Clinical Case: Acute Tubulointerstitial Nephritis

Patient Presentation

Physical Examination

Laboratory Results

Imaging

• Kidneys bilaterally enlarged (right 12.1 cm; left 12.4 cm), echogenic parenchyma
• No hydronephrosis, no stones, no masses
• Normal vascular flow on Doppler

Renal Biopsy

• Interstitium: Pronounced edema with dense mononuclear infiltrate (lymphocytes, macrophages). Prominent eosinophils and neutrophils present in clusters.
• Tubules: Tubulitis (lymphocytic infiltration into tubular epithelium); variable tubular injury and early regenerative changes.
• Glomeruli: Normal morphology (no glomerulonephritis).
• Vessels: No vasculitis.
• Granulomas: Absent in this case.

Diagnosis

Acute Tubulointerstitial Nephritis (ATIN) — Drug-induced (TMP-SMX and/or proton pump inhibitor)

Pathophysiology

1. Type I hypersensitivity (IgE-mediated): Elevated serum IgE, eosinophilia, and skin rash suggest involvement of this arm.
2. Type IV hypersensitivity (T cell–mediated): The dense mononuclear interstitial infiltrate and tubulitis are characteristic of delayed-type hypersensitivity.

• Latent period of ~10 days after drug initiation
• Idiosyncratic reaction (not dose-dependent)
• Triad of fever + rash + eosinophilia (present in ~25% of cases)
• Recurrence expected upon re-exposure

• Impaired urine concentration → polyuria/nocturia
• Impaired acid excretion → hyperchloremic metabolic acidosis (non-anion gap)
• Impaired potassium handling → hyperkalemia
• β₂-microglobulinuria → proximal tubule dysfunction

Differential Diagnosis

Management

1. Immediate cessation of offending drugs (TMP-SMX and omeprazole) — the most critical step. Recovery may take weeks to several months.
2. Corticosteroids: Prednisone 1 mg/kg/day (up to 60 mg/day) for 4–8 weeks with gradual taper, considered when renal function fails to improve within 1 week of drug withdrawal or in severe AKI.
3. Supportive measures:
   • IV fluids with close monitoring of fluid balance
   • Dietary potassium restriction; consider potassium binders if K⁺ remains elevated
   • Discontinue lisinopril temporarily (RAAS blockade may worsen hyperkalemia and AKI)
   • Hold metformin until renal function recovers (risk of lactic acidosis)
4. Close monitoring: Serum creatinine, electrolytes, and urinalysis every 48–72 hours during acute phase.
5. Avoidance of re-exposure to sulfonamides and PPIs; document allergy in medical record.
6. Nephrology referral given AKI stage 3 (creatinine 3.4 mg/dL from presumed baseline ~0.9 mg/dL).

Teaching Points

• ATIN accounts for up to 15–20% of AKI cases and is the second most common cause of drug-induced AKI after pyelonephritis. — Robbins, Cotran & Kumar Pathologic Basis of Disease
• The classic triad (fever, rash, eosinophilia) is present in only ~25% of patients; its absence does not exclude the diagnosis.
• PPIs and sulfa drugs are among the most frequent culprits today; immune checkpoint inhibitors are an increasingly recognized cause in oncology patients.
• Eosinophiluria (Hansel stain) supports the diagnosis but has limited sensitivity.
• Tubular dysfunction (non-anion gap acidosis, impaired concentration, β₂-microglobulinuria) distinguishes TIN from glomerulonephritis.
• Glomeruli are normal on biopsy unless NSAIDs are the cause, in which case concurrent minimal change disease and nephrotic syndrome may develop.
• Early recognition and drug withdrawal are the key determinants of reversibility.

Clinical Case: Acute Tubulointerstitial Nephritis

Patient Presentation

Physical Examination

• Temperature 38.2 °C, BP 148/92 mmHg
• Bilateral costovertebral angle tenderness (mild)
• Diffuse maculopapular rash on trunk and upper limbs
• No edema, no uveitis

Laboratory & Urinalysis

Renal Biopsy

• Pronounced interstitial edema with dense lymphocytic and macrophage infiltrate; eosinophils and neutrophils in clusters
• Tubulitis (lymphocytes infiltrating tubular epithelium); variable tubular injury
• Normal glomeruli; no granulomas; no vasculitis

Diagnosis

Acute Tubulointerstitial Nephritis — Drug-induced (TMP-SMX / PPI)

Pathophysiology

• Type I hypersensitivity (IgE-mediated): explains elevated IgE, eosinophilia, and rash
• Type IV hypersensitivity (T cell–mediated): explains the interstitial mononuclear infiltrate and tubulitis

Management

1. Stop the offending drugs immediately — the most critical step
2. Corticosteroids (prednisone 1 mg/kg/day) if creatinine does not improve within ~1 week of drug withdrawal
3. Hold lisinopril and metformin until renal function recovers
4. Fluid balance management and electrolyte correction (K⁺, HCO₃⁻)
5. Nephrology referral; document allergy and avoid re-exposure

Key Teaching Points

• The classic triad of fever + rash + eosinophilia is present in only ~25% of patients — its absence does not exclude ATIN
• PPIs and sulfa drugs are among the most common culprits today; immune checkpoint inhibitors are increasingly recognized
• Tubular dysfunction (non-anion gap acidosis, hyperkalemia, β₂-microglobulinuria) distinguishes ATIN from glomerulonephritis
• Glomeruli are normal on biopsy unless NSAIDs are the cause (concurrent minimal change disease may occur)
• Early drug withdrawal is the key determinant of reversibility; recovery may take several months — Harrison's Principles of Internal Medicine, 22nd ed.

