Does this patient have acute interstitial nephritis (AIN)?

What is the interstitium? the connective tissue surrounding/between the tubules (contains the peritubular capillaries, extracellular matrix and interstitial cells) (Figure 1)

Figure 1.

Acute interstial nephritis (light microscopy).

How do you define interstitial nephritis?

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  • Acute kidney injury (AKI) characterized by interstitial inflammation and edema that spares the glomeruli

  • Prevalence is 15-27% of cases of AKI, but the true prevalence is likely underestimated (most cases are not biopsied and treated empirically)

CLINICAL PEARL: accounts for ~ 15% of patients undergoing renal biopsy for UNEXPLAINED AKI

Likely immunologically mediated hypersensitivity reactionMost commonly secondary to: Drugs (75-90%) >> Infections (15%)>>Idiopathic (8%) >> Autoimmune Disorders>>Systemic Disease

  • T cell mediated reaction secondary to extrarenal antigens

  • NOT usually dose dependent

  • Usually recurs after re-exposure

  • Delayed-type hypersensitivity reaction may be responsible for renal granulomas

What are the most common causes of AIN?

Most commonly secondary to: Drugs (75-90%) >> Infections (15%) >> Idiopathic (8%) >> Autoimmune


  • Proton Pump Inhibitors: as represented by Omeprazole, though likely a class effect

    Timing from initiation to clinical presentation = 1 week to 9 months, and when rechallenged, occurs more rapidly

    May be the most common cause of drug induced AIN

  • Antibiotics: Penicillins [Methicillin = classic cause], but Cephalosporins, Sulfonamides [Trimethoprim-Sulfamethoxasole], Rifampin and Quinolones [Ciprofloxacin]

    Rifampin may be associated with: hemolysis, thrombocytopenia and malaise

    Renal biopsy may show associated features of acute tubular necrosis (ATN) in addition to AIN

  • Nonsteroidal antiinflammatory drugs (NSAIDs) and Salicylates: Aspirin, Fenoprofen, Ibuprofen, Napoxen and Piroxicam

  • Anticonvulsants: Phenytoin

  • Diuretics: Furosemide

  • Other: Allopurinol, Cimetidine, HAART

    Allopurinol may be associated with: rash and liver dysfunction

Mean latent period between initiation of drug and appearance of renal manifestations = 10 days (Latent period of months may be typical of NSAIDs)


  • Legionella, Leptospira, CMV, Pyelonephritis, Hantaan Virus and BK Virus

  • HIV

  • Salmonella species, Mycobacterium TB, EBV and Toxoplasmosis

  • May cause granulomatous interstitial nephritis

Idiopathic: Tubulointerstitial Nephritis with Uveitis (TINU), 1st described by Dobrin et al, American Journal of Medicine, 1975

  • Epidemiology

  • Female predominance = 3:1

  • Median age = 15 years (range 9-74)

  • Caucasian >> African American

  • Clinical Presentation

  • Uveitis, typically painful, bilateral and anterior, often sudden onset (may have visual impairment)

  • Bone marrow granulomas (see in the initial description of TINU)

  • Systemic symptoms: fever, weight loss, malaise, fatigue, abdominal/flank pain, arthralgias/myalgias and headache

  • Often underdiagnosed

  • 20% cases, ocular symptoms precede AIN

  • 15% cases, ocular symptoms are concurrent with AIN

  • 65% cases, ocular symptoms follow AIN

CLINICAL PEARL: hypertension and rash are unusual

  • Lab Findings

  • AKI

  • Sterile Pyuria

  • Normoglycemic glucosuria

  • Anemia with increased ESR

  • Low grade proteinuria (< 1 gm/24 hrs): Urinary β2 – microglobinuria levels may correlate with tubulointerstitial disease

  • IgG levels are increased

  • Microscopic hematuria

  • Unusual to see urinary eosinophils

  • Renal Ultrasound: nonspecific, increased echogenicity ± increased renal length

  • Pathogenesis

  • Poorly understood, but may be defects in both cell mediated and humoral immunity (possible genetic trigger)

