• NSAID-Associated AIN: Frequently presents with concurrent nephrotic syndrome due to associated minimal change disease or membranous nephropathy. This form shows poor response to corticosteroids.
• IgG4-Related AIN: Distinguished by a plasma cell-rich infiltrate, storiform fibrosis, and elevated serum IgG4 levels, often with systemic involvement such as sialadenitis, retroperitoneal fibrosis, or autoimmune pancreatitis.
  
  

Overview of Causative Categories

• AIN arises from a diverse range of aetiologies, predominantly drug reactions, systemic autoimmune disorders, and infections.
• Drug-induced cases account for over 70% of all AIN presentations in developed countries, with polypharmacy complicating identification of the exact culprit drug.
• In contrast, infection-related AIN remains prominent in developing regions, representing up to 50% of cases.
• A small number of cases are idiopathic or secondary to rarer immune mechanisms.
  
  
  

Drug-Induced AIN

• Represents the majority of AIN cases in industrialised countries.
• The reaction is typically a type IV hypersensitivity involving T-cell mediated inflammation of the renal interstitium.
• AIN is not dose-dependent; recurrence may follow even low-dose re-exposure.
  
  

• Antibiotics: Especially beta-lactams (penicillins, cephalosporins), sulfonamides, rifampicin, and fluoroquinolones.
• NSAIDs: All types, including COX-2 inhibitors; notable for a unique presentation with concurrent nephrotic syndrome.
• Proton-Pump Inhibitors: Omeprazole, lansoprazole; increasingly recognised as causes of silent AIN.
• Immune Checkpoint Inhibitors: Agents like pembrolizumab, nivolumab, atezolizumab, and ipilimumab—AIN is the predominant kidney lesion in affected patients.
• Diuretics: Including thiazides, loop agents (furosemide, bumetanide).
• H2-Receptor Antagonists: Cimetidine, and to a lesser extent, ranitidine.
• Other Agents: Allopurinol, mesalazine, warfarin, phenytoin, phenindione, sulfadiazine.
  
  

• Gastroesophageal reflux disease treated with PPIs.
• Cancer therapy with ICPis.
• Inflammatory bowel disease managed with 5-aminosalicylates.
• HIV patients exposed to nephrotoxic antivirals and antibiotics (e.g., abacavir, trimethoprim-sulfamethoxazole, foscarnet).
  
  

Systemic Autoimmune and Inflammatory Disorders

• Sarcoidosis: Frequently the most common systemic cause in biopsy series.
• Sjögren’s Syndrome: Often associated with distal renal tubular acidosis.
• IgG4-Related Disease: Notable for storiform fibrosis and IgG4-rich plasma cell infiltration.
• Systemic Lupus Erythematosus (SLE): AIN may coexist with glomerular lupus lesions or appear in isolation.
• TINU Syndrome: Tubulointerstitial nephritis with uveitis; typically affects younger patients.
• ANCA-Associated Vasculitis and Myelodysplastic Syndrome: Less frequent, but documented causes.
  
  

Infection-Associated AIN

• Bacterial: Legionella, Leptospira, Streptococcus, Corynebacterium diphtheriae, Enterococcus, E. coli, Brucella, Yersinia.
• Mycobacteria: Mycobacterium tuberculosis is classically implicated, especially in granulomatous forms.
• Viruses: CMV, EBV, BK virus, adenovirus.
• Fungi: Candida, Histoplasma, Coccidioides.
• Parasites and Spirochetes: Toxoplasma, Leishmania, Treponema.
• SARS-CoV-2: AIN has been reported during infection and post-vaccination, though causality remains uncertain.
  
  

• Some infections induce an immune-mediated interstitial response without direct renal invasion.
• Organism-specific DNA has been detected in kidney biopsies in some recent cases, suggesting a more direct pathogenic role.
  
