What are the acute and chronic causes of tubulointerstitial kidney disease?

Causes of Tubulointerstitial Kidney Disease

Tubulointerstitial kidney disease results from a diverse array of acute and chronic causes, including drugs (most commonly antibiotics, NSAIDs, and proton pump inhibitors), genetic mutations (UMOD, MUC1, REN, HNF1B), infections, immune-mediated disorders, obstructive uropathy, and metabolic diseases. 1, 2, 3

Acute Causes of Tubulointerstitial Nephritis

Drug-Induced (Most Common Acute Cause)

• β-lactam antibiotics and NSAIDs are the most frequent culprits, typically mediated through allergic mechanisms 2
• Proton pump inhibitors cause acute tubulointerstitial nephritis through immune-mediated mechanisms 1
• Protease inhibitors (in HIV patients) can trigger acute interstitial inflammation 1
• Immune checkpoint inhibitors cause interstitial nephritis in 2-5% of patients, typically 3-10 months after treatment initiation 4
• Sulfasalazine and 5-ASA cause dose-independent interstitial nephritis that is reversible if diagnosed early 4
• Tenofovir disoproxil fumarate causes proximal tubulopathy with characteristic dysmorphic mitochondria 1

Infection-Related

• Mycobacterial infection can trigger tubulointerstitial nephritis as an immune response 1
• Direct parenchymal infection by various pathogens occurs in immunocompromised states 1
• Acute pyelonephritis represents bacterial infection of the tubulointerstitium 3

Immunologic Acute Causes

• Diffuse infiltrative lymphocytosis syndrome (DILS) is a hyperimmune reaction against HIV involving kidneys in ~10% of cases, characterized by prominent CD8 T-cell infiltrates 1
• Immune restoration inflammatory syndrome (IRIS) causes inflammatory tubulointerstitial injury after ART initiation in HIV patients 1

Ischemic/Toxic Insults

• Acute tubular necrosis occurs with sepsis, volume depletion, and other ischemic or toxic insults 1

Chronic Causes of Tubulointerstitial Nephritis

Genetic/Hereditary (Autosomal Dominant Tubulointerstitial Kidney Disease)

ADTKD-UMOD (Uromodulin mutations):

• Most frequently encountered genetic form alongside ADTKD-MUC1 1
• Characterized by hyperuricemia with inappropriately low fractional urate excretion (<5%) and early-onset gout 1
• Gout can begin in teenage years, especially in males 1
• Caused by accumulation of mutant uromodulin in endoplasmic reticulum of thick ascending limb cells 1

ADTKD-MUC1 (Mucin-1 mutations):

• Second most common genetic form 1
• Frameshift mutation creates abnormal MUC1-fs protein that accumulates in distal tubular epithelial cells 1
• No characteristic extrarenal findings 1

ADTKD-REN (Renin mutations):

• Less common than UMOD and MUC1 forms 1
• Causes childhood anemia unrelated to GFR that resolves at puberty 1
• Patients have mild hypotension and increased risk for acute kidney injury due to renin-angiotensin system dysfunction 1
• Reduced renin staining in juxtaglomerular apparatus on histology 5

ADTKD-HNF1B (Hepatocyte nuclear factor 1β mutations):

• Presents with extrarenal manifestations including MODY5 diabetes, bilateral renal cysts, genital abnormalities, and pancreatic atrophy 1
• Can present prenatally or in childhood 1
• Associated with hypomagnesemia, hypokalemia, and liver function abnormalities 1

Chronic Drug/Toxin Exposure

• Heavy metals (lead, cadmium) cause chronic tubulointerstitial damage 3
• Ciclosporin causes chronic renal impairment with interstitial fibrosis and tubular nephropathy in up to 20% of patients 4
• Chronic analgesic use leads to progressive interstitial fibrosis 2

Obstructive/Structural

• Obstructive uropathy from any cause leads to chronic tubulointerstitial changes 3
• Nephrolithiasis causes recurrent obstruction and inflammation 3
• Vesicoureteral reflux disease results in chronic pyelonephritis with cortical scarring 3

Immune-Mediated Chronic Causes

• Granulomatous interstitial nephritis as an extra-intestinal manifestation of inflammatory bowel disease 4
• Chronic rejection in transplant kidneys manifests as tubulointerstitial fibrosis 2
• Sarcoidosis causes granulomatous tubulointerstitial inflammation 2

Metabolic Disorders

• Hyperuricemia/gout (independent of ADTKD) causes urate nephropathy 2
• Hypercalcemia/hypercalciuria leads to nephrocalcinosis and interstitial damage 3
• Hypokalemia from various causes produces chronic tubulointerstitial changes 3

Ischemic/Vascular

• Chronic ischemia from any cause leads to peritubular capillary loss and progressive fibrosis 6
• Arterionephrosclerosis in aging and hypertensive patients causes secondary tubulointerstitial damage 1

Neoplastic

• Multiple myeloma causes cast nephropathy and tubulointerstitial damage 3
• Lymphoproliferative disorders can infiltrate the tubulointerstitium 3

Idiopathic

• 10-25% of chronic tubulointerstitial nephritis cases remain idiopathic after thorough evaluation 7
• Diagnosis requires careful exclusion of all identifiable causes 7

Key Clinical Pitfalls

Common diagnostic errors to avoid:

• Reflexively diagnosing "HIV immune complex kidney disease" without workup for specific secondary causes (hepatitis B/C, lupus, IgA nephropathy) 1
• Missing drug-induced causes by failing to review all medications including over-the-counter NSAIDs and supplements 4
• Overlooking genetic causes (ADTKD) in patients with family history of "unknown" kidney disease and bland urinary sediment 1
• Attributing renal cysts to polycystic kidney disease when they actually represent advanced tubulointerstitial disease 1
• Delaying diagnosis of drug-induced interstitial nephritis, which reduces reversibility 4

Critical monitoring considerations:

• Patients on sulfasalazine/5-ASA require renal function monitoring every 4 weeks for first 3 months, then every 3 months for first year 4
• The highest risk period for drug-induced interstitial nephritis is the first few months of treatment 4
• ADTKD patients with REN mutations are at particular risk for volume depletion and acute kidney injury 1