\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAn inflammatory infiltrate in the renal interstitium is a key indicator of this kidney disease, predominantly located in the renal cortex [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. It consists mainly of T lymphocytes, monocytes, eosinophils, and other plasma cells [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The distribution of the infiltrate and the dominant cell type varied in our study. Eosinophils (EOS) were found in only 5.55% of all biopsies in our study, they were associated with an immune-allergic etiology in 50% of cases. In the literature, the presence of EOS in histology ranges from 18% in Muriithi's series [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] to 94% in Clarkson's series [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], where the drug etiology was dominant. The presence of EOS in the inflammatory infiltrate in immune-allergic AIN suggests the involvement of allergic hypersensitivity mechanisms [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHistologic examination revealed interstitial fibrosis in 27.77% of patients. In fact, kidney damage during AIN progresses to fibrosis and this progression typically occurs within 7 to 10 days following the onset of the acute inflammatory process [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The development towards interstitial fibrosis and tubular atrophy can be prevented by avoiding the offending agent or promptly initiating steroid treatment [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Review of the histologic features of AIN in our series, led us to believe that renal biopsy remains an important tool in cases of AIN, because even if the diagnosis can be made by other means [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], evaluation of the renal parenchyma remains important for prognostic purposes, given the high number of biopsies containing interstitial fibrosis and the high number of associated tubular lesions found in our patients.\u003c/p\u003e \u003cp\u003eOver the years, there has been a shift in etiology from the original description of AIN when infections were predominantly the main cause [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. At present, drugs are the main culprits in the majority of cases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Between 70 and 90% of all diagnosed cases of AIN are of immune-allergic origin [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our series, 41.66% of all patients had immune-allergic AIN. This scenario is further complicated by the increasing use of over-the-counter drugs such as NSAID or PPI [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Patients often perceive these drugs to be safe with minimal side effects and may use them for chronic conditions for extended periods, thereby increasing the risk of adverse effects [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR55\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Several studies suggest that the use of antibiotics is the main cause of immune-allergic AIN [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. In our series, antibiotics were the second most common cause, accounting for 28.56% of cases, and NSAID were the most common cause of immune-allergic AIN. However, other authors reported that NSAID were the second most common cause after antibiotics in the etiology of immune-allergic AIN [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eApart from the immune-allergic mechanism of drug-associated AIN, our series included one patient who presented with an unusual drug-associated AIN. This was a renal sarcoid-like reaction associated with rituximab after r-CHOP treatment for mantle cell lymphoma [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn different studies, the frequency of infectious interstitial nephritis (IIN) ranged from 3\u0026ndash;15% [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. In our study, IIN accounted for 13.88% of cases. It can occur as a result of direct renal invasion by microorganisms or the release of pro-inflammatory cytokines from a primary site of infection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Bacterial pyelonephritis is the most common form and involves organisms such as Streptococcus, Staphylococcus, Salmonella and Brucella [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Parasitic IIN associated with giardiasis has been reported [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e] and we observed a severe case associated with dermatitis and hemolytic anemia in a patient with a triple parasitic infection, a first reported case [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our series, 13.88% of patients had AIN secondary to systemic disease. The frequency of this etiology varies between studies from 1\u0026ndash;24% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTINU, with a prevalence of 3.5 cases/million population [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e], was diagnosed in only one patient in our series, whereas AIN was classified as idiopathic in 25% of cases. In the literature, idiopathic AIN represents 4% (6,21) to 20% [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]of AIN cases. Idiopathic cases in our series had no relevant known drug exposures and were classified as idiopathic after an investigative work-up. However, we believe that some of the idiopathic cases of AIN in our series are actually cases of TINU, since ocular abnormalities may appear later than renal damage [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Hence the importance of ophthalmological follow-up of patients with idiopathic AIN.