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Incidence
- AIN and CIN accounts for 10-15% of kidney disease.
- Peak incidence in women 60 to 70 years of age
Geriatric Considerations
The elderly (≥65 years) have more severe disease and increased risk of permanent damage due to their increased use of OFA, specifically more drug-induced AIN (87% vs. 64%), proton-pump inhibitor-induced AIN (18% vs. 6%), but less AIN due to autoimmune or systemic causes (7% vs. 27%) than younger adults (1)[B].
ETIOLOGY AND PATHOPHYSIOLOGY
- AIN
- Delayed drug hypersensitivity reactions
- Causes AKI
- Renal dysfunction generally is usually partially or completely reversible, possibly reflecting the regenerative capacity of tubules with a preserved basement membrane.
- Hypersensitivity to drugs (75%): not dose dependent. The three top drug causes were omeprazole (12%), amoxicillin (8%), and ciprofloxacin (8%) in a recent case series (2)[C].
- Antibiotics (e.g., penicillins, cephalosporins, sulfonamides, tetracycline, vancomycin, fluoroquinolones, macrolides, TB meds)
- Proton pump inhibitors
- Antivirals (Indinavir)
- NSAIDs (all, including Cox-2 inhibitors)
- Diuretics (thiazide, loop, and triamterene)
- Miscellaneous (allopurinol, H2 blockers, diphenylhydantoin, and 5-aminosaliclates such as Azulfidine and mesalamine)
- Infections: Legionella, Leptospira, streptococci, CMV, Mycobacterium tuberculosis (5-10%)
- Autoimmune disorders (e.g., SLE, Sj ¶gren syndrome, sarcoidosis, Wegener granulomatosis, cryoglobulinemia) (10-15%)
- Toxins (e.g., snake bite venom)
- CIN
- Follows long-term exposure to OFA (e.g., heavy metals, especially lead)
- Often found on routine labs or evaluation for hypertension (HTN)
- Characterized by interstitial scarring, fibrosis, and tubular atrophy, resulting in progressive chronic kidney disease (CKD)
GENERAL PREVENTION
- Early recognition and prompt discontinuation of OFA
- Avoid further nephrotoxic substances.
COMMONLY ASSOCIATED CONDITIONS
CIN
- Chronic pyelonephritis
- Abuse of analgesics
- Lithium use
- Gout and gout therapy
- Immune disorders
- Malignancy (lymphoma, multiple myeloma)
- Amyloidosis
- Exposure to heavy metals (e.g., lead, cadmium)
- Renal papillary necrosis
DIAGNOSIS
- AIN: suspected in a patient who presents with nonspecific signs and symptoms of AKI (e.g., malaise, fever, nausea, vomiting) with an elevated serum creatinine and an abnormal urinalysis
- AKI
- Elevated creatinine, BUN, and electrolyte abnormalities (e.g., hyperkalemia, low serum bicarbonate)
- Decreased urine output (oliguria in 51%)
- Signs of fluid overload or depletion
- Signs of systemic allergy (e.g., fever [27%], maculopapular rash [15%], peripheral eosinophilia [23%], arthralgias [45%], but less commonly found when NSAIDs are the OFA)
- White cells, red cells, and white cell casts
- CIN
- HTN
- Decreased urine output or polyuria
- Inability to concentrate urine
- Polydipsia
- Metabolic acidosis
- Anemia
- Fanconi syndrome
HISTORY
- Medications: Onset of AIN following drug exposure ranges from 3 to 5 days (as occurs with a second exposure to an OFA) to as long as several weeks to many months (the latter with NSAIDs, especially) (2)[B].
- Infections: may have symptoms related to an associated infection or systemic condition
- TINU patients present with interstitial nephritis and uveitis and occasionally systemic findings.
- Exposure to heavy metals
- Post organ transplant
PHYSICAL EXAM
- Increased BP
- Fluid retention/extremity swelling/weight gain
- Rash accompanying renal findings in acute AIN
- Lung crackles if fluid is overloaded
- Pericardial rub if uremic pericarditis
DIFFERENTIAL DIAGNOSIS
- AKI secondary to other causes:
- Prerenal (e.g., hypovolemia, shock, sepsis, renal artery emboli)
- Intrarenal (e.g., acute tubular necrosis, hypertensive nephropathy, DM nephropathy)
- Postrenal (e.g., obstructive uropathy)
- Some OFA that cause AIN can produce other forms of AKI as well:
- NSAIDs can exacerbate prerenal disease.
- Aminoglycosides can cause acute tubular necrosis.
- CKD secondary to long-standing HTN, diabetes, and chronic pyelonephritis
DIAGNOSTIC TESTS & INTERPRETATION
- Chemistry
- Elevated plasma creatinine: seen in all patients, with 40% requiring dialysis
- Hyperkalemia and acidosis
- CBC
- Eosinophilia (80%): NSAID-induced AIN is only associated with eosinophilia in ~15% of cases.
