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How does cART cause kidney disease?
cART involves multiple classes of agents, including protease inhibitors (PI), reverse transcriptase inhibitors, integrase strand inhibitors, and entry blockers.
Distinct syndromes are associated with certain classes of cART that must be kept in mind during the evaluation of each patient. PI can be associated with three main kidney side effects:
1. They can crystallize in the urinary tract and form either macroscopic stones, resulting in urinary obstruction (hydronephrosis), or they may crystallize inside the tubules, causing microtubular obstruction and ATN (no hydronephrosis).
2. They may lead to acute interstitial nephritis.
3. They inhibit the cytochrome P450 system, which may lead to nephrotoxicity from other drugs, especially in transplant patients on calcineurin inhibitors (CNI). In the presence of PIs, CNIs may need only once-a-week dosing due to impaired P450 metabolism.
Kidney Syndromes Associated With HAART
cART CLASS | REPRESENTATIVE DRUGS | KIDNEY SYNDROME(S) |
---|---|---|
Protease inhibitors | Indinavir, atazanavir, nelfinavir, saquinavir, ritonovir, amprenavir | Urolithiasis: obstructive uropathy, ATN Interstitial nephritis CKD |
Nucleoside reverse transcriptase inhibitors | Stavudine, zidovudine, didanosine, lamivudine | Mitochondrial cytopathy: hepatic steatosis, lactic acidosis, rhabdomyolysis, acute tubular necrosis |
Nucleotide reverse transcriptase inhibitors | Tenofovir, adefovir | Fanconi syndrome, ATN, CKD |
Integrase strand inhibitors | Raltegravir, Dolutegravir | — |
ATN , Acute tubular necrosis; CKD , chronic kidney disease.
Nucleaside reverse transcriptase inhibitors (NRTI) cause direct proximal tubular injury with tenofovir as the prototypic agent. Because the tubular injury is localized to the proximal tubule, a Fanconi syndrome may develop with typical Type II renal tubular acidosis and phosphaturia causing hypophosphatemia.
Long-term use of tenofovir may also lead to CKD with the development of irreversible interstitial fibrosis, especially in combination with PIs. CKD is now developing in 10% to 15% of long-term cART patients, and this growing global burden of CKD in this population is clinically important. HIV patients with CKD have the same increased mortality from cardiovascular disease as any CKD patient in the general population.
The development of a safer delivery form of tenofovir, called tenofovir alafenamide, instead of tenofovir disoproxil fumarate has significantly reduced the risk of nephrotoxicity of this agent, and may replace the previous version as the standard of care.