What diagnostic work‑up is recommended for a 56‑year‑old patient without diabetes or hypertension who has tubulointerstitial kidney disease?

Diagnostic Work-Up for Tubulointerstitial Kidney Disease in a 56-Year-Old Without Diabetes or Hypertension

For a 56-year-old patient with tubulointerstitial kidney disease lacking diabetes or hypertension, the diagnostic work-up must systematically exclude drug-induced causes, genetic forms (particularly ADTKD), autoimmune conditions, and infectious etiologies through detailed medication history, family history assessment, targeted laboratory testing, renal imaging, and consideration of kidney biopsy when the etiology remains unclear. 1, 2

Initial Clinical Assessment

Detailed Medication and Exposure History

• Review all medications systematically, including over-the-counter NSAIDs, proton pump inhibitors, antibiotics, and supplements, as drug-induced interstitial nephritis is frequently missed when this step is incomplete 2, 3
• Specifically inquire about recent use of proton pump inhibitors (common immune-mediated trigger), sulfasalazine, 5-ASA agents, immune checkpoint inhibitors, and tenofovir 2
• Document any herbal supplements or alternative medicines, as these are often overlooked nephrotoxins 3

Family History Evaluation

• Obtain a three-generation pedigree focusing on unexplained kidney disease, early-onset gout, childhood anemia, or diabetes (MODY5) in relatives, as autosomal dominant tubulointerstitial kidney disease (ADTKD) may present without obvious family history if relatives died young or were undiagnosed 1
• Ask specifically about family members requiring dialysis before age 60, as this pattern suggests genetic disease 1

Laboratory Investigations

Core Renal Function Tests

• Serum creatinine with estimated GFR calculation using the CKD-EPI equation to establish baseline kidney function 1, 4
• Urinalysis with microscopy to assess for bland sediment (typical of ADTKD), pyuria, eosinophiluria (suggests drug-induced), or casts 1, 3
• Urine albumin-to-creatinine ratio from a spot sample, as tubulointerstitial disease typically shows absent-to-mild proteinuria (<1 g/day) 1

Specialized Laboratory Testing

For ADTKD screening:

• Serum uric acid with fractional excretion of urate (<5% suggests ADTKD-UMOD, the most common genetic form) 1
• Serum electrolytes including magnesium and potassium, as hypomagnesemia and hypokalemia suggest ADTKD-HNF1B 1
• Urinary uromodulin excretion if available, as low levels support ADTKD-UMOD or ADTKD-REN 1

For autoimmune/systemic causes:

• Complete blood count to detect anemia (may indicate REN mutations if present since childhood) or eosinophilia (drug-induced) 1, 3, 5
• Serum complement (C3, C4) and immunoglobulins to exclude immune complex disease 1, 5
• Antinuclear antibodies, anti-dsDNA, ANCA panel if systemic autoimmune disease is suspected 3, 5
• Serum and urine protein electrophoresis with immunofixation to exclude monoclonal gammopathy-related tubulointerstitial disease 1

For infectious causes:

• HIV, hepatitis B and C serologies if risk factors present 2, 3
• Mycobacterial testing (QuantiFERON or PPD) if granulomatous disease suspected 2

Imaging Studies

Renal Ultrasound

• Perform renal ultrasound as the initial imaging modality to assess kidney size (normal or small in ADTKD), echogenicity, and presence of cysts 1
• Note that occasional renal cysts may occur in ADTKD-UMOD and ADTKD-MUC1 but are not medullary and do not cause the disease 1
• Small echogenic kidneys suggest chronic disease, while normal-sized kidneys with increased echogenicity may indicate acute or subacute interstitial nephritis 1, 3

Advanced Imaging Considerations

• Avoid iodinated contrast unless absolutely necessary given underlying kidney disease 1
• Consider non-contrast MRI if detailed anatomic assessment needed, particularly for suspected HNF1B-related disease with pancreatic or genital abnormalities 1

Kidney Biopsy Indications

Proceed with kidney biopsy when:

• The etiology remains unclear after initial work-up and the diagnosis would change management 1, 3
• Drug-induced interstitial nephritis is suspected but the offending agent cannot be identified or removed 3, 5
• Rapid progression of kidney dysfunction occurs without clear cause 3
• Atypical features are present (significant proteinuria >1 g/day, active urinary sediment with cellular casts, or severe hypertension early in disease) 1, 3

Expected biopsy findings in tubulointerstitial disease:

• Interstitial fibrosis and tubular atrophy with thickening and lamellation of tubular basement membranes 1
• Negative immunofluorescence for complement and immunoglobulins (distinguishes from immune complex disease) 1
• Possible tubular dilatation or microcysts 1
• In ADTKD-UMOD: intracellular uromodulin deposits in thick ascending limb profiles 1

Genetic Testing Strategy

Consider genetic testing for ADTKD when:

• Family history shows autosomal dominant pattern of CKD with bland sediment and minimal proteinuria 1
• Early-onset hyperuricemia or gout is present (especially before age 40 in males) 1
• Childhood anemia resolved at puberty (suggests REN mutations) 1
• Extrarenal manifestations include MODY5 diabetes, genital abnormalities, or pancreatic atrophy (suggests HNF1B) 1

Testing sequence:

• Begin with UMOD and MUC1 gene sequencing as these are the most common forms 1
• Add HNF1B deletion/duplication analysis if extrarenal features present 1
• Include REN sequencing if childhood anemia or hypotension documented 1
• Referral to specialized centers is recommended, as MUC1 testing remains technically challenging 1, 2

Critical Diagnostic Pitfalls to Avoid

• Do not assume all tubulointerstitial disease in the absence of diabetes/hypertension is genetic—drug-induced causes are more common and reversible if caught early 2, 3
• Do not delay kidney biopsy when drug-induced interstitial nephritis is suspected, as the likelihood of renal recovery decreases with prolonged exposure 2, 5
• Do not misattribute renal cysts to polycystic kidney disease when they actually reflect advanced tubulointerstitial disease 2
• Do not overlook ADTKD in patients with "sporadic" disease, as family members may have died young or been misdiagnosed 1, 2
• Do not assume negative family history excludes genetic disease—incomplete penetrance and variable expressivity occur in ADTKD 1

Establishing Chronicity

• Document that abnormalities persist for >3 months before diagnosing chronic kidney disease, as a single abnormal test is insufficient 1, 4
• Review any available prior creatinine measurements to determine duration of kidney dysfunction 4
• Serial measurements over 3 months are required if no prior data exist 1, 4