Venomous snakes belonging to the family Viperidae, Elapidae, Colubridae and Hydrophidae, produces snake venom in order to facilitate immobilization and digestion of prey, act as defense mechanism against threats. Venom contains zootoxins which is a highly modified saliva that is either injected via fangs during a bite or spitted. The modified parotid gland, encapsulated in a muscular sheath, present on each side of the head, below and behind the eye, have large alveoli which temporarily stores the secreted venom and later conveyed by a duct to tubular fangs through which venom is injected. Venoms are complex mixtures of more than 20 different compounds, mostly proteins and polypeptides, including proteins, enzymes and substances with lethal toxicity which are either neurotoxic or haemotoxic in action and exert effects on nervous/muscular impulses and blood components. Lots of research are directed to use venoms as important pharmacological molecules for treating various diseases like Alzheimer’s disease, Parkinson’s disease etc.

Bothrops are one of the most common medically important snakes found in Latin America. Its venom is predominantly hemotoxic and proteolytic, which means that local lesion (edema and redness) and hemorrhagic symptoms are recurrent in envenoming by this snake. Although hemorrhage is usually the major cause of death, snakebite-related acute kidney injury is another potentially fatal clinical complication that may lead to chronic kidney disease. The present review highlights the main studies on Bothrops venom-related acute kidney injury, including observational, cross-sectional, case-control and cohort human studies available up to December 2019. The following descriptors were used according to Medical Subject Headings (MeSH): on Medline/Pubmed and Google Scholar "acute kidney injury" or "kidney disease" and "Bothrops"; on Lilacs and SciELO "kidney disease" or "acute kidney injury" and "Bothrops". Newcastle-Ottawa quality assessment scale was used to appraise the quality of the cross-sectional and cohort studies included. The selection of more severe patients who looked for health care units and tertiary centers is a risk of bias. Due to the methodological heterogeneity of the studies, a critical analysis of the results was performed based on the hypothesis that the design of the included studies influences the incidence of acute kidney injury. Fifteen human studies (total participants 4624) were included according to stablished criteria. The coagulation abnormalities (hemorrhagic symptoms, abnormal fibrinogen and activated partial thromboplastin time) were associated with acute kidney injury in the most recent studies reported. The findings observed in this review provide up-to-date evidence about the acute kidney injury pathogenesis following Bothrops syndrome. Studies pointed out that coagulation abnormalities comprise the major pathway for acute kidney injury development. This review may improve patient management by primary healthcare providers, allowing earlier di The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated. Abstract Bothrops are one of the most common medically important snakes found in Latin America. Its venom is predominantly hemotoxic and proteolytic, which means that local lesion (edema and redness) and hemorrhagic symptoms are recurrent in envenoming by this snake. Although hemorrhage is usually the major cause of death, snakebite-related acute kidney injury is another potentially fatal clinical complication that may lead to chronic kidney disease. Severe kidney injury may also require renal replacement treatment (RRT) ranging from 0.7 to 75.0% of cases to maintain the homeostasis [ 5 , 6 , 8 - 11 ]. Moreover, hemotoxic snake venoms can provoke kidney abnormalities that contribute to chronic kidney diseases in developing countries [ 12 , 13 ]. Hence, this review focuses on the pathogenesis of Bothrops venom-related AKI, highlighting current studies under a perspective of clinical application. According to the literature, the main pathogenic mechanism of Bothrops venom-induced AKI is attributed to coagulation abnormalities [ 14 ]. BPPs: bradykinin-potentiating peptides; PLA 2 : phospholipase A 2 ; LAO: L-amino acid oxidase; CRISP: snake venom cysteine-rich secretory proteins [ 39 ]. (Reprinted with permission from: Cardoso KC, et al. A transcriptomic analysis of gene expression in the venom gland of the snake Bothrops alternatus (urutu). BMC Genomics. 2010;11:605.) SVMs degrade all types of extracellular matrix proteins, disrupt cellular matrix and adhesion, activate chemokines and cytokines, and cleave cell surface receptors. Moreover, they induce apoptosis of vascular adhesion cells. The renal cells exposed to Bothrops venom mimic the changes in the human body. The concentration of venom in the perfusion fluid was estimated according to the amount inoculated by Bothrops snakes in a person weighting 60 kg. Decreased renal vascular resistance is observed and can occur due to blockade of either [Na + ] and [Ca 2+ ] channels or opening of [K + ] channels [ 43 ]. Table 2. The hemodynamic changes in kidneys reported above ( Table 2 ) varied according to the snake species, but most cases presented a decrease in renal vascular resistance (RVR), glomerular filtration rate (GFR) and Hemorrhagins contained in venoms of some snakes such as Bothrops spp. [ 40 , 42 , 44 , 106 ] can cause this coagulopathy. Moura-da-Silva