What is the workup for a newly diagnosed case of chronic kidney disease (CKD) with an unknown etiology?

Workup for Newly Diagnosed Chronic Kidney Disease of Unknown Cause

The comprehensive workup for newly diagnosed chronic kidney disease (CKD) of unknown etiology should include assessment of kidney function, evaluation for albuminuria, imaging studies, and consideration of kidney biopsy to determine the underlying cause and guide appropriate management. 1

Initial Assessment

Laboratory Testing

• Kidney Function Assessment:

  • Serum creatinine with eGFR calculation using CKD-EPI equation 1, 2
  • Consider cystatin C measurement for more accurate GFR assessment in specific situations (e.g., extremes of muscle mass, malnutrition) 1, 2
  • If more precise GFR measurement is needed for clinical decisions, consider measured GFR using exogenous filtration markers 1

• Albuminuria/Proteinuria Assessment:

  • Urinary albumin-to-creatinine ratio (ACR) from spot urine sample 1, 2
  • Urinalysis with microscopic examination for cells, casts, and crystals 1
  • 24-hour urine collection for protein and creatinine clearance if needed 1

• Complete Blood Count:

  • Hemoglobin, white blood cell count with differential, platelet count 2
  • Absolute reticulocyte count 2

• Metabolic Assessment:

  • Serum electrolytes (sodium, potassium, chloride, bicarbonate) 1
  • Calcium, phosphorus, intact parathyroid hormone (iPTH) 2
  • Serum albumin 1
  • Lipid profile 2
  • Serum ferritin and transferrin saturation (TSAT) 2
  • Serum vitamin B12 and folate levels 2

• Additional Tests:

  • Hepatitis B and C serology 1
  • HIV testing (if risk factors present) 1
  • Antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA) 1
  • Complement levels (C3, C4) 1
  • Serum and urine protein electrophoresis 1
  • Serum free light chains (if myeloma suspected) 1
  • Anti-glomerular basement membrane (anti-GBM) antibodies 1

Imaging Studies

• Renal Ultrasonography: First-line imaging to assess kidney size, cortical thickness, echogenicity, and to rule out obstruction 1, 2
• Doppler Studies: To evaluate renal vascular disease if suspected 1
• CT or MRI: Consider if more detailed anatomical information is needed or if ultrasonography is inconclusive 1

Confirmation of Chronicity

Establish chronicity (duration ≥3 months) through 1:

1. Review of past GFR measurements
2. Review of past albuminuria/proteinuria measurements
3. Imaging findings (reduced kidney size, cortical thinning)
4. Medical history of conditions known to cause CKD
5. Repeat measurements beyond the 3-month point

Evaluation of Cause

Establish the cause of CKD using 1, 2:

• Clinical context and medical history (especially diabetes, hypertension)
• Personal and family history (genetic kidney diseases)
• Social and environmental factors (occupational exposures, toxins)
• Medication review (nephrotoxic medications)
• Physical examination findings
• Laboratory and imaging results

Kidney Biopsy Considerations

Consider kidney biopsy when 1:

• Nephrotic syndrome
• Rapidly progressive glomerulonephritis
• Persistent hematuria with proteinuria
• Unexplained rapid decline in kidney function
• Systemic diseases with potential kidney involvement
• When diagnosis would alter management decisions

Special Considerations for CKD of Unknown Etiology

When common causes (diabetes, hypertension, glomerulonephritis) have been ruled out 3:

• Detailed occupational history (agricultural work, chemical exposures)
• Environmental exposures (heavy metals, agrochemicals)
• Water source assessment (potential contaminants)
• Heat stress and dehydration history
• Family history of kidney disease

Referral to Nephrology

Promptly refer to a nephrologist when 1, 4:

• eGFR <30 mL/min/1.73 m²
• ACR ≥300 mg/g or protein/creatinine ratio >500 mg/g
• Rapid decline in eGFR (>5 mL/min/1.73 m² per year)
• Persistent hematuria
• Uncontrolled hypertension despite appropriate therapy
• Suspected genetic kidney disease
• Uncertainty about etiology of kidney disease

Common Pitfalls to Avoid

• Relying solely on serum creatinine: Can lead to overestimation of kidney function, especially in elderly or malnourished patients 2
• Dismissing mild GFR reduction in elderly patients: Even mild reductions can be associated with adverse outcomes 2
• Assuming a single abnormal test confirms CKD: Always confirm with repeat testing 1
• Overlooking non-traditional risk factors: In cases of unknown etiology, consider environmental exposures, occupational hazards, and genetic factors 3
• Delaying nephrology referral: Early specialist input can improve outcomes for patients with advanced or rapidly progressing CKD 1, 4

By following this systematic approach to the workup of newly diagnosed CKD of unknown cause, clinicians can identify the underlying etiology, stage the disease appropriately, and implement targeted interventions to slow progression and reduce complications.