Tenofovir-induced renal and bone toxicity: report of two cases and literature review

Abstract

Tenofovir Disoproxil Fumarate (TDF) is one of the drugs in the initial first-line antiretroviral regimen for the treatment of hepatitis B and HIV infections. Despite its effectiveness and few adverse effects, it is related to renal and bone toxicity. We described two cases of HIV-positive middle-aged women who had been using TDF for two and four years (cases 1 and 2, respectively) and were admitted to the emergency room. Case 1 presented with metabolic ileum and diffuse bone pain while case 2 presented with bilateral coxo-femoral pain after a fall from standing height. Both cases had similar laboratory tests: hyperchloremic metabolic acidosis, hypophosphatemia, hypokalemia, hypouricemia and elevated plasma creatinine. In urinary exams, there was evidence of renal loss of electrolytes, justifying the serum alterations, in addition to glucosuria and proteinuria. The bone pain investigation identified bone fractures and reduced bone mineral density, together with increased levels of parathyroid hormone, alkaline phosphatase and vitamin D deficiency. These two cases illustrate the spectrum of adverse renal and bone effects associated with TDF use. TDF was discontinued and treatment was focused on correcting the electrolyte disturbances and acidosis, in addition to controlling the bone disease through vitamin D and calcium supplementation. The renal changes found in both cases characterized the Fanconi's syndrome, and occurred due to TDF toxicity to proximal tubule cells mitochondria. Bone toxicity occurred due to direct interference of TDF in bone homeostasis, in addition to vitamin D deficiency and phosphaturia resulting from tubulopathy. During the follow-up, both cases evolved with chronic kidney disease and in one of them, the Fanconi's syndrome did not revert. We emphasize the need to monitor markers of bone metabolism and glomerular and tubular functions in patients using TDF.

Figure 1. Image exams referring to clinical cases 1 (A and B) and 2 (C and D): (A) MRI of the hip with osteonecrosis of the right femoral head (white arrow); (B) CT of the chest showing an incomplete fracture of the fifth left costal arch (white arrow); (C) CT of the pelvis showing fractures with partial consolidation of the right femoral neck (white arrow) and left subtrochanteric (yellow arrow); (D) Postoperative control - pelvis X-ray.

Figure 2. Potential pathogenic mechanisms of TDF-induced bone and renal toxicity: (Ia) After entering the proximal convoluted tubule (PCT) epithelial cells by OAT1/OAT3 transporters, TDF triggers functional and structural abnormalities in mitochondria through the inhibition of DNA polymerase γ enzyme (Polγ), compromising mitochondrial DNA (mtDNA) synthesis and production of respiratory chain proteins. In this scenario, there will be a reduction in the supply of ATP to the cell, in addition to the generation of oxidative stress, leading to decreased basolateral Na/K-ATPase activity, interfering with the trafficking and endosomal recycling of apical membrane transporters in polarized epithelial cells. Furthermore, the release of proteins from mitochondria to the cytosol, including cytochrome c (CytC), will stimulate apoptosis via caspase-9 pathway and damage to the cellular DNA; (Ib) In the distal nephron, collecting duct (CD) cells can also be targeted for damage by TDF through reduced expression of aquaporin-2 (AQP-2) channels on the luminal surface. However, since there is no expression of OAT1/OAT3 in human CD cells, the mechanisms of entry into cells, as well as the reduction in the expression of AQP-2 in the luminal membrane are still unknown. The spectrum of kidney damage includes acute tubular necrosis, Fanconi’s syndrome and nephrogenic diabetes insipidus; (II) TDF interferes directly with bone homeostasis, stimulating osteoclastic differentiation, and indirectly through PCT epithelial cells damage, reducing the production of calcitriol that is responsible for the development of secondary hyperparathyroidism, and inducing phosphaturia and systemic acidosis by bicarbonaturia.