and Baldo [ 44 ] reported the presence of jararhagin, a metalloproteinase isolated from B. jararaca venom. The targets of jararhagin comprise the vascular endothelium, platelets, coagulation factors and other cell systems as inflammatory cells and their mediators [ 44 ]. The mechanism of AIN in snakebite seems to be secondary to the immunogenic effects of snake venom [ 113 ]. Severe renal failure with a prolonged clinical course is common [ 92 ] with the necessity of hemodialysis in most cases [ 113 ]. Interestingly, this clinical course was unusually prolonged when compared with tubular necrosis [ 112 ]. Low platelets and oliguric renal failure are prevalent, but urine sediment could not have anything remarkable, like eosinophiluria [ 112 , 113 ]. Few cases are reporting the occurrence of AIN [ 111 -114] and the majority of these were in Russell’s viper snake. Sitprija et al. The use of electronic medias may improve the early diagnosis [ 4 ]. The recognition of risk factors of AKI development following Bothrops snakebites leads to earlier measures which reduce the renal damage [ 5 , 6 , 8 , 61 , 63 , 70 , 95 ]. Some information suggested a positive correlation among AKI and age, body surface area, prolonged time before treatment, bite site, hospitalization time, snake age and amount of inoculated venom. High level of lactate dehydrogenase (LDH) and local bleeding were recently independently associated with AKI development [ 66 ].

Snakebite envenomation has become a global public health challenge due to the widespread distribution of venomous snakes. Snake venom, a complex mixture containing various bioactive components, exhibits distinct characteristics across different families. The core toxic components of snake venom are mainly Three-Finger Toxins (3FTxs), phospholipase A2(PLA2), and proteases, which together form the material basis of the venom's multidimensional toxicity. Through synergistic effects, they activate common pathological pathways, enabling targeted disruption of multiple human organs., leading to acute injury and even multi-organ failure. Beyond the acute effects, some survivors may experience long-term sequelae such as chronic kidney disease or permanent musculoskeletal damage. Existing research suggests that snake venom may have modulatory effects on the immune system, however, the relevant evidence primarily comes from <i>in vitro</i> experiments or animal models, and its clinical significance requires further validation. In clinical management, treatment for snake envenomation involves immediate wound care, prompt medical attention, and rapid diagnosis to identify the snake species for the timely administration of specific antivenom, and a multidisciplinary collaborative treatment model. Moreover, adjunctive drug therapy is often necessary. Nevertheless, traditional antivenoms still face challenges in addressing local tissue damage and ensuring accessibility in resource-limited regions. This narrative review focuses on three major toxin families of snake venom toxins, analyzing their molecular characteristics and synergistic mechanisms to elucidate how these toxins induce systemic damage affecting the cardiovascular, neurological, and renal systems. It thereby reveals that multi-organ injury caused by snake venom is not an isolated event but rather a systemic process driven by the interplay and synergy of multiple common pathological pathways. This systematic analysis s Compared with previous reviews, the novelty of this framework lies in its departure from the traditional approach of describing organ damage in isolation; instead, it defines multi-organ injury for the first time as a systemic process driven by shared pathological pathways with mutual reinforcement, thereby directly pointing to a fundamental shift in clinical treatment strategies. The multidimensional toxicity of snake venom stems from compositional differences in venom composition among snakes of various families. Elapidae venoms are predominantly neurotoxic, Viperidae venoms are primarily hemotoxic ( Table 1 ), while Colubridae venoms exhibit evolutionary diversity. Notably, the toxin spectra of these two families are not entirely discrete—certain phospholipases A2 in viper venoms can display neurotoxicity ( Osip et al., 2023 ), whereas components of colubrid venoms may exhibit either elapid-like (neurotoxic) or viperid-like (hemotoxic) characteristics depending on the species ( McGivern et al., 2014 ). This toxin spectrum feature, characterized by a clear foundational framework and mutually permeable boundaries, constitutes the core basis of the multidimensional snake venom toxicity and provides an entry point for understanding the complex clinical manifestations of simultaneous involvement of multiple systems (e.g., neurological, circulatory, and renal) following snakebite. TABLE 1 Differences in venom of snake species in the families Elapidae and Viperidae. Phosphodiesterases (svPDEs) are present in the venom of almost all snake families; although their content is low, they exert auxiliary toxicological effects. The clinical pathological damage caused by these toxins, particularly local tissue destruction and systemic hemorrhage following viperid snakebites, is closely associated with their action ( Seneci et al., 2021 ; Alangode et al., 2020 ; Rudresha et al., 2020 ). Mechanism of multi-organ damage induced by snake venom When snake venom enters the human body, the toxic components rapidly disseminate through the bloodstream, triggering a complex and systemic pathophysiological process ( Gamulin et al., 2025 ; Si et al., 2023 ). Infographic diagram showing the progression of snakebite envenomation beginning with venom injection, local absorption into tissue, systemic entry into blood vessels, triggering direct cytotoxicity, systemic inflammation, coagulopathy, and hemodynamic instability, leading to multi-organ injury including cardiovascular, neural, and renal injury. 