  

Rare and Uncommon Causes

• Idiopathic Hypocomplementemic Tubulointerstitial Nephritis: Often presents with low complement levels and no identifiable systemic illness.
• Anti-Tubular Basement Membrane (TBM) Antibody Disease: Immunofluorescence shows linear Ig deposition along TBMs.
• IgM Plasma Cell-Mediated AIN: Characterised by IgM-positive plasma cell infiltrates, hypergammaglobulinaemia, and metabolic derangements.
• Antibrush Border Antibody (ABBA) Disease: Seen in elderly men; renal biopsy reveals IgG deposits along TBMs. Often associated with concurrent systemic diseases and poor prognosis despite immunosuppression.
  
  

Histopathological Features

• The hallmark finding on kidney biopsy is interstitial oedema accompanied by a dense cellular infiltrate. This infiltrate predominantly consists of T lymphocytes and monocytes, although eosinophils, plasma cells, and neutrophils may also be present.
• ‘Tubulitis’—the infiltration of inflammatory cells into the tubular basement membrane—is a classic lesion of AIN and serves as a key diagnostic feature.
• The degree and composition of the infiltrate may vary with the underlying cause.
  
  

Immunopathogenesis and Immune Cell Involvement

• AIN is primarily a cell-mediated immune injury. In most cases, particularly drug-induced AIN, the process reflects a delayed-type hypersensitivity (type IV) reaction
• Key immunological indicators include:
  • The selective susceptibility of only a minority of individuals exposed to the offending drug.
  • Association with systemic allergic features such as rash, fever, peripheral eosinophilia, and eosinophiluria.
  • Presence of eosinophils and IgE-containing cells in renal tissue.
  • Detection of elevated serum IgE in some patients.
  • Reactivation of disease upon re-exposure to the causative medication.
  • In vitro studies showing drug-specific activation of CD4+ T cells from patients with AIN, confirming the immunologic memory response.
    
    

• The severity of inflammation does not correlate with drug dosage, and reactions can occur unpredictably even after prolonged exposure.
• In NSAID-associated AIN, the pathology may demonstrate minimal change disease or, less commonly, membranous nephropathy, particularly if nephrotic-range proteinuria is present.
  
  

• Granulomas within the interstitium are a feature of specific causes and may point to sarcoidosis or infections.
• In high-resource settings, granulomatous AIN is often drug-induced, while in lower-resource regions, infectious aetiologies such as Mycobacterium tuberculosis, fungi (Histoplasma, Coccidioides), bacteria (Brucella, Chlamydia, Francisella), spirochetes (Treponema), and parasites (Leishmania, Toxoplasma) predominate.
• In biopsy series, sarcoidosis is frequently identified in granulomatous AIN, but drug-induced and mycobacterial causes can match or exceed this prevalence in some cohorts.
  
  

• Specific histological features include:
  • Storiform (whorled) interstitial fibrosis.
  • Dense infiltrates rich in IgG4-positive plasma cells.
  • Immune complex deposits along tubular basement membranes.
• IgG4-related disease may involve multiple organs and is occasionally associated with concurrent membranous nephropathy, further complicating the pathological picture.
  
  

• AIN in SLE is typically not isolated and often occurs alongside lupus glomerulonephritis.
• The interstitial inflammation may contribute significantly to kidney dysfunction even when glomerular lesions are modest.
  
  

Prevalence in Biopsy Series

• Acute interstitial nephritis is found in approximately 1–3% of all native kidney biopsies.
• When restricting analysis to biopsies performed for acute kidney injury (AKI), the prevalence rises substantially, ranging between 13–19%.
• In registry studies, AIN accounts for up to 18% of biopsies evaluating AKI and is the underlying cause of end-stage kidney disease (ESKD) in around 1% of patients.

Biopsy Underutilisation and Underestimation of Incidence:

• The actual incidence of AIN is believed to be higher than recorded due to:
  • A lack of confirmatory biopsy in elderly or frail patients where empirical treatment is pursued.
  • Mild or asymptomatic presentations leading to diagnostic oversight.
  • Perceived risks associated with renal biopsy in high-risk populations.
• As a result, many cases—particularly those induced by commonly used agents such as NSAIDs and proton pump inhibitors (PPIs)—go undiagnosed.
  
