What are the laboratory and clinical manifestations of Antiretroviral Therapy (ART) nephrotoxicity in a patient?

ART Nephrotoxicity: Laboratory and Clinical Manifestations

ART nephrotoxicity most commonly presents as proximal tubular dysfunction with low-level proteinuria and phosphaturia, progressing in 1-2% of cases to treatment-limiting tubulopathy with eGFR decline, while protease inhibitors can cause interstitial nephritis and nephrolithiasis. 1

Primary Clinical Presentations

Tenofovir Disoproxil Fumarate (TDF) Nephrotoxicity

Subclinical Proximal Tubular Dysfunction (Most Common)

• Low-level proteinuria without significant albuminuria (urinary albumin-to-protein ratio <0.4 suggests tubular rather than glomerular disease) 1
• Excessive phosphaturia with hypophosphatemia 1, 2
• Normoglycemic glycosuria (glucose in urine despite normal blood glucose) 2, 3
• These findings occur commonly but remain subclinical in most patients 1

Severe Tubulopathy (1-2% of TDF Recipients)

• Full or partial Fanconi syndrome with metabolic acidosis due to bicarbonate wasting 2, 3
• Progressive eGFR decline (>25% decrease from baseline) 1
• Osteomalacia and pathological fractures from chronic phosphate wasting 1
• Presents as treatment-limiting toxicity requiring drug discontinuation 1

Acute Kidney Injury

• Acute tubular necrosis with rapid decline in kidney function 3, 4
• Less common than chronic presentations but requires immediate TDF interruption 3

Protease Inhibitor Nephrotoxicity

Interstitial Nephritis and Crystal Nephropathy

• Atazanavir and indinavir most commonly implicated 1
• New-onset eGFR decline with or without proteinuria 1
• Nephrolithiasis (kidney stones) particularly with atazanavir and indinavir 1
• Other protease inhibitors implicated in case reports 1

Chronic Kidney Disease Progression

• Atazanavir and lopinavir/ritonavir linked to rapid eGFR decline and incident CKD in observational studies 1

Laboratory Findings

Essential Screening Parameters

Baseline and Ongoing Monitoring

• Serum creatinine with calculated eGFR (CKD-EPI equation preferred) 1
• Urinalysis for proteinuria, hematuria, and glycosuria 1
• Quantified proteinuria using spot urine protein:creatinine or albumin:creatinine ratio 1
• Serum phosphate in patients on TDF, especially if glycosuria detected 1

Important Caveat: Certain antiretrovirals alter creatinine handling without true kidney injury—dolutegravir, rilpivirine, ritonavir, and cobicistat cause average reductions in calculated creatinine clearance of 5-20 mL/min through inhibition of tubular creatinine secretion, not actual GFR decline 1

Specific Laboratory Patterns

TDF-Associated Tubulopathy

• Hypophosphatemia with elevated fractional excretion of phosphate 1, 2
• Normoglycemic glycosuria (pathognomonic for proximal tubular dysfunction) 2
• Low-molecular-weight proteinuria (tubular pattern) 1
• Metabolic acidosis (non-anion gap) from bicarbonate wasting in severe cases 2
• Hypokalemia may occur with Fanconi syndrome 5

Protease Inhibitor Toxicity

• Elevated serum creatinine with decreased eGFR 1
• Proteinuria (variable pattern) 1
• Hematuria particularly with nephrolithiasis 1

Clinical Risk Factors

High-Risk Populations Requiring Enhanced Monitoring 1

• Aging patients (cumulative toxicity increases with age)
• Advanced immunodeficiency (low CD4 counts)
• Diabetes mellitus
• Baseline CKD (eGFR <60 mL/min/1.73 m²)
• Prolonged TDF exposure
• Concomitant nephrotoxic medications, especially:
  • Ritonavir-boosted protease inhibitors with TDF 1, 2
  • Cobicistat (pharmacoenhancer) with TDF 1
  • NSAIDs 6
  • Didanosine with TDF 1

Monitoring Algorithm

Frequency of Assessment

Standard Risk Patients

• Baseline assessment prior to ART initiation (serum creatinine, eGFR, urinalysis, quantified proteinuria) 1
• 1-3 months after TDF initiation 3
• Every 6-12 months if stable 1, 3

High-Risk Patients (CKD, rapid eGFR decline, or risk factors)

• Every 3-6 months for eGFR 30-60 mL/min/1.73 m² 5
• 2-4 times per year for those on TDF with boosted protease inhibitors 1
• More frequent monitoring during hospitalization, especially with concomitant nephrotoxic medications 1

Threshold for Intervention

Discontinue or Switch from TDF When: 1, 5

• eGFR decreases >25% from baseline AND falls to <60 mL/min/1.73 m²
• Evidence of proximal tubular dysfunction (glycosuria, hypophosphatemia, increased phosphaturia)
• New-onset or worsening proteinuria
• Development of Fanconi syndrome 6

Management Considerations

Immediate Actions for Suspected Nephrotoxicity

• Review all medications for nephrotoxic agents and drug interactions 1
• Assess CKD risk factors (hypertension, diabetes, hepatitis C coinfection) 1
• Consider switching to tenofovir alafenamide (TAF) or abacavir if TDF-associated toxicity suspected 1, 5
• Discontinue atazanavir or lopinavir/ritonavir if protease inhibitor toxicity suspected; consider switching to darunavir 1

Critical Pitfall: Do not attribute all eGFR decline to ART—actively exclude other causes including HIV-associated nephropathy, immune complex glomerulonephritis, hypertensive nephrosclerosis, and diabetic nephropathy, as these are more common than drug toxicity 3, 7

TAF Considerations: While TAF has improved renal safety profile compared to TDF, postmarketing cases of renal impairment, proximal renal tubulopathy, and Fanconi syndrome have been reported with TAF-containing products, though often with confounding factors 6, 8