3.1. Damage mechanism of snake venom to cardiovascular system The cardiovascular system is one of the primary targets of snake venom attack. This not only forms the basis of hemorrhage in the cardiovascular system but also acts as the initiating factor for microvascular injury in the kidneys, while simultaneously potentially disrupting the blood-brain barrier and exacerbating nerve damage. Concurrently, some snake venoms can directly activate the complement system, releasing anaphylatoxins and recruiting inflammatory cells to infiltrate multiple organs, thereby amplifying tissue damage. Regarding the coagulation system, disseminated intravascular coagulation (DIC) not only affects the cardiovascular system but also contributes to multi-organ dysfunction by forming microthrombi that block the glomeruli and the small vessels supplying nerves. Furthermore, snake venom components induce cell death via free radical generation, with this oxidative stress-apoptosis mechanism being consistently demonstrated in cardiomyocytes, renal tubular epithelial cells, and neurons. These mechanisms are interwoven and collectively explain why snakebites often manifest a systemic cascade of multi-organ failure: initial local tissue damage triggers systemic inflammation and coagulation activation, leading to shock and reduced renal perfusion, which in turn exacerbates organ ischemia, creating a vicious cycle. This demonstrates that multi-organ damage caused by snake

Around the world, snake bite envenomation remains an underreported human health hazard. Envenomation can cause local and systemic complications, especially when there is a lack of antivenom availability. Although there are established guidelines regarding snake bite management acute care, there is a paucity of data regarding surgical intervention and the plastic surgeon's role treating this unique patient population. A review was conducted identifying relevant published articles involving snake bite management and treatment in PubMed and EMBASE. One hundred ten articles were identified and 77 met inclusion criteria. Snake bite envenomation can result in complications that are dependent upon a variety of variables. The literature has shown the best field treatment to be timely transportation to the nearest medical facility, along with antivenom administration. The cytotoxic, hemotoxic, and neurotoxic effects of venom can cause a variety of local soft tissue and systemic complications. Surgical interventions such as fasciotomies, wound debridements, skin grafts, and tissue flaps may be necessary in these patients to optimize functional and aesthetic outcomes. Disparities in access to care in resource limited settings are discussed. Global health disparities and insufficient antivenom distribution create an inequality of care in snake bite patients. Plastic surgeons have an important role in managing acute and chronic complications of snake bite envenomations that can lead to improved patient outcomes. The cytotoxic, hemotoxic, and neurotoxic effects of venom can cause a variety of local soft tissue and systemic complications. Surgical interventions such as fasciotomies, wound debridements, skin grafts, and tissue flaps may be necessary in these patients to optimize functional and aesthetic outcomes. Disparities in access to care in resource limited settings are discussed. Conclusions: Global health disparities and insufficient antivenom distribution create an inequality of care in snake bite patients. Plastic surgeons have an important role in managing acute and chronic complications of snake bite envenomations that can lead to improved patient outcomes. If patient presents with skin ecchymosis or need for high dose antivenom, they should be looked at for early surgical intervention. Taieb et al 68 Randomized controlled trial 98 Evaluate current healthcare worker knowledge of treating snake bites before and after information course Statistically significant improvement in knowledge along with correction of common treatment myths. Tincu et al, 2017 69 Case report 1 Evaluate case of rattlesnake bite in which DVT and compartment syndrome developed If high clinical suspicion for CS, early intervention is needed to improve outcome in these patients. Yildrim et al, 2006 76 Retrospective review 20 Evaluate if plasmapheresis in snake bite patients is beneficial Plasmapheresis should be considered for treatment of snake bit management as it is safe and effective. Rapidly resolved hematologic parameters that were off. Yuenyongviwat et al, 2014 77 Review and case report 1 Evaluate Calcific myonecrosis in post snake bite patient 66-y-old patient who was bit by Malayan pit viper at 14 y old has had 10 y history of progressively enlarged mass in the left leg. Broke through the skin when became infected. Excision followed by antibiotics was treatment. The majority of articles were classified as below level II quality of evidence and included retrospective reviews, systematic reviews, and case reports. One meta-analysis was identified. Venom Common symptomatology can be identified across snake species. 