Tenofovir and Acidosis
Yes, tenofovir can cause metabolic acidosis, particularly through proximal tubular dysfunction (Fanconi syndrome) with bicarbonate wasting, and this risk is substantially elevated in patients with impaired renal function. 1, 2
Mechanisms of Acidosis
Tenofovir-induced acidosis occurs through two primary pathways:
Proximal renal tubular acidosis (most common): Tenofovir causes proximal tubular dysfunction manifesting as Fanconi syndrome, which includes bicarbonate wasting leading to normoglycemic glycosuria, hypophosphatemia, proteinuria, and metabolic acidosis 1
Lactic acidosis (rare but severe): The FDA warns that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogs including tenofovir 2. This occurs through mitochondrial toxicity, particularly when tenofovir levels accumulate 3, 4
Distal renal tubular acidosis (extremely rare): At least one case report documents distal RTA from tenofovir without renal impairment, presenting as non-anion-gap metabolic acidosis with positive urine anion gap 5
High-Risk Populations
Patients with impaired renal function face dramatically increased risk because:
- Tenofovir is principally eliminated by the kidney, and renal impairment leads to drug accumulation and elevated plasma concentrations 2, 3
- Concurrent use of ritonavir-boosted protease inhibitors or cobicistat significantly increases tenofovir exposure and nephrotoxicity risk 1, 6, 3
- Underweight patients are at higher risk due to relatively higher drug exposure 3
- Patients with baseline CKD, diabetes, hypertension, or on other nephrotoxic medications require enhanced monitoring 6
Clinical Presentation
Watch for these warning signs of tenofovir-induced acidosis:
Lactic acidosis symptoms: Weakness or unusual fatigue, unusual muscle pain, shortness of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, dizziness or lightheadedness, fast or abnormal heartbeat 2
Fanconi syndrome manifestations: Persistent or worsening bone pain, pain in extremities, fractures, muscular pain or weakness (these may indicate proximal renal tubulopathy) 2, 7
Laboratory findings: Non-anion-gap metabolic acidosis, hypophosphatemia with elevated fractional excretion of phosphate, normoglycemic glycosuria, proteinuria 1, 6, 5
Monitoring Requirements
The FDA and multiple medical societies recommend the following monitoring protocol:
Assess estimated creatinine clearance in all patients before initiating tenofovir and as clinically appropriate during therapy 2
For high-risk patients (those with renal dysfunction, on ritonavir-boosted protease inhibitors, or cobicistat): Monitor estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to initiation and periodically during therapy 1, 2
Twice-yearly monitoring is recommended for patients on tenofovir plus ritonavir or cobicistat 1
Monitor every 6-12 months if stable, with more frequent monitoring for those with established CKD (eGFR < 50 mL/min/1.73 m²) 8
Immediate Management
If acidosis develops, tenofovir must be discontinued immediately:
Suspend tenofovir treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity 2
For TDF-associated nephrotoxicity with acidosis, switch to tenofovir alafenamide (TAF) or abacavir as first-line alternatives 6
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 6
Discontinue ritonavir-boosted protease inhibitors, cobicistat, or didanosine if used concurrently, as these significantly increase tenofovir exposure and toxicity risk 6, 4
Prevention Strategies
To minimize acidosis risk:
Avoid tenofovir in patients with pre-existing kidney disease (baseline eGFR < 50 mL/min/1.73 m²) when alternatives exist 1, 8
Reduce tenofovir dose based on estimated creatinine clearance in patients with renal impairment 1, 2
Avoid concurrent use of other potentially nephrotoxic drugs, especially ritonavir-boosted protease inhibitors and cobicistat 1, 6
Avoid high-dose or multiple NSAIDs, as cases of acute renal failure have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir 2
Critical Pitfall
Fatal outcomes have been reported: A case of fatal lactic acidosis and acute renal failure occurred after adding tenofovir to a regimen containing didanosine in a patient with stable chronic renal insufficiency 4. Progressive drug accumulation and pharmacologic interactions causing increased didanosine levels led to increased mitochondrial toxicity. This underscores the absolute necessity of avoiding tenofovir-didanosine combinations and carefully monitoring renal function in all patients, particularly those with any degree of baseline renal impairment.