  

Epidemiologic Trends and Risk Populations

• Incidence appears to be increasing, especially among older adults. Contributing factors include:
  • Expanding elderly populations.
  • Rising polypharmacy, especially use of medications like PPIs, NSAIDs, and antibiotics.
  • Broader criteria and clinical acceptance for performing kidney biopsies in the elderly.
• Drug-induced AIN is more frequently reported in older patients, with PPIs and antibiotics often implicated.
• Women have shown higher rates of immune-mediated AIN and NSAID-related cases in some series.
  
  
  

Population-Based Data

• Large pharmacoepidemiologic studies have attempted to quantify incidence beyond biopsy settings.
• Among users of proton pump inhibitors, the estimated incidence of AIN has been reported as approximately 3.2 cases per 10,000 person-years—highlighting the substantial contribution of drug exposure to disease burden.
  
  

Atypical Presentations

• AIN caused by agents such as PPIs, 5-aminosalicylates, and NSAIDs may present without the classic features of rash or eosinophilia, making clinical detection more difficult.
• Such cases may be identified only upon biopsy or retrospective recognition after drug withdrawal.
  
  
  

Onset and Temporal Association with Drugs

• Drug-induced AIN typically develops within 10 days of exposure to the offending agent. However, latency is highly variable:
  • As short as 1 day with rifampicin.
  • Up to 18 months in NSAID-associated cases.
• Re-exposure to the same or a structurally similar medication leads to a more rapid onset, often within 3–5 days.
  
  

General Features Related to Kidney Dysfunction

• Patients may present with nonspecific symptoms such as:
  • Nausea
  • Vomiting
  • Malaise
• The decline in kidney function is usually acute or subacute, evolving over days to weeks
• A history of reduced urinary output (oliguria) may be noted in about half of cases, though many maintain normal urine volumes (non-oliguric AKI).
• Proteinuria is generally mild; however, in NSAID-related AIN, concurrent nephrotic syndrome due to minimal change disease or membranous nephropathy may occur.
  
  

Features Suggestive of Drug Hypersensitivity

• Classical signs include fever, skin rash, and eosinophilia, but this triad is now recognised as relatively uncommon:
  • Rash in 15–22% of patients
  • Fever in 27–36%
  • Eosinophilia in 23–35%
  • Complete triad in fewer than 10–11%
• Arthralgia is reported in nearly half of patients in some cohorts.
• A clear temporal relationship between the introduction of a new medication and symptom onset should heighten suspicion, especially with agents such as antibiotics, NSAIDs, proton-pump inhibitors, and immune checkpoint inhibitors.
  
  

Drug-Specific Presentations

• NSAIDs: Often present with oedema secondary to nephrotic syndrome; systemic allergic features (rash, fever) are less common.
• PPIs: Increasingly recognised cause of AIN, often presenting silently without overt hypersensitivity symptoms.
• Checkpoint Inhibitors: AKI may appear after weeks of therapy, with AIN as the predominant renal lesion. Symptoms can improve with cessation and corticosteroid therapy.
  
  

Systemic Disease-Related Symptoms

• In non-drug-induced AIN, history may reveal features of a systemic condition:
  • Sarcoidosis: Fatigue, dyspnoea, or hypercalcaemia-related symptoms.
  • Sjögren’s Syndrome: Dry mouth, dry eyes.
  • Systemic Lupus Erythematosus (SLE): Photosensitive rash, joint pain, serositis.
  • IgG4-Related Disease: Pancreatitis, dacryoadenitis, salivary gland enlargement, lymphadenopathy.
  • TINU Syndrome: Presents in younger individuals with interstitial nephritis and uveitis. Systemic symptoms may include fever, fatigue, weight loss, anorexia, myalgia, headache, polyuria, and nocturia.
    
    

Demographic and Risk Considerations

• Older adults (>65 years) are at increased risk, likely due to polypharmacy and age-related changes in drug metabolism.
• Women may be more susceptible to immune-mediated and NSAID-induced forms of AIN.
• Chronic inflammatory conditions (e.g., autoimmune diseases) further elevate risk.
   

General Physical Examination

• May be present as a low-grade pyrexia, particularly in drug-induced cases.
• However, fever is present in fewer than 30% of patients and often not diagnostically helpful in isolation.
  
