Treatment of Antiretroviral Therapy (ART) Nephrotoxicity

Immediate Management Steps

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, as recommended by the Kidney International guidelines 1, 2
For TDF-associated nephrotoxicity, switching to tenofovir alafenamide (TAF) or abacavir as first-line alternatives is recommended, as TDF discontinuation and switches to TAF have been associated with improved kidney function, according to the Kidney International guidelines 1, 2
For protease inhibitor toxicity, discontinuing atazanavir or lopinavir/ritonavir and switching to ritonavir-boosted darunavir is recommended, which has been associated with improved kidney function, as stated in the Kidney International guidelines 1

Aggressively managing hypertension and diabetes is recommended, as traditional CKD risk factors are of increasing concern with improved longevity among HIV-positive individuals, according to the Kidney International guidelines 1
Treating hepatitis B or C co-infection is recommended, which is associated with 2- to 3-fold increased risk of progressive CKD, as stated in the Kidney International guidelines 1
Monitoring patients with advanced immunodeficiency more closely is recommended, as this is a risk factor for tubulopathy, according to the Kidney International guidelines 1, 2

Consulting resources such as www.hiv-druginteractions.org is recommended, as several antiretrovirals induce or inhibit absorption, hepatic metabolism, and tubular excretion of co-administered medications, as stated in the Kidney International guidelines 1
The pharmacoenhancer cobicistat increases tenofovir exposure and may increase toxicity risk, though it is not well studied, according to the Kidney International guidelines 1, 2
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, as recommended by the Kidney International guidelines 1
Ritonavir-boosted protease inhibitors, cobicistat, and didanosine significantly increase tenofovir exposure and nephrotoxicity risk and should be avoided or substituted, as stated in the Clinical Infectious Diseases guidelines 3 and Kidney International guidelines 1

The American Academy of HIV Medicine and the International AIDS Society recommend that 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 4
The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest that low-level proteinuria without significant albuminuria (urinary albumin-to-protein ratio <0.4) is indicative of tubular rather than glomerular disease 4, 5
The European AIDS Clinical Society recommends monitoring for excessive phosphaturia with hypophosphatemia, which is a common finding in patients with TDF-associated nephrotoxicity 4, 6

The National Kidney Foundation recommends baseline and ongoing monitoring of serum creatinine with calculated eGFR (CKD-EPI equation preferred), urinalysis for proteinuria, hematuria, and glycosuria, and quantified proteinuria using spot urine protein:creatinine or albumin:creatinine ratio 7
The American College of Physicians suggests that hypophosphatemia with elevated fractional excretion of phosphate is a characteristic laboratory finding in TDF-associated tubulopathy 4, 6

The Centers for Disease Control and Prevention recommend that high-risk populations requiring enhanced monitoring include aging patients, those with advanced immunodeficiency, diabetes mellitus, baseline CKD, and those on concomitant nephrotoxic medications 4, 8
The Infectious Diseases Society of America suggests that ritonavir-boosted protease inhibitors with TDF, cobicistat, and didanosine with TDF are concomitant nephrotoxic medications that require careful monitoring 4, 6

The American Academy of HIV Medicine recommends reviewing all medications for nephrotoxic agents and drug interactions, assessing CKD risk factors, and considering switching to tenofovir alafenamide (TAF) or abacavir if TDF-associated toxicity is suspected 4, 5, 9
The European Renal Association suggests that discontinuing atazanavir or lopinavir/ritonavir and considering switching to darunavir may be necessary if protease inhibitor toxicity is suspected 4, 10