How do you treat Antiretroviral Therapy (ART) nephrotoxicity?

Treatment of Antiretroviral Therapy (ART) Nephrotoxicity

The primary treatment for ART nephrotoxicity is immediate discontinuation or switching of the offending agent, with tenofovir disoproxil fumarate (TDF) requiring replacement with tenofovir alafenamide (TAF) or abacavir, and protease inhibitors like atazanavir or lopinavir/ritonavir requiring substitution with darunavir or other alternatives. 1

Immediate Management Steps

Discontinue or Switch the Offending Agent

• For TDF-associated nephrotoxicity: Switch to tenofovir alafenamide (TAF) or abacavir as first-line alternatives, as TDF discontinuation and switches to TAF have been associated with improved kidney function 1
• For protease inhibitor toxicity: Discontinue atazanavir or lopinavir/ritonavir and switch to ritonavir-boosted darunavir, which has been associated with improved kidney function 1, 2
• For acute kidney injury (AKI): TDF should be interrupted in all cases and either replaced with an alternative agent or ART should be interrupted altogether 3
• Recovery is typically observed within 3 months after switching from TDF to TAF, with 57.9% of patients recovering from renal dysfunction and significant improvement in tubulopathy 4

Review All Concomitant Medications

• Immediately discontinue or avoid concurrent nephrotoxic agents, particularly high-dose or multiple NSAIDs, as cases of acute renal failure requiring hospitalization and renal replacement therapy have been reported 5
• Ritonavir-boosted protease inhibitors, cobicistat, and didanosine significantly increase tenofovir exposure and nephrotoxicity risk and should be avoided or substituted 1, 2
• Consider alternatives to NSAIDs in patients at risk for renal dysfunction 5

Dose Adjustment Strategy

For Continued TDF Use (When Alternatives Unavailable)

When TDF must be continued due to lack of alternatives (such as in hepatitis B co-infection):

• eGFR 30-49 mL/min/1.73 m²: Reduce TDF dose to every 48 hours 5
• eGFR 10-29 mL/min/1.73 m²: Reduce TDF dose to every 72-96 hours 5
• Hemodialysis patients: Administer TDF every 7 days or after approximately 12 hours of dialysis (assuming 3 sessions weekly) 5
• eGFR <10 mL/min without hemodialysis: No dosing data available; TDF should be avoided 5

The FDA label specifies that dose adjustment should be considered when eGFR is <60 mL/min/1.73 m² (or <70 mL/min/1.73 m² with eGFR decline) 1, 5

Monitoring During Recovery

Laboratory Assessment Schedule

• Monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein on a clinically appropriate schedule 5
• In patients with chronic kidney disease, also assess serum phosphorus 5
• Evaluate for hypophosphatemia with elevated fractional excretion of phosphate, which is characteristic of TDF-associated tubulopathy 2, 6
• Check for normoglycemic glycosuria, proteinuria, and metabolic acidosis due to bicarbonate wasting, which indicate Fanconi syndrome 6

Clinical Monitoring

• Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may indicate proximal renal tubulopathy and should prompt immediate evaluation of renal function 5
• For atazanavir-associated nephrolithiasis or cholelithiasis, consider temporary interruption or discontinuation 7

Risk Factor Management

Address Modifiable CKD Risk Factors

• Aggressively manage hypertension and diabetes, as traditional CKD risk factors are of increasing concern with improved longevity among HIV-positive individuals 1
• Treat hepatitis B or C co-infection, which is associated with 2- to 3-fold increased risk of progressive CKD 1
• Monitor patients with advanced immunodeficiency more closely, as this is a risk factor for tubulopathy 1

High-Risk Populations Requiring Enhanced Monitoring

• Aging patients, those with diabetes mellitus, baseline CKD, prolonged TDF exposure, and those on concomitant nephrotoxic medications require more frequent monitoring 2, 6
• Patients with pre-existing renal impairment before switching to second-line ART may experience further decline and require closer surveillance 8

Special Considerations

When to Refer to Nephrology

• If kidney function does not improve after addressing reversible causes of renal failure, referral to a nephrologist is appropriate 3
• In severe CKD, timely referral for planning renal replacement therapy is recommended 3
• Consider discontinuation of atazanavir in patients with progressive renal disease 7

Drug-Drug Interactions

• Consult resources such as www.hiv-druginteractions.org, as several antiretrovirals induce or inhibit absorption, hepatic metabolism, and tubular excretion of co-administered medications 1
• The pharmacoenhancer cobicistat increases tenofovir exposure and may increase toxicity risk, though it is not well studied 1

Common Pitfalls to Avoid

• Do not dose reduce TDF for hyperbilirubinemia alone, as most patients experience asymptomatic increases in indirect bilirubin that are reversible upon discontinuation 7
• Do not continue TDF in settings where TAF, abacavir, and darunavir are available for patients with CKD, rapid eGFR decline (>3-5 mL/min/1.73 m² per year), or at high CKD risk 1
• Do not overlook alternative causes of AKI or CKD, as TDF as a cause is uncommon and clinicians should actively exclude other etiologies 3
• Atazanavir is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis 7