  • Hypergammaglobulinemia

  • Possible Infectious trigger

  • Possible Medications: may be association with NSAID or Antibiotic exposure

CLINICAL PEARL: TINU may be difficult to distinguish from other systemic diseases, i.e. Sarcoidosis, Sjögren’s Syndrome, systemic lupus erythematosis (SLE) , Tuberculosis or Behçet’s Disease, but in these disorders, interstitial nephritis is less common as a renal manifestation and typically presents as proliferative glomerulonephritis, secondary amyloidosis or vasculitis.

  • Renal Biopsy

  • Interstitial inflammation with lymphocyte predominance

  • Interstitial eosinophils ± neutrophils may be seen (30%)

  • Non-caseating granulomas

  • Immunofluoresecence is typically negative

  • Prognosis

  • Ocular complications = good in ~ 75% of patients

  • No long term studies to characterize follow-up of nephritis

  • Treatment

  • May resolve spontaneously or after discontinuation of inciting medications

  • Systemic corticosteroids (Prednisone 1-2mg/kg/day), have been used, median duration = 2.5 months

  • AIN typically responds without relapse

  • Steroid sparing strategies have been used in isolated cases: Mycophenolate Mofetil or Cyclosporine A

  • Uveitis (unresponsive to topical corticosteroids) tends to recur In ~ 40% of patients within 6 month


  • Sjögren’s Syndrome

  • Sarcoidosis

  • SLE

  • Hypocomplementemic tubulointerstitial nephritis

  • IgG4 nephritis associated with: autoimmune pancreatitis or Miculicz Syndrome

Symptoms and clinical findings

Nonspecific extra-renal symptoms: nausea, vomiting, generalized arthralgias and malaise

  • Mild-moderate flank or lumbar pain (secondary to distention of the renal capsule)

  • Loin pain (~20%)

  • Blood pressure is typically normal

  • No edema on exam

Acute kidney injury (acute renal dysfunction) with oliguria (~50%)

TRIAD: fever (27%), maculo-papular rash (15-20%) and eosinophilia (23%)

  • CLINICAL PEARL: Triad is (+) in only < 10-15% (more classically seen with exposure to Methicillin)

  • Most important = temporal relationship of drug/infection to onset of symptoms and signs

Eythrocyte sedimentation rate (ESR) is INCREASED (100%)

Fractional Excretion of Sodium (FENa) = > 1%

Urine Sediment: hematuria, pyuria, proteinuria and eosinophiluria, though may be bland

Hematuria: present in 90% of cases

  • Macroscopic (Gross) hematuria is
    classically seen with Methicillin (70% cases)

  • Microscopic hematuria is seen in ~90% cases of Methicillin related and ~60% Non-Methicillin (other drug related) cases of AIN

CLINICAL PEARL: Presence of RBC casts should suggest an alternative diagnosis

Pyuria (Leukocyturia)

  • Pyuria should be checked PRIOR to testing for eosinophils

  • May be associated with WBC casts

CLINICAL PEARL: Pyuria is COMMON (~80% Methicillin related cases of AIN and > 50% in drugs OTHER than Methicillin)

  • Absence of pyuria does NOT rule out interstitial nephritis

Proteinuria: usually < 1 gram/day

CLINICAL PEARL: Nephrotic range proteinuria is seen in up to 75% of cases of NSAID or COX II inhibitor associated AIN

  • Usually pts > 50 years old

  • Most episodes occur after months of therapy (days to years)

  • Eosinophiluria (<= 40%), Pyuria (~40%) and Microscopic hematuria (<40%)

  • Extra-renal symptoms are UNCOMMON

  • May have associated glomerular pathologic findings of Minimal Change Disease or Membranous Glomerulonephritis (GN)

