A historical perspective on ARV-associated kidney damage
The introduction of highly active antiretroviral therapy (HAART) revolutionized HIV treatment, transforming a fatal diagnosis into a manageable chronic condition. However, the increased lifespan has brought long-term drug-related toxicities, including those affecting the kidneys, into focus. Early research identified associations between certain antiretrovirals (ARVs) and renal impairment, though distinguishing between drug-induced damage and damage caused by the HIV infection itself (HIV-associated nephropathy, or HIVAN) proved challenging.
The most prominent example of an ARV linked to kidney issues is tenofovir disoproxil fumarate (TDF), a cornerstone of early HIV treatment. Studies of patients on long-term TDF-based therapy showed a statistically significant, albeit small, decline in estimated glomerular filtration rate (eGFR) and an increased risk of kidney events. Some of these effects were not always fully reversible upon discontinuation. This led to a significant shift in clinical practice toward using newer, safer drug options.
Mechanisms of antiretroviral nephrotoxicity
Not all ARVs affect the kidneys in the same way, and many modern drugs carry a minimal risk. The mechanisms of nephrotoxicity vary by drug class:
- Proximal Tubular Damage: The proximal tubules of the kidneys are responsible for reabsorbing nutrients and electrolytes. Older ARVs, particularly TDF, can accumulate in these cells, leading to mitochondrial damage and dysfunction. This can cause proximal tubulopathy, a condition characterized by wasting of electrolytes like phosphate and glucose in the urine (Fanconi syndrome).
- Crystal Formation: Certain protease inhibitors (PIs) and other drugs can form crystals that build up in the kidneys and urinary tract, potentially causing stones and obstruction. Indinavir and atazanavir are historical examples of ARVs associated with this issue.
- Acute Interstitial Nephritis (AIN): This is an inflammatory kidney reaction that has been reported with some ARVs like atazanavir, indinavir, and abacavir. It is often a reversible reaction, but can lead to acute kidney injury (AKI).
- Drug Interactions: Some ARVs, especially ritonavir, can boost the concentration of other drugs by inhibiting efflux transporters. This can increase the level of a drug like tenofovir in the kidney cells, magnifying its toxic effects. The newer boosting agent cobicistat can also raise levels, though clinical significance varies.
Comparison of tenofovir formulations
Tenofovir is a critical component of many HIV regimens and is available in two main prodrug formulations with different renal safety profiles. The shift from the older TDF to the newer tenofovir alafenamide (TAF) has been a major advancement in managing kidney safety.
| Feature | Tenofovir Disoproxil Fumarate (TDF) | Tenofovir Alafenamide (TAF) |
|---|---|---|
| Plasma Concentration | Higher | Significantly lower (86% lower) |
| Intracellular Concentration | High in renal tubules, leading to potential toxicity | High in target cells, but lower in plasma and kidney cells |
| Mechanism of Entry | Enters kidney cells via organic anion transporters (OAT1 and OAT3) | Not a substrate for OAT1/OAT3, preventing kidney cell accumulation |
| Associated Renal Risks | Risk of proximal tubulopathy, Fanconi syndrome, and eGFR decline | Lower risk of kidney toxicity and smaller changes in renal function markers |
| Effect on Kidney Function | Predictable small decrease in eGFR; potentially irreversible damage | No significant changes in eGFR beyond normal age-related declines observed in long-term studies |
| Risk Factors | Higher risk in older patients, those with comorbidities, or with boosted PIs | Can be used more safely in individuals with risk factors for kidney disease |
Risk factors and monitoring
While specific ARVs like TDF carry known risks, not every patient will develop kidney problems. Multiple factors contribute to an individual's overall renal risk:
- Pre-existing kidney disease: Patients with lower baseline kidney function (eGFR <60 mL/min) are at higher risk.
- Advanced HIV: Lower CD4 cell counts and higher viral loads are associated with increased kidney issues.
- Age and Gender: Older age is a significant risk factor, and some studies suggest differences between sexes.
- Comorbidities: Conditions like hypertension, diabetes, and hepatitis C coinfection greatly increase kidney disease risk.
- Concomitant Drugs: Using other nephrotoxic medications, such as NSAIDs, can increase risk.
Regular monitoring of kidney function is crucial for all people with HIV on ART, regardless of the regimen. Healthcare providers typically track serum creatinine to estimate GFR, check for proteinuria or albuminuria, and may monitor for tubular dysfunction. For patients on TAF-based regimens, monitoring is still recommended, especially if risk factors are present, but with less intensive focus on the drug's direct renal impact.
Management and advancements
When a patient experiences declining kidney function on an ARV regimen, the treatment plan can be adjusted. For those on TDF, switching to a TAF-based regimen is a common strategy to improve or stabilize kidney function. The shift away from TDF has significantly improved the long-term renal safety profile of HIV care.
For patients with significant kidney disease or end-stage renal disease (ESRD), ART dose adjustments are necessary to prevent drug accumulation. The use of older, more toxic drugs is generally avoided in this population, and newer, more renally safe options are prioritized. A comprehensive approach involving managing comorbidities like hypertension and diabetes is also critical for protecting kidney health.
Conclusion
While some older antiretroviral drugs, most notably TDF, carry a risk of causing kidney damage, modern HIV treatment has significantly improved renal safety. The advent of newer formulations like TAF has provided highly effective options with less impact on kidney function. For individuals with existing kidney issues or other risk factors, careful drug selection and regular monitoring are essential to prevent and manage kidney disease. As HIV continues to be a lifelong condition for many, ongoing vigilance and personalized care ensure that the benefits of potent ART are not overshadowed by long-term kidney complications. The overall outcome for kidney health in people with HIV on ART has improved, and ongoing research continues to refine treatment strategies to reduce risk further.