\u003c/p\u003e \u003cp\u003eConcerning therapeutic management, there is a general agreement that discontinuation of the suspected causative medication is the primary approach in treating drug induced AIN [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIf kidney function does not show signs of recovery within 5\u0026ndash;7 days after discontinuing the suspected medication, studies recommend initiating treatment with steroids [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Prednisolone is consistently described as the reference molecule. The initial dose varies from 0.5 mg/kg/day to 1 mg/kg/day depending on the series [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR68\" citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. However, intravenous methylprednisolone therapy at a dose of 500 mg/day for 3 days followed by oral corticosteroid therapy may be proposed [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. From another perspective, some studies suggest the use of other immunosuppressive agents such as mycophenolate mofetil, especially in the setting of corticosteroid failure [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. In view of the rapid onset of interstitial fibrosis in AIN, as demonstrated in this series, we recommend early initiation of corticosteroid therapy in this etiology of AIN within no more than 7 days of diagnosis, since discontinuation of the drug alone would not be sufficient to repair the histological damage.\u003c/p\u003e \u003cp\u003eOur management aligns with the literature data where corticosteroid therapy represents the primary treatment for idiopathic interstitial nephritis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]. Few studies suggest immunosuppressants as the first alternative [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe standard protocol for TINU involves systemic corticosteroid therapy, typically using prednisolone at a dosage of 1 to 1.5 mg/kg/day for a 4-week period, with possible extensions based on the patient's initial response. Specialized management of ophthalmological complications is also essential for cases that are recurrent or refractory [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. Corticosteroid therapy is the mainstay treatment for interstitial nephritis associated with systemic diseases, supported by evidence of its effectiveness in managing the condition [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]. In cases of resistance to corticosteroids, alternative immunosuppressive treatments like rituximab or mycophenolate mofetil may be considered.\u003c/p\u003e \u003cp\u003eIn our series, the median follow-up was 2.2 years, in line with the median follow-up found in the literature, which varies between two and three years in the majority of studies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe course of renal function in AIN is often favorable. The time to renal recovery in AIN is often described in the literature as highly variable. Indeed, recovery can take from two weeks to three months. In our series, the evolution of renal function was generally favorable. Twenty patients, or 71.42% of cases, achieved renal recovery. Our results are similar to those reported in the literature (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRenal recovery in the literature and in our series\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeries\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal recovery of renal function\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePartial recovery of renal function\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo recovery of renal function\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFernandez et al. (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41,2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45,6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13,2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuriithi et al. (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTao Su et al. (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45,9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22,9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29,2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYun et al. (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41,1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10,8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45,1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHadded (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOur serie\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46,42%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28,57%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt the end of follow-up in our series, two of our patients were on end-stage hemodialysis. This result is comparable with those published in the literature, with a rate varying between 4% and 14% in the majority of studies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn AIN, mortality is rarely related to renal damage per se [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Rather, it is the consequence of infectious complications and cardiovascular and neoplastic comorbidities. Indeed, the mortality rate in AIN described in the literature varies from 4% in Chabchoub's study to 17% in Clackson's and Yun's series [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]. There were no deaths in the acute phase of AIN in our study. The only death was of undetermined cause remote from the AIN episode.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations of the study\u003c/h2\u003e \u003cp\u003eThe limitations of our study were primarily the number of cases and the retrospective nature of our research. However, in the literature, most studies on AKI were retrospective and based on data from renal biopsy registries.\u003c/p\u003e \u003cp\u003eThe main strengths were the diversity of pathological conditions associated with AIN including some exceptional causes.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis study has presented a case series of biopsy-proven AIN in Tunisian adults confirming that AIN is a common cause of AKI and also a significant contributor to CKD. Our findings also confirmed that the clinical presentation of AIN can be misleading with nonspecific symptoms at times. In this study, the etiology of AIN was predominantly drug-induced immune-allergic; however, a significant rate of idiopathic AIN was identified, suggesting potentially undiagnosed cases of NITU and highlighting the need for ophthalmological follow-up. The etiological spectrum of AIN remains broad, including rare and likely still unrecognized causes. The anatomoclinical correlation in AIN in this series underscores the crucial role of renal biopsy in diagnosis and prognostication of the disease. Management depends on the etiology, thus initiating treatment promptly is advisable to improve prognosis and limit progression of histological lesions towards chronicity.