  • Few cases associated with: Ampicillin, Rifampin, Lithium, Pamidronate and Phenytoin

Eosinophiluria: defined by > = 1% of WBCs in the urine = eosinophils

  • Poor Sensitivity (67%) and Low Positive Predictive Value (PPV, 50%) though Specificity is good (87%), even when only patients with AKI are considered

  • Eosinophiluria is MORE COMMON with Methicillin induced AIN

CLINICAL PEARL: the absence of eosinophiluria should NOT exclude the diagnosis

  • Hansel stain is more sensitive than Wright’s stain

  • Eosinophils are also: ATN, post-infectious glome, Atheroembolic Disease, UTI, Prostatitis, Rapidly Progressive glomerulonephritis and pre-renal azotemia

What tests to perform?

Lab Testing

1. Complete Blood Count with Differential (look for peripheral eosinophilia)

2. Renal or Comprehensive Metabolis Panel (Liver Function Tests if suspect Rifampin or Allopurinol induced AIN)

3. Urinalysis with Microscopy

  • Careful review for: red blood cells (RBCs), white blood cells (WBCs) and WBC casts

4. Urine for eosinophils

5. Spot Urine for Protein and Creatinine

6. Fractional Excretion of Sodium (FENa) may be useful if oliguria

7. CLOSE monitoring of DAILY AM weights and STRICT Intake and Output records each 24hrs

Imaging Studies

1. Renal Ultrasound: kidney size is normal to enlarged, but may be associated with increased echogenicity

2. Gallium 67 Scanning is NOT specific for AIN

Renal Biopsy
  • The only definitive way to make the diagnosis

  • Consider biopsy if:

1. Uncertainty about the diagnosis

2. Progressive renal failure despite cessation of drug or resolution of infectious process

3. Consideration of steroid usage (but NOT absolutely required for steroid usage)

  • Light Microscopy

1. Patchy inflammatory infiltrations (CD4+ T cells) within the interstitium ± tubulitis

  • May include: eosinophils, plasma cells and macrophages

  • Neutrophil predominant may suggest Infectious AIN

  • Lymphocytes predominant infiltrate in NSAID induced AIN

2. Predominant findings in deep cortex and outer medulla

3. Glomeruli and vessels are typically normal

4. Granulomas (non-necrotic) may be observed in association with: Drugs, Sarcoidosis, TB, EBV, Salmonella and Toxoplasmosis

5. Features of interstitial fibrosis may be seen within 7-10 days and may be accompanied by tubular atrophy and portend a POOR prognosis with the development of variable degrees of CKD

  • Immunofluorescence

1. Often negative

2. Graanular or Linear deposits of IgG/Complement along the tubular basement membrane (TBM)

3. Homogenous Linear deposits of IgG along the TBM may be seen in:

  • Anti-TBM disease

  • Drug associated AIN: NSAIDs, Phenytoin or Allopurinol

  • Electron Microscopy

1. Nonspecific unless accompanied by nephrotic proteinuria/nephrotic syndrome

2. May see Diffuse effacement of foot processes (in those with associated Minimal Change Disease ± FSGS)

Interpretation of Test Results

Consideration of AIN if:

  • Temporal relation of drug, infection or systemic process and progressive rise in serum creatinine ± possibly oliguria associated with:

  • Extra-renal systemic symptoms: Flank or Loin pain, Fever, Maculo-papular rash and Eosinophilia

  • Abnormal Urinary Sediment: Pyuria ± WBC casts, Microscopic or Gross hematuria, Proteinuria or Eosinophiluria

  • Disease manifestations develop within 3 weeks of initiation of inciting drug, though average latency period is 10 days

  • Duration of onset may be longer with NSAIDs (mean latent period = 2-3 months)

How should patients with AIN be managed?

