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Tubulointerstitial Diseases of the Kidney

Chapter 328 | Harrison's 22e · Part 9 – Renal & Urinary Tract Disorders · Chapter 328

Key Clinical Points

  1. Tubulointerstitial diseases primarily affect the tubules and interstitium, with relative sparing of the glomeruli and renal vessels.
  2. Acute Interstitial Nephritis (AIN) is frequently triggered by drugs (antibiotics, NSAIDs, diuretics, anticonvulsants, immune modulators), infections, or autoimmune conditions.
  3. Chronic tubulointerstitial nephritis (TIN) presents with impaired concentrating ability (nephrogenic diabetes insipidis) and proximal tubular dysfunction (Fanconi's syndrome).
  4. Acid-base disturbances in chronic TIN include Type II RTA (bicarbonaturia) and Type IV RTA (hyperkalemia, metabolic acidosis due to impaired ammoniagenesis).
  5. Proteinuria is typically modest (<2 g/d); however, nephrotic-range albuminuria may occur if secondary focal segment glomerulonephritis (FSGS) develops.
  6. Management of AIN involves identifying and withdrawing the offending agent followed by supportive care; corticosteroids or immunosuppressives are used based on clinical progression and biopsy results.
  7. Imaging can identify 'medical renal disease' features, such as increased echogenicity, loss of corticomedullary differentiation, and cortical scarring.
  8. Myeloma cast nephropathy is characterized by eosinophilic casts (Bence-Jones protein) in atrophic tubules surrounded by giant cell reactions.
  9. Obstructive uropathy and reflux nephropathy can cause significant parenchymal scarring and hydronephrosis.
  10. Papillary necrosis may result from analgesic nephropathy, sickle cell nephropathy, diabetes with UTI, or prolonged NSAID use.

DEFINITION & CLASSIFICATION

• Definition: A group of disorders that primarily affect the tubules and interstitium, with relative sparing of the glomeruli and renal vessels. • Distinction: These are distinct from secondary parenchymal changes resulting from glomerular or vascular diseases. • Classification (Table 328-1): • Acute Tubulointerstitial Disorders: ◦ Acute Interstitial Nephritis (AIN): → Triggered by: Therapeutic agents (Antibiotics, NSAIDs, Diuretics, Anticonvulsants, Immune modulators); Infections (Bacteria, Viruses, others); or Autoimmune conditions (TINU, Sjögren’s, SLE, Granulomatous, IgG4-related). ◦ Acute Obstructive Disorders: → Examples: Light chain cast nephropathy ("myeloma kidney"), Acute phosphate nephropathy, Acute urate nephropathy. • Chronic Tubulointerstitial Disorders: ◦ Examples: Vesicoureteral reflux/reflux nephropathy, Sickle cell disease, Chronic exposure to toxins or therapeutic agents (Lithium, Heavy metals, Aristolochic acid), Analgesics (phenacetin), Calcineurin inhibitors. • Metabolic Disturbances: ◦ Examples: Hypercalcemia/nephrocalcinosis, Hyperuricemia, Prolonged hypokalemia, Hyperoxaluria, Cystinosis. • Cystic and Hereditary Disorders: ◦ Examples: Polycystic kidney disease, Nephronophthisis, Autosomal dominant tubulointerstitial kidney disease (medullary cystic kidney disease), Medullary sponge kidney. • Miscellaneous: ◦ Examples: Aging, Chronic glomerulonephritis, Chronic urinary tract obstruction, Ischemia and vascular disease, Radiation nephritis.

ETIOLOGY & PATHOPHYSIOLOGY

• Acute Interstitial Nephritis (AIN): ◦ Mechanism: Acute inflammation or fibrosis of the renal interstitium and atrophy of the tubular compartment. ◦ Pathogenesis: Triggered by aggressive inflammatory infiltrates leading to tissue edema, tubular cell injury, and compromised flow; or by frank obstruction of the tubules with casts, cellular debris, or crystals.