  

• A macular or maculopapular rash is occasionally observed.
• This typically appears in the context of a hypersensitivity reaction, especially with antibiotics.
• Overall prevalence of rash in AIN is around 15–22%, with the full triad (fever, rash, eosinophilia) found in only about 10–11% of patients.
  
  

• Most commonly associated with NSAID-induced AIN due to concurrent nephrotic syndrome.
• Generalised oedema may indicate hypoalbuminaemia secondary to heavy proteinuria.
  
  

• Physical signs such as dry mucous membranes or reduced bladder filling may reflect oliguria.
• Nonetheless, most patients are non-oliguric, and reduced urinary volume is not always clinically evident.
  
  

Findings Suggestive of Systemic or Underlying Disease

• Seen in patients with tubulointerstitial nephritis with uveitis (TINU) syndrome.
• Anterior uveitis can be confirmed by slit-lamp examination (often conducted by ophthalmology).
• The presence of eye redness or photophobia should prompt examination for ocular inflammation.
  
  

• Sarcoidosis: May show lymphadenopathy or signs of granulomatous disease in other systems.
• Sjögren’s Syndrome: Dry mucous membranes (xerostomia, dry conjunctivae) may be evident.
• Systemic Lupus Erythematosus (SLE): Malar rash, oral ulcers, or serositis may be detectable.
• IgG4-Related Disease:
  • Examination may reveal organomegaly, sialadenitis (parotid/lacrimal gland swelling), or periorbital puffiness.
  • Associated with diverse extrarenal findings including pancreatitis, lymphadenopathy, and pulmonary nodules.
    
    

Musculoskeletal Examination

• Non-specific joint pain without obvious inflammation is a relatively frequent complaint.
• In some series, reported in up to 45% of patients.

• May be present as part of a systemic inflammatory syndrome, especially in IgG4-related or autoimmune disease-related AIN.
  
  

Additional Considerations on Examination

• While eosinophilia is typically confirmed on blood tests, physical findings such as urticaria or angioedema are rare.
  
  

• Useful in distinguishing between true oliguria and prerenal causes of AKI.
• Mild hypertension may be present in nephrotic presentations, particularly NSAID-induced disease.
  
  

Routine Blood and Urine Tests

• A hallmark of AIN is a rise in serum creatinine, which may evolve acutely or subacutely. Elevation of urea typically parallels creatinine and reflects impaired glomerular filtration.
  
  

• Eosinophilia may be present, though it is seen in fewer than one-third of cases. When observed, it lends support to a hypersensitivity-mediated aetiology.
  
  

• Sterile pyuria (white cells without bacterial growth) is common and strongly indicative of AIN in the appropriate clinical context.
• White cell casts, when present, are suggestive of tubulointerstitial inflammation.
• Mild to moderate proteinuria is typical; nephrotic-range proteinuria warrants consideration of coexisting glomerular pathology, particularly in NSAID-related cases.
• The absence of red blood cell casts and dysmorphic red cells helps to differentiate AIN from glomerulonephritis.
  
  

• Essential for ruling out urinary tract infection. A negative culture in the presence of pyuria supports non-infectious inflammation, raising suspicion for AIN.
  
  

Assessment of Causality

• Temporarily discontinuing a suspected causative drug may lead to improvement in renal function. If this occurs, a retrospective diagnosis of drug-induced AIN may be made without the need for biopsy.
  
  

Autoimmune and Vasculitis Screening

• Useful when systemic lupus erythematosus is part of the differential. Positive results indicate possible lupus nephritis.
  
  

• Should be tested in individuals with systemic features suggestive of small vessel vasculitis.
  
  

• Low complement levels may suggest immune complex–mediated disease such as lupus nephritis or post-infectious glomerulonephritis.
  
  
  

Imaging Studies

• Although not diagnostic, ultrasound can help exclude structural causes of AKI, such as obstruction. AIN may present with enlarged, echogenic kidneys due to inflammation, though these findings are non-specific.
  