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAIN\u0026nbsp;: Acute interstitial nephritis\u003c/p\u003e\n\u003cp\u003eAKI\u0026nbsp;: Acute kidney injury\u003c/p\u003e\n\u003cp\u003eCKD\u0026nbsp;: Chronic kidney disease\u003c/p\u003e\n\u003cp\u003eeGFR\u0026nbsp;: Gomerular filtartion rate\u003c/p\u003e\n\u003cp\u003eEOS\u0026nbsp;: Eosinophils\u003c/p\u003e\n\u003cp\u003eHTN: arterial hypertension\u003c/p\u003e\n\u003cp\u003eHSM\u0026nbsp;: Hepatosplenomegaly\u003c/p\u003e\n\u003cp\u003eIgA: Immunoglobulin A\u003c/p\u003e\n\u003cp\u003eIgG4: Immunoglobulin G4\u003c/p\u003e\n\u003cp\u003eIIN: Infectious interstitial nephritis\u003c/p\u003e\n\u003cp\u003eLYMPH: lymphocytes\u003c/p\u003e\n\u003cp\u003eNEUT: neutrophils\u003c/p\u003e\n\u003cp\u003eNSAID: Nonsteroidal anti-inflammatory drug\u003c/p\u003e\n\u003cp\u003eNS\u0026nbsp;: Nephrotic syndrome\u003c/p\u003e\n\u003cp\u003ePPI:\u0026nbsp;Proton pump inhibitors\u003c/p\u003e\n\u003cp\u003eSLE: Systemic Lupus Erythematosus,\u003c/p\u003e\n\u003cp\u003eTINU : Tubulointerstitial Nephritis and Uveitis Syndrome\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e: Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e : Both SM, NBA and DZ were major contributors in writing the manuscript. RB, AF, WS,AA,N BA and NT, analyzed and interpreted the patients data and contributed to the manuscript, NA and MM performed the histological examination of the kidney, and contributed to the manuscript . All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: No funds to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e : The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e : The study was approved by the ethics committee of the faculty of medicine of Sousse Reference number : CEFMS 105/2022.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;:\u003c/strong\u003e Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e:The authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMoledina DG, Obeid W, Smith RN, Rosales I, Sise ME, Moeckel G, et al. 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Br J Ophthalmol. juin 2020;104(6):742‑7. \u003c/li\u003e\n\u003cli\u003eClive DM, Vanguri VK. The Syndrome of Tubulointerstitial Nephritis With Uveitis (TINU). American Journal of Kidney Diseases. juill 2018;72(1):118‑28. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Nephritis, Acute kidney injury, Drug, Fibrosis, Acute interstitial nephritis","lastPublishedDoi":"10.21203/rs.3.rs-4535564/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4535564/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcute interstitial nephritis (AIN) is a leading cause of acute kidney injury that shows variability in incidence and etiology based on geography. In recent years, there have been significant changes in its diagnostic and therapeutic approach.\u003c/p\u003e\n\u003cp\u003eThe study aimed to offer an understanding of the characteristics and root causes of AIN, its diagnosis methods, treatment strategies, and results within a Tunisian population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively gathered data on biopsy proven AIN from a Nephrology center over a 16-year period. The collected data consisted of demographic information, initial clinical and biochemical findings, renal biopsy results, treatment approaches, and follow-up details.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe gathered 36 confirmed cases of biopsy proven AIN with an annual incidence rate of 2.5 cases. The average age of the patients was 50.58 years, with a male-to-female ratio of 0.71. The predominant clinical signs were fatigue (58%) and fever (22%). The mean levels of creatinine and eosinophils were 691.58 µmol/l and 481.66 10^9/L, respectively. On kidney biopsy, interstitial infiltrate was significant in 52.77% of cases, with eosinophils present in only 5.55% of cases and fibrosis noted in 27.77% of cases. Drug-related causes accounted for 46.66% of AIN cases, while infections and systemic diseases were responsible for 16.66% and 11.11% of cases, respectively. We have identified two exceptional causes of AIN, one associated with treatment with Rituximab and the other with a triple parasitic infection. AIN associated with malignancies were seen in 2.77% of cases, with some cases (25%) lacking an identifiable cause. Corticosteroid treatment was recommended for 93.33% of cases presenting with immune allergic AIN and those associated with systemic diseases. The median follow-up duration was 2.2 years. Seven patients required hemodialysis during the acute phase, and 71.42% showed recovery in renal function. The presence of interstitial fibrosis correlated with the progression to chronic kidney disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcute Interstitial Nephritis (AIN) is a leading cause of acute kidney injury that can progress to chronicity. Interstitial fibrosis is associated with the progression to chronic kidney failure. The primary etiology is drug intake, and some causes are yet to be identified.\u003c/p\u003e","manuscriptTitle":"Acute tubulointerstitial nephritis in adults: A retrospective case series from a nephrology center in Tunisia and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-03 19:07:01","doi":"10.21203/rs.3.rs-4535564/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c02df28d-dbab-4e5c-8867-a810b64a9dc6","owner":[],"postedDate":"July 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-03T19:07:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-03 19:07:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4535564","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4535564","identity":"rs-4535564","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}