CLINICAL FEATURES

• Acute Interstitial Nephritis (AIN): ◦ Presentation: Acute kidney injury (AKI). ◦ Symptoms: Flank pain due to distention of the renal capsule. ◦ Urinalysis: Often active with leukocytes and cellular casts. • Chronic Tubulointerstitial Nephritis (TIN): ◦ Concentrating Ability: Impaired, leading to nephrogenic diabetes insipidis. ◦ Proximal Tubular Function: Deficits resulting in Fanconi's syndrome (glycosuria, phosphaturia, aminoaciduria, hypokalemia). ◦ Acid-Base Disorders: ◦ Type II RTA: Characterized by bicarbonaturia. ◦ Type IV RTA: Characterized by hyperkalemia and non-anion-gap metabolic acidosis due to impaired ammoniagenesis. ◦ Proteinuria: Typically modest (<2 g/d); however, nephrotic-range albuminuria may occur if secondary focal segment glomerulonephritis (FSGS) develops.

DIAGNOSTIC APPROACH

  1. Clinical History: Identify exposure to drugs (Antibiotics, NSAIDs, Diuretics, Anticonvulsants, Immune modulators), infections, or toxins.
  2. Urinalysis: Assess for leukocyte activity and cellular casts.
  3. Laboratory Analysis: ◦ Monitor serum creatinine/BUN; evaluate electrolytes to identify RTA (Type II: bicarbonaturia; Type IV: hyperkalemia) or Fanconi's syndrome.
  4. Imaging (Ultrasound): Identify "medical renal disease" features: ◦ Increased echogenicity of the renal parenchyma. ◦ Loss of corticomedullary differentiation. ◦ Prominence of the renal pyramids. ◦ Cortical scarring.
  5. Renal Biopsy: Used to differentiate between clinical phenotypes when diagnosis is not clear from history or imaging alone (e.g., distinguishing Classic AIN, Granulomatous/Immune IN, or Fibrosis).

MANAGEMENT & TREATMENT

  1. Initial Management: Identify and withdraw the offending agent (e.g., Antibiotics, NSAIDs, Diuretics) → Initiate supportive care and close observation.
  2. Evaluation at 1 Week: Assess for improvement or rapid progression of renal failure.
  3. Decision Pathway (Flowchart 1): • Initial Step: AKI with features of AIN → Withdraw offending agent → Supportive care/observation. • Assessment Point: After 1 week (or if rapid progression occurs): ◦ Improvement → Continue observation. ◦ No improvement in 1 week OR rapid progression → Determine phenotype: ◦ Classic allergic AIN → Corticosteroids. ◦ Atypical features → Renal biopsy → Identify pathology: ◦ Granulomatous or other immune IN → Immunosuppressive drugs. ◦ Fibrosis → Conservative management.
  4. Corticosteroid Indications (Table 328-2): • Absolute Indications: Sjögren's syndrome, Sarcoidosis, SLE interstitial nephritis, Adults with TINU, IgG4-related systemic disease, Idiopathic and other granulomatous interstitial nephritis. • Relative Indications (Drug-induced or idiopathic AIN with:) ◦ Rapid progression of renal failure ◦ Diffuse infiltrates on biopsy ◦ Impending need for dialysis ◦ Delayed recovery ◦ Children with TINU ◦ Postinfectious AIN with delayed recovery (?).

COMPLICATIONS & PROGNOSIS

• Myeloma Cast Nephropathy: Characterized by atrophic tubules filled with eosinophilic casts (Bence-Jones protein) surrounded by giant cell reactions. • Obstructive Uropathy/Reflux Nephropathy: Can lead to hydronephrosis, parenchymal scarring, and loss of corticomedullary differentiation. • Papillary Necrosis (Table 328-3): Major causes include Analgesic nephropathy, Sickle cell nephropathy, Diabetes with urinary tract infection, and prolonged NSAID use (rare).

KEY PEARLS & HIGH-YIELD POINTS

• AIN Diagnosis: Often clinically suspected; biopsy is not always required if the offending agent is identified. • Proteinuria Rule: Most tubulointerstitial diseases present with low protein levels (<2 g/d); high levels suggest secondary glomerular involvement (FSGS). • Medical Renal Disease: Ultrasound findings of increased echogenicity and loss of corticomedullary differentiation are hallmark signs of chronic interstitial damage.