  

Advanced or Confirmatory Testing

• Provides definitive diagnosis and insight into disease severity and chronicity.
• Histology typically reveals an interstitial infiltrate rich in lymphocytes, eosinophils, and plasma cells, along with evidence of tubulitis (inflammatory invasion of the tubular epithelium).
• May also identify concurrent glomerular lesions, such as minimal change disease or membranous nephropathy in NSAID-associated cases.
• Indications for biopsy include:
  • Unclear diagnosis after initial evaluation.
  • Lack of renal recovery following cessation of the suspected drug.
  • Consideration of corticosteroid therapy where histological confirmation is needed.
    
    

• A non-invasive option when biopsy is contraindicated. Uptake in the kidneys may support a diagnosis of AIN, though sensitivity and specificity are limited.
  
  

• May help differentiate AIN from other causes of AKI, but their role remains investigational and not yet standard in clinical practice.

Key Urinary Findings in Differentials

• AIN: Sterile pyuria, white blood cell casts, low-grade proteinuria. May have eosinophiluria, though this is neither sensitive nor specific.
• Acute Tubular Necrosis (ATN): Granular ("muddy brown") casts, epithelial cell casts, tubular epithelial cells in sediment.
• Acute Glomerulonephritis (GN): Red blood cell casts, dysmorphic red cells, and more pronounced proteinuria.
• Prerenal AKI or Obstruction: Often normal or bland urinary sediment.
  
  

Conditions That Mimic AIN

• Often follows ischaemia or exposure to nephrotoxins (e.g., aminoglycosides, contrast agents).
• Urinalysis reveals granular casts and sloughed epithelial cells.
• Typically does not respond to drug withdrawal.
  
  

• Haematuria with dysmorphic red cells and red cell casts is characteristic.
• May present with nephritic syndrome (hypertension, oedema, proteinuria).
• Renal biopsy reveals glomerular immune deposits or structural damage.
• Will not improve solely by discontinuing medications.
  
  

• Seen in elderly patients, often post-angiographic or vascular procedures.
• Clinical clues include livedo reticularis, digital ischaemia, eosinophilia, and possible eosinophiluria.
• May be confused with AIN, but the distribution of skin lesions and recent vascular intervention often aid in differentiation.
  
  

• Associated with systemic infection: fever, chills, flank pain, nausea, vomiting.
• Positive urine culture is diagnostic; WBC casts may also occur.
• Typically responds to antibiotics, not drug withdrawal.
  
  

• Flank pain, haematuria, or systemic vasculitis features may be present.
• Imaging (e.g., MR angiography, renal Doppler) can detect vessel occlusions or inflammation.
• Blood tests may show elevated ANCA titres in vasculitis.
  
  

Glomerular Disorders as Differentials

• Presents with nephrotic syndrome.
• Biopsy reveals segmental scarring of glomeruli.
• Not responsive to stopping medications.
  
  

• Presents with proteinuria and possible nephrotic syndrome.
• Biopsy shows thickened glomerular basement membranes and subepithelial immune deposits.
• Often associated with malignancy or hepatitis B/C infection.
  
  

• Typically presents with episodic macroscopic haematuria, often after an upper respiratory infection.
• Urine microscopy shows red blood cell casts and dysmorphic red cells.
• Confirmed by renal biopsy showing IgA deposition in the mesangium.
  
  

• Common in patients with longstanding diabetes and retinopathy.
• Presents with proteinuria and gradual decline in renal function.
• Biopsy may show mesangiolysis, nodular sclerosis (Kimmelstiel-Wilson nodules).
• High HbA1c supports the diagnosis; not responsive to drug cessation.
  
  

Emerging Diagnostic Tools

• Urinary interleukin-9, tumour necrosis factor-alpha (TNF-α), CXCL9, and retinol-binding protein-to-creatinine ratio are under investigation to distinguish AIN from other causes of AKI.
• These remain investigational with limited availability and uncertain clinical utility.
  
  

• May aid in diagnosing AIN in select cases where biopsy is contraindicated.
• More research is needed to determine its diagnostic accuracy.
   

General Approach and Initial Management

• Prompt consultation with a nephrologist is advised if renal function does not improve within one week of intervention, or if diagnostic uncertainty necessitates a kidney biopsy.