- Anemia
- Urinalysis with urine electrolytes
- Hematuria (95%)
- Mild and variable proteinuria: usually <1 g/24 hr, except in AIN-associated with NSAIDs where it is significantly higher (3)[B]
- Urine sediment: white cells, red cells, white cell casts. Red blood cell casts are rare.
- Eosinophiluria but has no clinical utility specific for AIN (4)[C]
- Fractional excretion of sodium (FENa >1%) indicative of tubular damage
- Normal urinalysis does not rule out AIN.
- CXR to evaluate for pulmonary tuberculosis, sarcoidosis, and other infections
- Serologic testing for immunologic disease (e.g., sarcoidosis, Sj ¶gren syndrome, Wegener granulomatosis, Beh §et syndrome) or infectious causes (e.g., histoplasmosis, coccidiomycosis, toxoplasmosis, EBV)
- Serum levels of angiotensin-converting enzyme and serum Ca++ for sarcoidosis
- Antinuclear antibody (ANA) and dsDNA to exclude SLE
- Urinary antigen to exclude Legionella infection
- Anti-Ro/SSA, anti-La/SSB antibodies, CRP, and rheumatoid factor to exclude Sj ¶gren syndrome
- Liver function tests: elevated serum transaminase levels in patients with associated drug-induced liver injury
- Renal US may demonstrate kidneys that are normal to enlarged in size with increased cortical echogenicity, but no US findings will reliably confirm or exclude AIN versus other causes of AKI.
- IV pyelography (IVP) and CT scans with contrast are relatively contraindicated because of the associated nephrotoxicity and limited diagnostic yield.
Follow-Up Tests & Special Considerations
Patients who do not recover renal function and those with CIN should receive long-term follow-up care to protect kidneys from further potentially nephrotoxic therapies.
Diagnostic Procedures/Other
- Renal biopsy is the definitive method of establishing the diagnosis of AIN. Ideally, it should be performed to:
- Patients treated with an OFA known to cause AIN but have normal urinalysis
- Patients who are being considered for steroid therapy
- Patients who are not on glucocorticosteroid therapy initially and do not have spontaneous recovery following cessation of the OFA
- Patients with advanced renal failure of recent onset (<3 months)
- Patients with any features (e.g., high-grade proteinuria) that makes the diagnosis of AIN uncertain
- Contraindications: Renal biopsy is contraindicated in bleeding diathesis, solitary kidney, end-stage renal disease (ESRD) with small kidneys, uncontrolled HTN and sepsis, or renal parenchymal infection.
Test Interpretation
- Acute
- Marked interstitial infiltrate consisting of T lymphocytes and monocytes. Eosinophils, plasma cells, and neutrophils also may be found.
- In general, the urinary findings will distinguish AIN from other causes (e.g., acute tubular necrosis, glomerulonephritis)
- Chronic: CIN is characterized by tubular atrophy, fibrosis, and cellular infiltration with mononuclear cells.
TREATMENT
For AIN, data on corticosteroids' efficacy have been limited (5)[B].
GENERAL MEASURES
- Discontinue offending agent. If topical NSAIDs are in use, discontinue these as well.
- Reduce exposure to other nephrotoxic agents (e.g., furosemide, aminoglycosides).
- Supportive measures:
- Maintain adequate hydration.
- Symptomatic relief for fever, rash, and so forth
- Control of BP and anemia
- Correct acidosis and electrolyte imbalances.
- Possible short-term dialysis until recovery of renal function (5)[B]
MEDICATION
- Mainstay of treatment is supportive therapy.
- If patient is taking multiple offending agents, a reasonable clinical approach should include substitution of the suspected drug with another medication.
- If AKI persists after removing the offending agent, attempt medication therapy.
First Line
- Optimal therapy of AIN is unknown because there are no randomized controlled trials (RCTs) or large observational studies.
- Immunosuppressive therapy employed if no subsequent improvement within 3 to 7 days after discontinuation of OFA.
- A renal biopsy is preferred to confirm AIN and to exclude other possible diseases or CIN, where immunosuppressive Rx not indicated.
- Prednisone 1 mg/kg/day PO or equivalent IV dose to a max of 40 to 60 mg/day for 1 to 2 weeks, beginning a gradual taper after serum creatinine has returned to near baseline for a duration of 2 to 3 months, followed by a gradual taper over 3 to 4 weeks (6)[B]. Complete recover is noted in 49% and partial in 39% (1)[C].
- Steroids started within 7 days of withdrawal of offending agent more likely to recover function than those who started later (odds ratio [OR] 6.6).
Second Line
- There is limited experience with treating AIN in patients who are steroid dependent (i.e., relapse during prednisone taper), steroid resistant (as with NSAID-induced disease), or cannot tolerate steroids.
- Mycophenolate mofetil may be considered in these patients who have biopsy-proven AIN (7)[C]. Rx may need to be continued for 1 to 3 years.
- Lead toxicity: Chelation may improve function.
- Succimer 10 mg/kg (max 500 mg) PO q8h for 5 days, then q12h for 14 days, or
- EDTA 2 g IV/IM; if IM, use with 2% lidocaine.
