Interstitial Nephritis

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Basics

Description

  • Acute and chronic tubulointerstitial diseases result from the interplay of renal cells and inflammatory cells. Lethal or sublethal injury to renal cells leads to new local antigen expression, inflammatory cell infiltration, and proinflammatory activation and cytokines. Cytokines are produced by macrophages, lymphocytes, and renal cells (i.e., proximal tubule, vascular endothelial cells, interstitial cells, fibroblasts). The outcome is acute interstitial nephritis (AIN) or chronic interstitial nephritis (CIN).
  • Central component in AIN is altered tubular function, which precedes decrements in filtration rate.
  • AIN presents as acute kidney injury (AKI) after the use of offending drugs or agents (OFA) and is associated with typical findings of proteinuria, hematuria, and white cell casts. Less frequently, AIN is secondary to infections, systemic diseases, and mixed connective tissue disease (MCTD).
  • System(s) affected: renal/urologic, endocrine/metabolic, immunologic
  • Synonym(s): acute interstitial allergic nephritis

Epidemiology

Pediatric Considerations

  • Children with history of lead poisoning are more likely to develop CIN as young adults.
  • Tubulointerstitial nephritis with uveitis (TINU) presents in adolescent females with mean age of 15 years.

Incidence
  • AIN accounts for 15–20% of AKI and about 15% of hospital cases of AKI.
  • Peak incidence in women 60 to 70 years of age

Geriatric Considerations
Elderly (≥65 years) have severe disease and increased risk of permanent damage given polypharmacy, specifically drug-induced AIN (87% vs. 64%), proton pump inhibitor–induced AIN (18% vs. 6%), but less AIN from autoimmune or systemic causes (7% vs. 27%) than younger adults (1)[B].

Etiology and Pathophysiology

  • AIN
    • Immune-mediated pathology whereby T-cell activation by an antigen leads to delayed drug hypersensitivity reactions, which leads to interstitial inflammatory infiltrates that damage tubules
    • Causes AKI
    • Renal dysfunction generally is partially or completely reversible, possibly reflecting the regenerative capacity of tubules with a preserved basement membrane.
    • Hypersensitivity to drugs (75%): not dose dependent. The top three drug causes were omeprazole (12%), amoxicillin (8%), and ciprofloxacin (8%) (2)[C].
      • NSAIDs (all, including Cox-2 inhibitors)
      • Antibiotics (e.g., penicillins, cephalosporins, sulfonamides, tetracycline, vancomycin, rifampin, fluoroquinolones, macrolides)
      • Proton pump inhibitors
      • Diuretics (thiazide, loop, and triamterene)
      • AEDs (phenytoin, valproate)
      • Antivirals (indinavir)
      • Anticancer drugs (immune checkpoint inhibitors)
      • Miscellaneous (allopurinol, H2 blockers, diphenylhydantoin, and 5-aminosalicylates such as sulfasalazine [Azulfidine] and mesalamine)
    • Infections: streptococci, Legionella, Leptospira, CMV, HIV, Mycobacterium tuberculosis (5–10%)
    • Autoimmune disorders (e.g., sarcoidosis, SLE, Sjögren syndrome, granulomatosis with polyangiitis, 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

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Basics

Description

  • Acute and chronic tubulointerstitial diseases result from the interplay of renal cells and inflammatory cells. Lethal or sublethal injury to renal cells leads to new local antigen expression, inflammatory cell infiltration, and proinflammatory activation and cytokines. Cytokines are produced by macrophages, lymphocytes, and renal cells (i.e., proximal tubule, vascular endothelial cells, interstitial cells, fibroblasts). The outcome is acute interstitial nephritis (AIN) or chronic interstitial nephritis (CIN).
  • Central component in AIN is altered tubular function, which precedes decrements in filtration rate.
  • AIN presents as acute kidney injury (AKI) after the use of offending drugs or agents (OFA) and is associated with typical findings of proteinuria, hematuria, and white cell casts. Less frequently, AIN is secondary to infections, systemic diseases, and mixed connective tissue disease (MCTD).
  • System(s) affected: renal/urologic, endocrine/metabolic, immunologic
  • Synonym(s): acute interstitial allergic nephritis

Epidemiology

Pediatric Considerations

  • Children with history of lead poisoning are more likely to develop CIN as young adults.
  • Tubulointerstitial nephritis with uveitis (TINU) presents in adolescent females with mean age of 15 years.

Incidence
  • AIN accounts for 15–20% of AKI and about 15% of hospital cases of AKI.
  • Peak incidence in women 60 to 70 years of age

Geriatric Considerations
Elderly (≥65 years) have severe disease and increased risk of permanent damage given polypharmacy, specifically drug-induced AIN (87% vs. 64%), proton pump inhibitor–induced AIN (18% vs. 6%), but less AIN from autoimmune or systemic causes (7% vs. 27%) than younger adults (1)[B].

Etiology and Pathophysiology

  • AIN
    • Immune-mediated pathology whereby T-cell activation by an antigen leads to delayed drug hypersensitivity reactions, which leads to interstitial inflammatory infiltrates that damage tubules
    • Causes AKI
    • Renal dysfunction generally is partially or completely reversible, possibly reflecting the regenerative capacity of tubules with a preserved basement membrane.
    • Hypersensitivity to drugs (75%): not dose dependent. The top three drug causes were omeprazole (12%), amoxicillin (8%), and ciprofloxacin (8%) (2)[C].
      • NSAIDs (all, including Cox-2 inhibitors)
      • Antibiotics (e.g., penicillins, cephalosporins, sulfonamides, tetracycline, vancomycin, rifampin, fluoroquinolones, macrolides)
      • Proton pump inhibitors
      • Diuretics (thiazide, loop, and triamterene)
      • AEDs (phenytoin, valproate)
      • Antivirals (indinavir)
      • Anticancer drugs (immune checkpoint inhibitors)
      • Miscellaneous (allopurinol, H2 blockers, diphenylhydantoin, and 5-aminosalicylates such as sulfasalazine [Azulfidine] and mesalamine)
    • Infections: streptococci, Legionella, Leptospira, CMV, HIV, Mycobacterium tuberculosis (5–10%)
    • Autoimmune disorders (e.g., sarcoidosis, SLE, Sjögren syndrome, granulomatosis with polyangiitis, 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

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