Treatment Strategy
  • PROMPT withdrawal of offending drug

  • Identify potential infectious or systemic process

  • Consider renal biopsy early if: serum creatinine is NOT improving or consideration of steroid usage

  • Use of corticosteroids

  • All studies are
    retrospective and the use of steroids for the treatment of AIN remains

  • Conventional Dosing Strategy: though there are NO prospective trials, TYPICAL dosing = Prednisone orally (0.5-1.0 mg/kg/day, 30-60mg/day) tapering over 4-8 weeks

  • Alternative Dosing Strategy: Gonzalez et al, Kidney International, 2008 (PUBMED:18185501): studied 61 patients with drug induced AIN (antibiotics [56%], NSAIDs [37%] and other [7%])

  • 52 patients were treated with steroids (Methylprednisolone IV 125-500mg DAILY for 3-4 consecutive days, followed by Prednisone orally, 1 mg/kg/day tapering off over 8-12 weeks)

  • Steroids lead to: significant lowering of final serum creatinine in treated versus non-treated patients

  • > 50% patients showed complete recovery of baseline renal function

  • 2/52 (8.3%) patients treated with steroids required chronic dialysis versus 4/9 (44%) in the non-treated group

  • Steroids should be started within 7 days of drug withdrawal (significant correlation between the delay in steroid treatment and the final serum creatinine)

  • ** There was NO correlation between the offending drug and histologic findings on renal biopsy

CLINICAL PEARL: steroids should be considered in AIN if:

  • Classic presentation of AIN or

  • Biopsy proven AIN and NO improvement in serum creatinine within 7 days (despite removal of unsuspected offending drug)

  • Steroids are the mainstay of treatment for AIN associated with: SLE, Mixed Connective Tissue Disease (MCTD), Sjögren’s Syndrome, Sarcoidosis and TINU

  • AVOID steroids if: brittle Diabetes Mellitus, active infection, non-healing wounds or processes which would be exaccerbated by steroid usage

5. Alternative Agents: Mycophenolate Mofetil (MMF)

  • Preddie et al study: 8 cases of steroid-dependent (or intolerant), biopsy proven AIN (> 6 months of steroid therapy)

  • Mean decline in serum creatinine from 2.3mg/dL (range 1.5-3.2 mg/dL) to 1.6 mg/dL over a mean of 24.3 months

  • Maximum urine protein < 1.5 gm/day

  • Not all patients had drug induced AIN

  • Doses: 500mg twice daily –> 1000mg twice daily

  • 5/8 patients were able to discontinue MMF (mean of 6.4 months) and ALL discontinued steroid therapy

What happens to patients with AIN?

Natural History and Prognosis
  • 23-58% of patients require acute renal replacement therapy (RRT), but up to 44% (3-44%) require chronic RRT

  • This number may be REDUCED with steroid therapy

  • Steroids, if used within 7 days, may reduce progression of renal dysfunction, the necessity for RRT and the development of CKD

CLINICAL PEARL: In patients who do NOT develop ESRD, ~ 40% may be left with MODEST residual CKD

  • Due to progressive interstitial fibrosis (advanced tubulointerstitial injury, silent inflammation and progressive scarring)

  • Interstitial fibrosis on renal biopsy portends a POOR prognosis

  • Progressive increase in serum creatinine may be associated with an increase in cardiovascular morbidity and mortality

CLINICAL PEARL: clinical course may be stuttering, initial improvement in renal function may be followed by a progressive rise in serum creatinine over days

How to utilize team care?

Specialty Consultations

Nephrology consultation if:

  • Serum creatinine is rising (especially if associated with oligo-anuria)

  • Renal biopsy is required

  • Assure proper dispensing of medications and verification of medication allergies

  • Assist with identification of skin rashes and skin protection to prevent potential denudation and development of associated cellulitis

  • May assist in the identification of medications frequently associated with AIN

  • If AKI is present, assist with proper medication dosing based on eGFR

  • Assist in obtaining a medic alert bracelet to document prior drug reactions and document drug-induced reactions in EHR (electronic health record)

  • Assist with dietary manipulation to reduce: sodium ± potassium (if progressive renal dysfunction)

Are there clinical practice guidelines to inform decision making?

