Mark Perazella, MD
Yale University

Proximal Tubular Damage

1. Tenofovir: protienuria and rapid decline of kidney function (VHA database).
2. Elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate: (new HIV drug): Once daily dose. Two phase 3 trials showed that adverse renal effects were higher than other tenofovir -containing drugs, and Fanconi syndrome and AKI were described.
3. Animal studies showed that tenofovir is a mitochondrial toxin. Herlitz et al KI paper in 2010 showed that mitochondrial injury occurred in patients treated with tenofovir. 50% had CKD.
4. Why proximal tubule?: because where the drug is secreted. Underlying CKD, endogenous competition of transport, transporter mutations and increased mitochondrial sensitivity might all be risk factors (KI 2010, Perazella)
5. Deferasirox: oral iron chelator used for iron overload state. Increased serum creatinine in 38% of phase 2/3 trials were reversible with drug discontinuation. Case reports noted Fanconi syndrome in 11 patients and 2 with AKI and 2 with AIN. Vacuolization of proximal tubular cells and via binding iron. By reducing mitochondrial iron, reduces ATP and causes cell injury. Studies  in rats showed ATN with dose dependence of this drug. Caspase-3 and 7 activation lead to cell death. It enters cell via BL membrane, binds iron and depletes ATP, and causes cell death.

Osmotic Nephropathy

1. Hetastarch: Volume expansion with smaller volume. Their molecular weight is high 130-670 kDa and higher molar substitution. So higher the molar substitution and MW, the better is the volume expansion.
2. Excreted by kidneys: They accumulate, massively causing swollen vacuoles and tubular damage as these substances accumulate (Dickenmann et al AJKD, 2008), which is still evident 6 months after use of the agent. First described in kidney transplant patients and brain dead donors. Cochrane meta-analysis increased creatinine in septic patients. RRT and creatinine elevation were highest in 10% of patients treated with hydroxyethyl starch (Brunkhorst et al NEJM, 2008). Recently, hydroxyethyl starch 6% vs LR. More death, more RRT, and more AKI in patients treated with hydroxyethyl starch (Perner et al NEJM, 2012). Hence proven now that. Hydroxyethyl starch 6% vs saline: no difference in mortality but more RRT needed in hydroxyethyl starch (Myburgh et al NEJM, 2012).

Loop of Henle drug toxins

Bartter-like syndrome from aminoglycosides: interaction with CaSR in BL membrane causes decline in ROMK and Bartter-like syndrome. Sassen et al KI paper in 2006 showed that in rats showing lower dose causing reduced NKCC2 expression and leading to polyuria, sodium, potassium, magnesium, and calcium wasting. Higher dose leads to Fanconi syndrome and AKI, which is verified by studies in patients. Prospective study of 127 patients exposed to AG showed low potassium in 13%.

Cetuximab:

Monoclonal antibody against EGFR used in treating malignancies. Severe low magnesium. Panitumumab less severe. Cetuximab interacts with EGFR receptor in distal convoluted tubule and leadings to TRPM6 (magnesium channel) doesn’t get to apical membrane, leading to magnesium wasting, which has been  well shown in colorectal cancer trials.

Atazanavir:

Indinavir, MTX, acyclovir all have been noted cause crystal nephropathy. Atazanavir is a PI and can lead to stone formation and crystal formation, and many cases of AIN. Very similar to indinavir. Usually dehydrated patients, alkaline urine. Stones are pure atazanavir or mixed with calcium. Rod like crystals can also form on pathology (Silva et al AJKD, 2012).

Post by Dr. Kenar Jhaveri, eAJKD Blog Editor.

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