Zahed Karimi
1 
, Fariba Jafari Khabaz
2 , Elham Kebriyaei
3 , Ahmadreza Maghsoudi
4 , Feruza Djalolova
5 , Karimov Zafar
6 , Dilbar Kurbanova
7 , Tolliboyeva Marjona
8 , Abdulloev Mukhriddin
9 , Naeem Nikpour
10* 1 Department of Internal Medicine, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
2 Department of Nursing, Faculty of Nursing and Midwifery, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
3 Clinical Research Development Unit, Valiasr Hospital, Fasa University of Medical Sciences, Fasa, Iran
4 Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
5 Department of Oncology, Andijan State Medical Institute, Andijan, Uzbekistan
6 Department of Radiation Diagnostics and Therapy, Samarkand State Medical University, Samarkand, Uzbekistan
7 Department of Children’s Diseases, Tashkent State Medical University, Tashkent, Uzbekistan
8 Fergana Medical Institute of Public Health, Fergana, Uzbekistan
9 Department of Infectious Diseases and Infectious Diseases of Children, Bukhara State Medical Institute named after Abu Ali ibn Sino, Bukhara, Uzbekistan
10 Department of Hematology and Medical Oncology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
Abstract
Malignancy-associated hypercalcemia represents a severe metabolic complication frequently observed in advanced renal cell carcinoma (RCC), often precipitating acute kidney injury (AKT) and limiting therapeutic options. Though systemic volume depletion and renal vasoconstriction contribute to renal disturbance, direct tubular toxicity mediated by intrinsic mitochondrial dysfunction remains underexplored. This review discusses on mechanistic framework linking excessive extracellular calcium load to renal tubular epithelial failure. Hypercalcemia induces profound intracellular calcium overload within proximal tubular cells, triggering mitochondrial calcium uniporter activation. Consequently, mitochondrial membrane potential collapses due to permeability transition pore opening, effectively uncoupling oxidative phosphorylation. This bioenergetic crisis generates excessive reactive oxygen species (ROS), promoting lipid peroxidation, protein oxidation and DNA damage. Simultaneously, cytochrome c release initiates apoptotic cascades, whereas severe ATP depletion triggers necrotic cell death. The resulting tubular obstruction, cast formation, and inflammation exacerbate glomerular filtration rate loss. Furthermore, tumor-derived factors like parathyroid hormone-related protein (PTHrP) may sensitize mitochondria to calcium-induced stress, amplifying injury. Dysregulated mitochondrial dynamics, including fission and fusion imbalance, further compromise cellular resilience against calcium stress. Identification this pathway highlights mitochondria as critical therapeutic targets beyond standard hydration and bisphosphonates. Interventions stabilizing mitochondrial integrity, modulating calcium handling, or scavenging ROS could mitigate tubular injury. Eventually, deciphering these molecular events offers novel strategies to preserve renal function in patients with advanced renal cancer suffering from hypercalcemic crises. Such approaches may significantly improve survival outcomes and enable continued systemic therapy, addressing a critical unmet need in oncology nephrology where renal preservation dictates treatment eligibility and quality of life during palliative care.
Implication for health policy/practice/research/medical education:
Malignancy-associated hypercalcemia frequently complicates advanced renal cancer, driving acute kidney injury (AKT) through distinct mechanistic pathways involving cellular energy failure. Elevated serum calcium induces renal vasoconstriction and direct tubular toxicity, mediated by severe mitochondrial dysfunction. Excessive intracellular calcium overload disrupts mitochondrial membrane potential, triggering oxidative stress and impairing ATP production essential for cellular homeostasis. This bioenergetic failure compromises proximal tubular integrity, leading to widespread cell death by apoptosis and necrosis. Consequently, glomerular filtration rate deteriorates sharply, exacerbating uremic toxicity. Calcium crystals within tubules exacerbate obstruction and inflammation, creating vicious injury cycles. This framework highlights mitochondria as critical hubs linking systemic hypercalcemia to tubular injury. Recognizing this pathway is vigorous for developing targeted therapies beyond standard hydration and bisphosphonates. Protecting mitochondrial function could mitigate AKT severity, improving overall outcomes in patients with advanced renal malignancies. Eventually, addressing calcium-mediated mitochondrial toxicity offers a promising strategy to preserve renal function during aggressive cancer progression.
Please cite this paper as: Karimi Z, Jafari Khabaz F, Kebriyaei E, Maghsoudi A, Djalolova F, Zafar K, Kurbanova D, Marjona T, Mukhriddin A, Nikpour N. Mitochondrial dysfunction and renal tubular injury in malignancy-associated hypercalcemia; a mechanistic framework for acute kidney injury in advanced renal cancer. J Nephropathol. 2026;15(4):e28722. DOI: 10.34172/jnp.28722.