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Kidney injury in hand, foot, and mouth disease; focus on immune and metabolic dysregulation
Hojjat Eghbali Jelodar
1 
, Baharak Maddahi
2 , Faezeh Nesaei
3 , Mohammad Pourmahmoudian
4 , Elham Kebriyaei
5 , Shirin Taraz Jamshidi
6 , Ahmad Shajari
7 , Arsalan Afzal Toosi
8 , Ali Emadzadeh
9* 1 Department of Surgery and Orthopedic, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
2 Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3 Department of Nursing, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4 Department of Orthopedic Surgery, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
5 Clinical Research Development Unit, Valiasr Hospital, Fasa University of Medical Sciences, Fasa, Iran
6 Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
7 Department of Medicine, YMS.C., Islamic Azad University, Yazd, Iran
8 Department of Orthopedic and Trauma Surgery, Imam Hossein Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
9 Department of Internal Medicine, MMS.C., Islamic Azad University, Mashhad, Iran
Abstract
Hand, foot, and mouth disease (HFMD), primarily caused by enteroviruses, notably EV-A71 is typically a self-limiting childhood illness. However, severe cases, often linked to EV-A71, can manifest systemic complications, including acute kidney injury (AKI), which significantly increases morbidity and mortality. The neurological and cardiopulmonary involvement are well-recognized; however, renal impairment is increasingly documented but mechanistically underexplored. Several studies showed that AKI in severe HFMD is not merely a consequence of hypovolemia or shock but involves significant immune and metabolic dysregulation. A dysregulated host immune response, characterized by a cytokine storm, drives systemic inflammation and endothelial damage, potentially leading to acute tubular necrosis and glomerular dysfunction. Viral persistence or molecular mimicry may further exacerbate renal inflammation. Concurrently, metabolic disturbances are serious, like severe systemic inflammation induces insulin resistance, catabolism, and mitochondrial dysfunction in renal tubules. Electrolyte imbalances, lactic acidosis from tissue hypoperfusion or direct viral effects, and potential rhabdomyolysis-associated myoglobinuria contribute to renal stress and injury. The interaction of hyperinflammation and metabolic chaos disrupts renal hemodynamics, cellular energy production, and repair mechanisms. Therefore, recognizing the dual pathway in this disease is crucial, as it shifts management beyond fluid resuscitation towards targeted immunomodulation and meticulous metabolic support.
Keywords: Acute kidney injury,
Chronic kidney disease,
Endothelial damage,
Kidney injury,
Cytokine storm,
Rhabdomyolysis,
Reactive oxygen species,
Acute tubular necrosis,
Hand, foot, and mouth disease
Implication for health policy/practice/research/medical education:
The hand, foot, and mouth disease (HFMD) is typically self-limiting disease. In severe cases, which is often linked to enterovirus A71, can trigger acute kidney injury (AKI), contributing to poor outcomes. Emerging evidence implicates profound immune and metabolic dysregulation as central mechanisms beyond direct viral cytopathy. A dysregulated host immune response, characterized by excessive pro-inflammatory cytokine release, drives systemic inflammation and endothelial damage, potentially leading to renal hypoperfusion, microthrombosis, and direct tubular injury. Concurrently, metabolic disturbances, including severe lactic acidosis and electrolyte imbalances from systemic stress and neurogenic pulmonary edema, further impair renal perfusion and function. This immune-metabolic axis creates a vicious cycle, exacerbating AKI. Identification of the intertwined pathways is crucial for identifying at-risk patients and developing targeted interventions beyond supportive care to mitigate renal complications in severe HFMD.
Please cite this paper as: Eghbali Jelodar H, Maddahi B, Nesaei F, Pourmahmoudian M, Kebriyaei E, Taraz Jamshidi Sh, Shajari A, Afzal Toosi A, Emadzadeh A. Kidney injury in hand, foot, and mouth disease; focus on immune and metabolic dysregulation. J Renal Inj Prev. 2026; x(x): e38758. doi: 10.34172/jrip.38758.