Clinical Case: Chronic Tubulointerstitial Nephritis

Patient Presentation

Physical Examination

• BP 162/96 mmHg; HR 78 bpm; afebrile
• Pallor of mucous membranes (anemia)
• No significant edema
• No costovertebral angle tenderness
• No rash or uveitis

Laboratory & Urinalysis

Imaging

• Bilateral small kidneys (right 8.6 cm; left 8.9 cm) with irregular cortical contour and atrophic scars
• Increased parenchymal echogenicity
• Papillary calcifications visible on CT (characteristic of analgesic nephropathy)
• No hydronephrosis

Renal Biopsy

• Interstitium: Diffuse tubulointerstitial fibrosis with collagen deposition; scattered chronic infiltrate of lymphocytes and macrophages (less abundant than in acute TIN)
• Tubules: Tubular atrophy with loss of tubular epithelium; dilated tubular lumens in some areas
• Glomeruli: Relatively spared early; global sclerosis in advanced foci
• Vessels: Hyaline arteriolosclerosis (related to hypertension)
• No eosinophils, no granulomas

Diagnosis

Chronic Tubulointerstitial Nephritis — Analgesic nephropathy (chronic combination analgesic use)

Pathophysiology

1. Toxic metabolites (particularly from acetaminophen) that concentrate in the renal medulla via the normal urinary concentrating mechanism — medullary cells are selectively exposed to high toxic concentrations
2. Medullary ischemia — aspirin inhibits prostaglandin-mediated vasodilation of vasa recta, reducing medullary blood flow
3. Papillary necrosis — combined ischemia and toxicity leads to coagulative necrosis of the papillae, with eventual sloughing and calcification
4. Over years: progressive cortical scarring, fibrosis, and CKD

Management

1. Complete cessation of all analgesic combinations — the single most important intervention; progression may halt if stopped early
2. BP control — target <130/80 mmHg; avoid NSAIDs; ACE inhibitor or ARB preferred for renoprotection
3. Correct metabolic acidosis — oral sodium bicarbonate supplementation
4. Anemia management — erythropoiesis-stimulating agents ± iron if EPO-deficient anemia confirmed
5. Hold metformin given eGFR <30 mL/min/1.73 m²
6. Screen for urothelial malignancy — increased risk of transitional cell carcinoma of renal pelvis, distal ureter, and bladder in analgesic nephropathy; urine cytology + cystoscopy
7. Nephrology referral for CKD stage 4 management and preparation for renal replacement therapy planning

Key Teaching Points

• Chronic TIN is insidious — patients often present with advanced CKD; analgesic use frequently goes unreported
• Anemia out of proportion to the degree of renal failure is a characteristic early clue
• Tubular dysfunction precedes significant GFR loss: nocturia, fixed specific gravity, glycosuria, RTA, and β₂-microglobulinuria
• The classic CT finding is bilateral small kidneys with papillary calcifications and irregular cortical scarring
• On biopsy: interstitial fibrosis replaces the acute inflammatory infiltrate — far less cellular than acute TIN
• Chronic analgesic use raises the risk of uroepithelial malignancy — screening is mandatory
• Unlike acute TIN, there is no fever, rash, or eosinophilia; the course is slow and smoldering — Goldman-Cecil Medicine

Clinical Case: Chronic Tubulointerstitial Nephritis

Patient Presentation

Physical Examination

• BP 162/96 mmHg; HR 78 bpm; afebrile
• Pallor of mucous membranes (anemia)
• No significant edema
• No costovertebral angle tenderness
• No rash or uveitis

Laboratory & Urinalysis

Imaging

• Bilateral small kidneys (right 8.6 cm; left 8.9 cm) with irregular cortical contour and atrophic scars
• Increased parenchymal echogenicity
• Papillary calcifications visible on CT (characteristic of analgesic nephropathy)
• No hydronephrosis

Renal Biopsy

• Interstitium: Diffuse tubulointerstitial fibrosis with collagen deposition; scattered chronic infiltrate of lymphocytes and macrophages (less abundant than in acute TIN)
• Tubules: Tubular atrophy with loss of tubular epithelium; dilated tubular lumens in some areas
• Glomeruli: Relatively spared early; global sclerosis in advanced foci
• Vessels: Hyaline arteriolosclerosis (related to hypertension)
• No eosinophils, no granulomas

Diagnosis

Chronic Tubulointerstitial Nephritis — Analgesic nephropathy (chronic combination analgesic use)

Pathophysiology

1. Toxic metabolites that concentrate in the renal medulla via the normal urinary concentrating mechanism — medullary cells are selectively exposed to high toxic concentrations
2. Medullary ischemia — aspirin inhibits prostaglandin-mediated vasodilation of vasa recta, reducing medullary blood flow
3. Papillary necrosis — combined ischemia and toxicity leads to coagulative necrosis of the papillae, with eventual sloughing and calcification
4. Over years: progressive cortical scarring, fibrosis, and CKD

Management

1. Complete cessation of all analgesic combinations — the single most important intervention
2. BP control — target <130/80 mmHg; avoid NSAIDs; ACE inhibitor or ARB preferred for renoprotection
3. Correct metabolic acidosis — oral sodium bicarbonate supplementation
4. Anemia management — erythropoiesis-stimulating agents ± iron if EPO-deficient anemia confirmed
5. Hold metformin given eGFR <30 mL/min/1.73 m²
6. Screen for urothelial malignancy — increased risk of transitional cell carcinoma of renal pelvis, distal ureter, and bladder; urine cytology + cystoscopy
7. Nephrology referral for CKD stage 4 management and renal replacement therapy planning