Which antiretroviral agents are most commonly associated with an increase in serum creatinine?

Antiretroviral Drugs Causing Elevated Serum Creatinine

The antiretrovirals most commonly associated with increased serum creatinine fall into two distinct categories: those causing true nephrotoxicity (tenofovir disoproxil fumarate, atazanavir, lopinavir/ritonavir) and those causing benign creatinine elevation through inhibition of tubular secretion (integrase inhibitors dolutegravir and bictegravir, and the pharmacokinetic booster cobicistat). 1

Agents Causing True Nephrotoxicity

Tenofovir Disoproxil Fumarate (TDF)

• TDF is the most clinically significant nephrotoxic antiretroviral, causing cumulative kidney damage in approximately 1-2% of recipients who develop treatment-limiting tubulopathy. 1
• TDF causes subclinical proximal tubular dysfunction (proteinuria, phosphaturia), decreased eGFR, and in severe cases can progress to Fanconi syndrome with osteomalacia and pathological fractures. 1
• Risk is substantially amplified when TDF is co-administered with ritonavir-boosted protease inhibitors or cobicistat, which increase tenofovir plasma concentrations. 1, 2
• Additional risk factors include aging, immunodeficiency, diabetes, prolonged exposure, and concomitant use of didanosine. 1
• TDF should be avoided in patients with CKD, rapid eGFR decline (>3-5 mL/min/1.73 m² per year), or high CKD risk; switch to tenofovir alafenamide (TAF) when available. 1

Protease Inhibitors

• Atazanavir and lopinavir/ritonavir are linked to rapid eGFR decline and incident CKD in observational cohorts. 1
• Atazanavir and indinavir are most commonly associated with interstitial nephritis and nephrolithiasis. 1
• Switching from ritonavir-boosted atazanavir or lopinavir to boosted darunavir has been associated with improved kidney function. 1

Agents Causing Benign Creatinine Elevation (Inhibition of Tubular Secretion)

Integrase Strand Transfer Inhibitors

• Dolutegravir raises serum creatinine by 0.1-0.15 mg/dL through inhibition of OCT2 transporter in the proximal tubule, blocking tubular secretion of creatinine without affecting true glomerular filtration. 1, 3, 4
• Bictegravir raises serum creatinine by approximately 0.1 mg/dL through the same mechanism. 1
• These increases occur early (within 4 weeks), plateau, and are non-progressive—they do not represent actual kidney injury. 3, 4, 5
• Raltegravir does NOT cause creatinine elevation and has the fewest drug interactions among integrase inhibitors. 1
• Elvitegravir requires cobicistat boosting, which itself raises creatinine (see below). 1

Pharmacokinetic Boosters

• Cobicistat raises serum creatinine by 0.1-0.15 mg/dL by inhibiting MATE1 transporter in the luminal membrane of proximal tubular cells. 1, 3, 4
• Cobicistat produces consistently higher serum creatinine increases compared to ritonavir in head-to-head trials. 6
• Ritonavir also inhibits creatinine secretion but to a lesser degree than cobicistat. 3

Additive Effects with Multiple Inhibitors

• Combining two or more inhibitors of creatinine tubular secretion (e.g., darunavir/cobicistat + dolutegravir and/or rilpivirine) produces additive creatinine elevation, with adjusted median Cr-eGFR decrease of -3.5 mL/min/1.73 m² at 48 weeks compared to single agents. 7
• Patients on multiple inhibitors are more likely to experience Cr-eGFR decreases ≥15 mL/min/1.73 m² (adjusted OR 3.233). 7

Clinical Algorithm for Interpretation

When serum creatinine rises after starting antiretrovirals:

1. Identify the timing: Early rise (within 2-4 weeks) that plateaus suggests benign inhibition of tubular secretion; progressive rise suggests true nephrotoxicity. 3, 4

2. Check which agents are involved:

   • Dolutegravir, bictegravir, cobicistat, or rilpivirine → expect 0.1-0.15 mg/dL benign rise 1, 3, 4
   • TDF (especially with boosted PIs) → suspect true nephrotoxicity 1, 2
   • Atazanavir or lopinavir/ritonavir → suspect true nephrotoxicity 1

3. Assess for true kidney injury:

   • Obtain urinalysis for proteinuria, serum phosphate, urine phosphate excretion, and check for normoglycemic glycosuria. 1, 4
   • If proteinuria, hypophosphatemia, or glycosuria present → true tubular dysfunction, likely TDF-related. 1, 4
   • If these are absent and creatinine rise is modest and stable → benign inhibition of secretion. 3, 4

4. Consider alternative GFR estimation: Serum cystatin C may better estimate true GFR in patients on creatinine secretion inhibitors, though it is not universally available. 1

Critical Monitoring Recommendations

• Baseline assessment: Calculate creatinine clearance using Cockcroft-Gault formula and obtain urinalysis before starting any tenofovir-containing regimen. 8
• Do not rely on serum creatinine alone—always calculate CrCl or eGFR, as serum creatinine can be misleading in patients with reduced muscle mass. 8
• For patients on dolutegravir, bictegravir, or cobicistat: Monitor monthly for the first 3 months, then quarterly. 4
• For patients on TDF with boosted PIs: Monitor renal function every 2-4 weeks initially, then every 3-6 months. 1, 4
• Discontinue TDF immediately if eGFR drops >25% from baseline to <60 mL/min/1.73 m², particularly with evidence of proximal tubular dysfunction. 8

Common Pitfalls to Avoid

• Do not discontinue dolutegravir or bictegravir for isolated creatinine rise of 0.1-0.15 mg/dL without evidence of true kidney injury—this represents benign inhibition of tubular secretion, not nephrotoxicity. 1, 3, 4
• Do not continue TDF in patients with CrCl ≤30 mL/min when alternatives (TAF, abacavir) are available. 8
• Do not use fixed-dose emtricitabine/TDF tablets when CrCl <30 mL/min, as the tablet cannot be split for dose adjustment. 8
• Do not overlook the increased risk when combining TDF with ritonavir-boosted PIs or cobicistat—this combination substantially increases tenofovir exposure and nephrotoxicity risk. 1, 2