Reference Tables

TABLE 328-1 Classification of the Causes of Tubulointerstitial Diseases of the Kidney Acute Tubulointerstitial…

Harrison's 22e, p.2437

328 Tubulointerstitial
Diseases of the Kidney
Laurence H. Beck, Jr., David J. Salant

TABLE 328-1 Classification of the Causes of Tubulointerstitial Diseases of the Kidney

  • Acute Tubulointerstitial Disorders
  • Acute Interstitial Nephritis
    Therapeutic agents
    • Antibiotics (β-lactams, sulfonamides, quinolones, vancomycin, erythromycin,
    linezolid, minocycline, rifampin, ethambutol, acyclovir)
    • Nonsteroidal anti-inflammatory drugs, COX-2 inhibitors
    • Diuretics (rarely thiazides, loop diuretics, triamterene)
    • Anticonvulsants (phenytoin, valproate, carbamazepine, phenobarbital)
    • Immune modulators (immune checkpoint inhibitors, vedolizumab,
    lenalidomide)
    • Miscellaneous (proton pump inhibitors, H blockers, captopril, mesalazine,
    2
    indinavir, allopurinol)
    Infection
    • Bacteria (Streptococcus, Staphylococcus, Legionella, Salmonella, Brucella,
    Yersinia, Corynebacterium diphtheriae)
    • Viruses (EBV, CMV, hantavirus, polyomavirus, HIV)
    • Miscellaneous (Leptospira, Rickettsia, Mycoplasma, Histoplasma)
    Autoimmune
    • Tubulointerstitial nephritis with uveitis (TINU)
    • Sjögren’s syndrome
    • Systemic lupus erythematosus
    • Granulomatous interstitial nephritis
    • IgG4-related systemic disease
    • Tubulointerstitial disease related to checkpoint inhibitors
    • Anti-brush border disease (anti-LRP2 nephropathy)
    • Idiopathic autoimmune interstitial nephritis
    Acute Obstructive Disorders
    • Light chain cast nephropathy (“myeloma kidney”)
    • Acute phosphate nephropathy
    • Acute urate nephropathy
  • Chronic Tubulointerstitial Disorders
  • • Vesicoureteral reflux/reflux nephropathy
    • Sickle cell disease
    • Chronic exposure to toxins or therapeutic agents
    • Analgesics, especially those containing phenacetin
    • Lithium
    • Heavy metals (lead, cadmium)
    • Aristolochic acid (Chinese herbal and Balkan endemic nephropathies)
    • Calcineurin inhibitors (cyclosporine, tacrolimus)
    • Chronic interstitial nephritis in agricultural communities
  • Metabolic Disturbances
  • • Hypercalcemia and/or nephrocalcinosis
    • Hyperuricemia
    • Prolonged hypokalemia
    • Hyperoxaluria
    • Cystinosis (see Chap. 327)
  • Cystic and Hereditary Disorders (see Chap. 327)
  • • Polycystic kidney disease
    • Nephronophthisis
    • Autosomal dominant tubulointerstitial kidney disease (medullary cystic kidney
    disease)
    • Medullary sponge kidney
  • Miscellaneous
  • • Aging
    • Chronic glomerulonephritis
    • Chronic urinary tract obstruction
    • Ischemia and vascular disease
    • Radiation nephritis (rare)

TABLE 328-2 Indications for Corticosteroids and Immunosuppressives in Interstitial Nephritis Absolute Indications •…

Harrison's 22e, p.2438

  • Absolute Indications
  • • Sjögren’s syndrome
    • Sarcoidosis
    • SLE interstitial nephritis
    • Adults with TINU
    • Interstitial nephritis from IgG4-related disease
    • Idiopathic and other granulomatous interstitial nephritis
  • Relative Indications
  • • Drug-induced or idiopathic AIN with:
    • Rapid progression of renal failure
    • Diffuse infiltrates on biopsy
    • Impending need for dialysis
    • Delayed recovery
    • Children with TINU
    • Postinfectious AIN with delayed recovery (?)

TABLE 328-3 Major Causes of Papillary Necrosis Analgesic nephropathy Sickle cell nephropathy Diabetes with urinary…

Harrison's 22e, p.2442

  • Analgesic nephropathy
  • Sickle cell nephropathy
  • Diabetes with urinary tract infection
  • Prolonged NSAID use (rare)