3 Presenting symptoms of any envenomation can include generalized weakness, numbness, paresthesia, and pain. 79 A snake’s venom is composed of a variety of enzymes and proteins that are responsible for both local tissue damage and systemic manifestations. Each species has altering levels of gene expression that control which proteins and enzymes are expressed. 82 If local swelling, erythema, or pain are progressing, the affected extremity can be elevated as long as no systemic symptoms are present. 81 Importantly, the medical facility should be called in advance to allow enough time for the antivenom to be prepared or transferred as it is not universally stocked. 6 Antivenom is costly and not available in most low-middle income countries (LMICs). Common misconceptions about snake bite management abound. The use of a tourniquet, thought to reduce the return of venom to the central circulation, actually restricts essential blood flow to the affected tissue, increasing local edema and potentiating the venom’s local effects. Venom Primary Affect Effect at Cellular Level Clinical Symptoms Altered Laboratory Values Hemotoxic Metalloproteinases and other cytotoxic enzymes lyse membranes and cellular adhesions, leading to rubor, tumor, and tissue necrosis Tachycardia, petechia, confusion, vomiting, disseminated intravascular coagulation, acute renal failure, shock and compartment syndrome Depleted fibrin levels, anemia (intravascular hemolysis, thrombocytopenia, elevated BUN, elevated creatinine, elevated prothrombin time, elevated partial thromboplastin time Neurotoxic Inhibit neurotransmission signals in different ways to disrupt neurologic function. 5 , 45 55 , 68 This results in higher rates of secondary complications than seen in HICs, indicating even more of a need for plastic surgeons to treat the resulting sequelae in this patient population. Efforts in LMICs should be focused on envenomation education as treatment myths can potentiate local effects of the venom’s cytotoxic enzymes, worsening local tissue injury, and patient outcomes. Although antivenom availability can be limited in LMICs, receiving treatment at a healthcare facility should be encouraged. Plastic surgeons are well suited to care for the acute and chronic management of snake bite victims through reconstructive procedures.

More than 5 million people are bitten by venomous snakes annually and more than 100,000 of them die. In Europe, one person dies due to envenomation every 3 years. There is only one venomous snake species in Lithuania--the common adder (Vipera berus)--which belongs to the Viperidae family; however, there are some exotic poisonous snakes in the zoos and private collections, such as those belonging to the Elapidae family (cobras, mambas, coral snakes, etc.) and the Crotalidae subfamily of the Viperidae family (pit vipers, such as rattlesnakes). Snake venom can be classified into hemotoxic, neurotoxic, necrotoxic, cardiotoxic, and nephrotoxic according to the different predominant effects depending on the family (i.e., venom of Crotalidae and Viperidae snakes is more hemotoxic and necrotoxic, whereas venom of Elapidae family is mainly neurotoxic). The intoxication degree is estimated according to the appearance of these symptoms: 1) no intoxication ("dry" bite); 2) mild intoxication (local edema and pain); 3) moderate intoxication (pain, edema spreading out of the bite zone, and systemic signs); 4) severe intoxication (shock, severe coagulopathy, and massive edemas). This topic is relevant because people tend to make major mistakes providing first aid (e.g., mouth suction, wound incision, and application of ice or heat). Therefore, this article presents the essential tips on how first aid should be performed properly according to the "Guidelines for the Management of Snake-Bites" by the World Health Organization (2010). Firstly, the victim should be reassured. Rings or other things must be removed preventing constriction of the swelling limb. Airway/breathing must be maintained. The bitten limb should be immobilized and kept below heart level to prevent venom absorption and systemic spread. Usage of pressure bandage is controversial since people usually apply it improperly. Incision, mouth suction, or excision should not be performed; neither a tourniquet nor ice or heat should be applied. A doctor must monitor respiratory rate, blood pressure, heart rate, renal function, fluid balance, and coagulation status. The only specific treatment method is antivenin--serum with antibodies against antigens of snake venom. Antivenins against pit vipers used in the United States are Antivenin Crotalidae Polyvalent (ACP) and a more purified and hence causing less adverse reactions--Crotalidae Polyvalent Immune Fab (CroFab). In Europe, a polyvalent antiserum against Viperidae family snakes (including the common adder) can be used. Antivenins often may cause severe hypersensitivity reactions because of their protein nature. The bite of the common adder (the only poisonous snake in such countries as Lithuania and Great Britain) relatively rarely results in death; thus, considering the risk of dangerous reactions the antivenin causes itself, the usage of it is recommended to be limited only to life-threatening conditions.