• Discontinuation of suspected causative medications is the first step.
• Prolonged exposure to the offending drug is associated with worse renal outcomes.
• If multiple potential triggers exist, safer alternatives from different drug classes should be used (e.g., replace penicillin with a fluoroquinolone, omeprazole with ranitidine).
• Some patients may require stopping entire drug classes, particularly if allergy cross-reactivity is a concern.
  
  

• Daily monitoring of renal function and electrolytes.
• Sodium, potassium, and phosphate intake may need restriction.
• Diuretics may be used to manage fluid overload, but should be replaced with agents from a different class if implicated as the trigger.
• Dialysis may be necessary for severe AKI or metabolic complications unresponsive to conservative treatment.
  
  

Corticosteroid Therapy

• Consider corticosteroids in patients who do not show improvement in renal function within 3–7 days after drug withdrawal.
• Initiation is ideally based on histological confirmation of AIN from a kidney biopsy.
  
  

• Prednisone at 1 mg/kg/day (or equivalent) is standard.
• Some clinicians use intravenous methylprednisolone (500–1000 mg/day for 3 days) before transitioning to oral therapy.
• Tapering begins after 2 weeks of full-dose therapy if improvement is observed, with a gradual dose reduction over 4–12 weeks depending on clinical response.
  
  

• Observational studies suggest early corticosteroid initiation (within 7–14 days of diagnosis) improves renal recovery.
• Not all studies have shown benefit; outcomes may be poorer in patients with delayed therapy or NSAID-induced AIN, which is typically steroid-unresponsive.
  
  
  

Management in Severe or Non-Responsive Cases

• Patients requiring dialysis within 24–72 hours should undergo biopsy (unless contraindicated) and start glucocorticoids immediately to limit renal injury.
• If biopsy is delayed, steroids may still be commenced if AIN is strongly suspected.
  
  

• If renal function does not improve after 3–4 weeks of steroid therapy:
  • Re-evaluate diagnosis (consider repeat or initial biopsy if not previously performed).
  • Assess for chronic histological changes (fibrosis, atrophy) that may limit reversibility.
• If biopsy reveals ongoing inflammation (e.g., eosinophilic infiltrates), steroid therapy may be extended up to 12 weeks or replaced with a second-line agent.
  
  

• Mycophenolate mofetil (MMF) may be used in patients unable to tolerate steroids or with steroid-dependent disease.
• Dosing: Initiate at 1 g/day in divided doses, titrating to 2 g/day if tolerated.
• Reports of success with cyclosporine and cyclophosphamide exist, but data are limited.
  
  

AIN from Autoimmune or Inflammatory Causes

• AIN may occur in the context of:
  • Sarcoidosis
  • Sjögren's syndrome
  • Systemic lupus erythematosus (SLE)
  • IgG4-related disease
  • Tubulointerstitial nephritis with uveitis (TINU) syndrome
    
    

• Corticosteroids are the mainstay of therapy.
• Longer courses (2–3 months) are typically required compared to drug-induced AIN.
• Discontinue any concurrent nephrotoxic or sensitising medications.
• Supportive measures are similar to drug-induced AIN.
• Relapse may necessitate re-initiation of steroids; chronic or dependent cases may require long-term immunosuppression.
  
  

AIN from Immune Checkpoint Inhibitors (ICPi)

• Discontinue the offending ICPi.
• Initiate corticosteroids promptly.
• Rechallenge with ICPi may be considered cautiously in selected patients, as recurrence risk is relatively low.
  
  

AIN from Infection

• Directed antimicrobial therapy for the underlying infection is the cornerstone of management.
• Immunosuppression is generally avoided unless immune-mediated features dominate the histology or clinical picture.
  
  

Recovery Outcomes

• Most data on prognosis derive from cases induced by methicillin, where recovery rates were high with either cessation of the drug or steroid therapy.
• Recovery in AIN triggered by other drugs tends to be less complete, and prognosis is more heterogeneous.
• Renal function typically begins to improve within weeks of discontinuing the causative agent; however, recovery may remain incomplete in a notable subset of patients.
• Persistent elevation in serum creatinine is observed in up to 40% of individuals.
• Dialysis may be temporarily required during the acute phase, although long-term dialysis dependence occurs in only about 10% of cases.
  