- SLE nephritis: steroids + cyclophosphamide or azathioprine
- Urate nephropathy: urate-lowering agents
- Allopurinol starting at 100 mg/day, increasing to 300 mg/day to achieve serum urate level <6 mg/dL
- Dose may need to be adjusted down depending on level of renal impairment.
- Allopurinol itself can be a cause of AIN.
- Discontinue thiazide.
- Lithium-induced nephritis: Use amiloride as adjunct.
- Indinavir-induced nephritis: Use probenecid as adjunct.
ISSUES FOR REFERRAL
Most patients presenting with AKI, proteinuria, and acid-base and/or electrolyte disorders require consultation with a nephrologist.
INPATIENT CONSIDERATIONS
Patients with AKI and/or with serious electrolyte or acid-base disorders may require inpatient care until stabilization or resolution.
Admission Criteria/Initial Stabilization
- Persistent oliguria or anuria
- Severe acidosis and/or electrolyte abnormalities
- ECG changes
Discharge Criteria
- Stable vitals; correction of all electrolyte imbalances, including magnesium; and resolution of acute ECG changes
- Normal urine production
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
If patients must remain on nephrotoxic agents, measure renal function, electrolytes, and phosphorus frequently.
DIET
- Low potassium (<2 g/day)
- Low sodium
- Low protein
PATIENT EDUCATION
Printed materials for patients are available at the National Kidney Disease Education Program, (866) 4-KIDNEY, http://www.niddk.nih.gov/health-information/health-communication-programs/nkdep/Pages/default.aspx.
PROGNOSIS
- If the associated AIN is detected early (within 1 week of the rise in serum creatinine) and the offending agent is discontinued promptly, the long-term outcome is favorable for a return to baseline or near baseline serum creatinine levels, except in the instance of NSAID-induced AIN.
- Renal biopsy reveals extent of damage.
- AIN
- Recovery within weeks to months (8)[C]
- Acute dialysis is needed for 1/3 of patients before resolution.
- Rarely progresses to ESRD
- CIN: can progress to ESRD
- Renal disease may remit in 1 year if untreated.
- TINU has relapsing course, requiring systemic corticosteroids.
- Untreated severe AKI has 45-70% mortality.
COMPLICATIONS
- Chronic tubulointerstitial disease may progress to ESRD, requiring dialysis or transplantation.
- Analgesics increase the risk of transitional cell cancers of the uroepithelium.
REFERENCES
11 Muriithi AK, Leung N, Valeri AM, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney Int. 2015;87(2):458-464.22 Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.33 Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1984;310(9):563-572.44 Muriithi AK, Nasr SH, Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol. 2013;8(11):1857-1862.55 Koselj M, Kveder R, Bren AF, et al. Acute renal failure in patients with drug-induced acute interstitial nephritis. Ren Fail. 1993;15(1):69-72.66 Clarkson MR, Giblin L, O'Connell FP, et al. Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dial Transplant. 2004;19(11):2778-2783.77 Preddie DC, Markowitz GS, Radhakrishnan J, et al. Mycophenolate mofetil for the treatment of interstitial nephritis. Clin J Am Soc Nephrol. 2006;1(4):718-722.88 Rossert J. Drug-induced acute interstitial nephritis. Kidney Int. 2001;60(2):804-817.
ADDITIONAL READING
- Braden GL, O'Shea MH, Mulhern JG. Tubulointerstitial diseases. Am J Kidney Dis. 2005;46(3):560-572.
- Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev. 2009;(3):CD001892.
CODES
ICD10
- N12 Tubulo-interstitial nephritis, not spcf as acute or chronic
- N10 Acute tubulo-interstitial nephritis
- N11.9 Chronic tubulo-interstitial nephritis, unspecified
- N16 Renal tubulo-interstitial disord in diseases classd elswhr
- N11.8 Other chronic tubulo-interstitial nephritis
- N11.1 Chronic obstructive pyelonephritis
- M35.04 Sicca syndrome with tubulo-interstitial nephropathy
ICD9
- 583.89 Nephritis and nephropathy, not specified as acute or chronic, with other specified pathological lesion in kidney
- 580.89 Acute glomerulonephritis with other specified pathological lesion in kidney
- 582.89 Chronic glomerulonephritis with other specified pathological lesion in kidney
- 583.81 Nephritis and nephropathy, not specified as acute or chronic, in diseases classified elsewhere
SNOMED
- 28689008 Interstitial nephritis (disorder)
- 28637003 Acute interstitial nephritis (disorder)
- 60926001 chronic interstitial nephritis (disorder)
- 418839003 Tubulointerstitial nephritis with uveitis syndrome (disorder)
- 66993009 Acute infectious tubulointerstitial nephritis
- 439990003 Drug-induced interstitial nephritis (disorder)
- 236374007 Chronic infective interstitial nephritis (disorder)
CLINICAL PEARLS
- First step in treatment is to remove OFA.
- Most common OFA in elderly is PPIs and antibiotics.
- A renal biopsy is preferred to confirm AIN.
- Immunosuppressive therapy is employed if no subsequent improvement within 3 to 7 days after discontinuation of OFA.