Interstitial Nephritis

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Description

  • Acute and chronic tubulointerstitial diseases result from interactions between renal and inflammatory cells.
  • Injury to renal cells triggers new antigen expression, inflammatory cell infiltration, and proinflammatory activation. The outcome is acute interstitial nephritis (AIN) or chronic interstitial nephritis (CIN).
  • In AIN, altered tubular function precedes decreased glomerular filtration rate.
  • AIN typically presents as acute kidney injury (AKI) after exposure to offending drugs or agents (OFA), often with predominantly non-albumin, that is, tubular proteinuria, sterile pyuria, microscopic hematuria, and white cell casts.

Epidemiology

Incidence

  • AIN accounts for 15–20% of patients with AKI.
  • Peak incidence is in women aged 60 to 70 years. Tubulointerstitial nephritis with uveitis (TINU) typically presents in adolescent females IgG4-related disease occurs more commonly in men >50 years.

Pediatric Considerations
Children with prior lead poisoning are at higher risk for CIN as young adults.Geriatric Considerations
Older patients (≥65 years) typically have more severe disease, higher risk of permanent damage, especially from drug-induced AIN (87% vs. 64%), and more proton pump inhibitor-induced AIN (18% vs. 6%), but less AIN from autoimmune or systemic causes (7% vs. 27%).

Etiology and Pathophysiology

  • AIN
    • T cell activation by an antigen leads to delayed drug hypersensitivity reactions, which leads to interstitial inflammatory infiltrates that damage tubules.
    • Renal dysfunction generally is partially or completely reversible.
    • Hypersensitivity to drugs (75%): not dose dependent; the top three were omeprazole (12%), amoxicillin (8%), and ciprofloxacin (8%) (1)[C]; many implicated; NSAIDs, antibiotics, proton pump inhibitors, diuretics, AEDs, antivirals, anticancer drugs, allopurinol, H2 blockers, diphenylhydantoin, sulfasalazine, and mesalamine
    • Infections (10–15%): Streptococci, Legionella, Leptospira, Leishmania, Escherichia coli, Campylobacter, Salmonella, Treponema pallidum, Mycobacterium tuberculosis, Histoplasma, Coccidioides, Toxoplasma, CMV, EBV, HSV, HIV, and perhaps the SARS-CoV-2 (COVID-19) virus (2)
    • Autoimmune (10–15%): sarcoidosis, SLE, Sjögren syndrome, granulomatosis with polyangiitis, cryoglobulinemia
    • Toxins (e.g., snake bite venom)
    • Idiopathic (5–10%): TINU syndrome and anti-tubular basement membrane (anti-TBM) disease
  • CIN
    • Characterized by interstitial scarring, fibrosis, and tubular atrophy, resulting in progressive CKD
    • Often follows long-term exposure to OFA (e.g., heavy metals, especially lead); long-term exposure to agents that cause AIN (PPIs, NSAIDs) can also cause CIN.
    • CIN in agricultural communities (CINAC) or Mesoamerican nephropathy or CKD of unknown etiology (CKDu): In farming communities from Central America (mainly Nicaragua and El Salvador); etiology is not known but could be related to pesticide exposure, heat stress, and genetic predisposition.
    • May be found incidentally on routine labs

Genetics

Significant associations have been reported between certain HLA genotypes and AIN, especially drug-induced AIN. These genetic associations influence susceptibility to AIN, disease severity, and treatment response. In the future, HLA typing may help stratify risk in patients prescribed high-risk medications (PPIs, antibiotics, ICIs). Discussion of these genetic associations is beyond the scope of this chapter.

General Prevention

  • Review need for medication (e.g., PPIs) at every visit and discontinue when not needed or when safer alternatives are available (e.g., H2 receptor blockers).
  • Ask for over-the-counter medications especially “herbal supplements” and “alternative/natural/holistic medications” as these may contain heavy metals or other chemicals with potential to cause AIN.
  • Early recognition and prompt discontinuation of OFA

Commonly Associated Conditions

  • 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
  • Uveitis

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