  

• Between 40% and 60% of patients develop CKD (eGFR <60 mL/min/1.73 m²) after an episode of AIN.
• Tubulointerstitial fibrosis identified on kidney biopsy is a key predictor of poor long-term recovery.
• Chronic changes such as fibrosis, tubular atrophy, and granulomatous inflammation on histology correlate with reduced likelihood of renal functional improvement.
  
  

Predictors of Poor Prognosis

• In a multicentre study of 182 patients with biopsy-confirmed AIN, >50% interstitial fibrosis on initial biopsy was associated with significantly lower rates of renal recovery (defined as <25% improvement in glomerular filtration) at six months.
• The presence of granulomas or chronic atrophic changes also signals a guarded prognosis.
  
  

• Delayed withdrawal of the offending medication.
• Delay in corticosteroid initiation when indicated.
• Prolonged duration of kidney impairment (typically beyond three weeks).
• NSAID-associated AIN, which tends to be steroid-unresponsive and carries a higher risk of progression to CKD.
  
  
  

Immune Checkpoint Inhibitor–Associated AIN

• Despite causing AKI, AIN linked to immune checkpoint inhibitors (ICPis) is associated with lower all-cause mortality at one year when compared to non-AIN immune-related AKI.
• The development of AIN in this setting may serve as a surrogate marker for a robust immune response and favourable oncological outcome.
• Most patients improve with drug discontinuation and corticosteroids, and rechallenge with ICPis may be considered cautiously.
  
  

• Fibrosis resulting from inflammation is a frequent sequela and limits renal recovery.
• Some patients become corticosteroid-dependent and require long-term immunosuppressive strategies.
• Ongoing nephrological follow-up is essential to monitor renal function, manage CKD progression, and adjust immunomodulatory therapy if needed.
  
  

Chronic Kidney Disease (CKD)

• Persistent renal impairment is common, with many patients experiencing incomplete recovery of baseline kidney function.
• In a cohort of 205 patients, 27% of those without recurrence and over 50% of those with recurrent AIN progressed to stage 4 or 5 CKD within a median follow-up of 30 months.
• Tubulointerstitial fibrosis and tubular atrophy seen on biopsy are strongly predictive of progression to CKD.
  
  

• Annual assessment of renal function is recommended in all patients with a history of AIN.
• Early intervention with renin-angiotensin system inhibitors (e.g., ACE inhibitors) may be beneficial to slow progression in those with evidence of proteinuria or declining glomerular filtration.
  
  

• Re-exposure to known or suspected causative drugs should be strictly avoided to prevent recurrence and further renal deterioration.
  
  

Hypertension

• AIN-induced fibrosis and nephron loss may activate the renin-angiotensin-aldosterone system, leading to fluid retention and vasoconstriction.
• Increased intrarenal angiotensin II activity contributes to elevated systemic vascular resistance and sodium retention.
  
  

• Hypertension may present or worsen as renal function declines, particularly in older adults or those with coexistent vascular disease.
• Even patients with previously normal blood pressure should undergo routine annual monitoring.
  
  

• First-line therapy typically includes ACE inhibitors or angiotensin receptor blockers (ARBs).
• Additional antihypertensives may be required for blood pressure control in resistant cases.
  
  

Anaemia

• Inflammatory damage to the proximal tubules can reduce erythropoietin synthesis or impair the responsiveness of the bone marrow.
• Chronic inflammation may contribute to anaemia of chronic disease through hepcidin-mediated iron restriction and blunted erythropoiesis.
  
  

• Anaemia can manifest insidiously and may be mistaken for symptoms of uremia.
• Monitoring of haemoglobin and iron indices is warranted in patients with ongoing renal impairment post-AIN.

Progression to End-Stage Renal Disease (ESRD)

• If significant fibrosis is present at the time of diagnosis, especially when >50% of the interstitium is affected, progression to ESRD becomes more likely.
• Delays in drug withdrawal or immunosuppressive initiation also correlate with worse outcomes.

• Nephrology input is essential for long-term care planning.
• Dialysis or kidney transplantation may be required in patients who advance to ESRD.
   

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