There are NO guidelines to guide clinical practice

The use of Steroids and Mycophenolate Mofetil is based on retrospective studies and remains controversial

Other considerations


Important to document:

  • What is the presumed cause of AIN: drug, infection, idiopathic or systemic process?

  • Acute or chronic process?

  • Associated conditions: hypertension, volume overload, hyperkalemia or metabolic acidosis?

Typical Lengths of Stay
  • Depends upon progression of renal function and necessity for RRT

  • Use of steroids/MMF do NOT require inpatient monitoring but close outpatient monitoring in cooperation with Nephrology

What is the evidence?

Clarkson, MR, Giblin, L, O’Connell, FP, O’Kelly, P, Walshe, JJ, Conlon, P, O’Meara, Y, Dormon, A, Campbell, E, Donohoe, J. “Acute InterstitialNephritis: clinical features and response to corticosteroid therapy”. Nephrol Dial Transplant. vol. 19. 2004. pp. 2778-2783. (One of the first retrospective studies to document the clinical, laboratory and histological features of AIN and compare patients treated with Corticosteroids versus those managed conservatively. 42 patients (26 managed conservatively and 16 treated with corticosteroids) were followed for 1 year and there was NO discernible difference in outcome.Strengths of the study: ALL patients had biopsy proven AIN and they were similarly matched groups both clinically and histologically (interestingly, the steroid treated group had a LOWER serum creatine versus the conservatively managed, 6.2mg/dL versus 7.9 mg/dL)Limitations of this study: small number of patients, majority (44%) were related to NSAIDs and only 60% received corticosteroids.)

Gonzalez, E, Gutiérrez, E, Galeano, C, Chevia, C, de Sequera, P, Bernis, C, Parra, EG, Delgado, R, Sanz, M, Ortiz, M, Goicoechea, M, Quereda, C, Olea, T, Bouarich, H, Hernández, Y, Segovia, B, Praga, M. “Early steroid treatment improves the recovery of renal function in patients with drug-Induced acute Interstitial nephritis”. Kidney Int. vol. 73. 2008. pp. 940-946. (Details of this studies are documented in the management section.)

Perazella, MA, Markowitz, GS. “Drug-Induced Acute Interstitial Nephritis”. Nature Reviews Nephrology. vol. 6. 2010. pp. 461-470. (A detailed review article that summarizes the presentation and management of AIN. It includes a table of frequent drug associated causes of AIN and reviews the sensitivity and specificity of eosinophiluria in the diagnosis of AIN.)

Preddie, DC, Markowitz, GS, Radhakrishnan, J, Nickolas, TL, D’Agati, VD, Schwimmer, JA, Gardenswartz, M, Rosen, R, Appel, GB. “Mycophenolate mofetil for thetreatment of interstitial nephritis”. J Am Soc Nephrol. vol. 1. 2006. pp. 718-722. (Details of this studies are documented in the management section.)

Rossert, J. “Drug-Induced acute Interstitial Nphritis”. Kidney Int. vol. 60. 2001. pp. 804-817. (Classic paper in a case description format with a frequently cited figure comparing: classic Methicillin-induced AIN versus AIN induced by drugs other than Methicillin versus NSAID-induced AIN.)

Herlitz, LC, Chun, MJ, Stokes, MB, Markowitz, GS. “Uveitis and Acute Renal Failure”. Kidney International. vol. 72. 2000. pp. 1554-1557. (Case presentation with a detailed review of TINU Syndrome including the original description by Dobrin and aspects of management.)

Mackensen, F, Billing, H. “Tubulointerstitial nephritis and uveitis syndrome”. Curr Op Opthalmol. vol. 20. 2009. pp. 525-531. (An article that reviews the topic of TINU from both a nephrologist's and opthalmologist's viewpoint and higlights the usage of Beta-2 microglobulin in the urine.)