Role of heat shock proteins in renal function and adaptation to heat stress: Implications for global warming

Abstract

The escalating global temperature, with 2024 as the hottest year, emphasizes the critical link between climate change and kidney health. Extreme heat, a consequence of global warming, causes multifaceted effects on human physiology, including renal function alterations. This review investigates physiological and molecular mechanisms of heat stress-induced kidney injury, including acute kidney injury, chronic kidney disease (CKD), and urinary stone formation. It highlights how heat stress contributes to renal dysfunction via dehydration, electrolyte imbalances, and activation of the renin-angiotensin-aldosterone system and antidiuretic hormone pathways, particularly in vulnerable populations like outdoor workers, the elderly, and pregnant women. The review also emphasizes the roles of heat shock proteins (HSPs)-HSP27, HSP60, HSP70, and HSP90-in maintaining cellular integrity by preventing protein aggregation and repairing damaged proteins in renal tissues. Dysregulation of these proteins under prolonged heat stress is implicated in CKD progression. This review highlights the urgent need for targeted public health interventions: (1) Hydration; (2) Workplace cooling; (3) Community education; and (4) Developing pharmacological therapies targeting HSPs. A multidisciplinary approach involving nephrology, environmental science, and public health is essential to mitigate the increasing burden of heat-related kidney disease in the era of global climate change.

Key Words: Heat stress; Global warming; Acute kidney injury; Chronic kidney disease; Heat shock proteins

Core Tip: Heat stress is an emerging factor whose effect on renal dysfunction is increasingly being recognized, particularly through mechanisms such as dehydration, electrolyte imbalance, and neurohormonal activation. Identifying high-risk populations, such as outdoor workers, elderly individuals, and pregnant women, can facilitate early clinical interventions. Heat shock proteins (HSPs), especially HSP70 and HSP90, have demonstrated cytoprotective roles in renal cells and represent promising therapeutic targets. Integrating workplace modifications, hydration strategies, and HSP-based interventions, along with clearly defining the specific roles that different disciplines can play, may help mitigate heat-related kidney injury in the context of global warming.

INTRODUCTION

A stable core body temperature of 37 °C is vital for preserving homeostasis, ensuring optimal enzyme activity, and facilitating stable biochemical processes[1]. When the body temperature increases above the normal threshold, typically exceeding 38 °C-39 °C (fever or hyperthermia), the body activates compensatory mechanisms to dissipate heat, such as increased sweating and peripheral vasodilation[2]. Nevertheless, when the temperature escalates beyond 40 °C, severe effects on internal organs, particularly the kidneys, become evident. The kidneys play a vital role in maintaining water and electrolyte balance and eliminating toxins. Elevated body temperatures reduce renal perfusion due to vasoconstriction, resulting in a decreased glomerular filtration rate (GFR), increased risk of developing acute kidney injury (AKI), and electrolyte imbalances such as hyperkalemia or sodium loss through excessive sweating. Furthermore, heat stress and inflammatory processes can damage renal cells, causing the accumulation of toxic substances in the bloodstream. On a systemic level, elevated body temperature can trigger multiorgan dysfunction, including disruption of homeostasis and excessive production of inflammatory cytokines, further exacerbating kidney damage and impairing other organ systems. Therefore, controlling body temperature and prioritizing kidney protection are vital in managing cases of severe hyperthermia.

Recently, the world has experienced a series of unprecedented heat waves across continents, largely driven by climate change. Since 1981, global temperatures have increased at an approximate rate of 0.2 °C per decade[3]. By 2024, the planet recorded the hottest year in history since 1850, with an average global temperature of 15.10 °C (0.12 °C higher than the previous record in 2023). The decade leading to 2024 has been the warmest ever recorded, with global land and ocean surface temperatures increasing by +0.95 °C compared with historical averages. This relentless increase in temperature disrupts the ability of the body to effectively regulate heat, resulting in heat stress. Such conditions exert diverse adverse effects on bodily systems, including immune function and overall health, with significant effects on renal function. Elevated temperatures exacerbate heat stress and substantially contribute to renal dysfunction[4-6]. In the context of research investigating kidney adaptation and regulation under thermal stress, substantial evidence from both human and animal studies indicates that exposure to high temperatures induces cellular stress in the kidneys[7-9].

A study conducted in Adelaide, South Australia, by Borg et al[10] revealed 83519 emergency department visits and 42957 hospitalizations due to temperature-related conditions over 10 warmer seasons. Increasing daily temperatures were a major factor for hospital admissions, predominantly for kidney-related diseases such as AKI, chronic kidney disease (CKD), and kidney stones[10]. Similarly, a study in Brazil reported that for every 1 °C increase in average temperature, the risk of hospitalization due to kidney disease increased by 0.9%[11]. Another study in the Greater Madrid area of Spain also confirmed a correlation between extreme heat waves and increased kidney-related hospitalizations[12]. International studies also corroborate these findings[13-15]. In the United States, numerous heat-related deaths have been reported, including among migrants along the United States-Mexico border. In Mexico alone, over 200 deaths have been attributed to extreme heat. Countries such as Spain, Italy, Greece, Cyprus, Algeria, and China have also reported fatalities related to high temperatures, along with a remarkable increase in hospitalizations due to heat-related illnesses. Large segments of the population in Italy and Spain, as well as more than 100000000 people in the southern United States, are currently under high-temperature advisories[16].

Agricultural workers are considered one of the most vulnerable groups to the adverse health effects of increasing global temperatures[17,18]. The mortality rate from heat-related illnesses in this group is 20 times higher than that in the general civilian workforce in the United States. Workers engaged in strenuous activities under temperatures > 35 °C are at considerable risk of heat stress[19]. Moreover, occupations such as welders, blacksmiths, foundry workers, and firefighters often involve outdoor environments with high ambient temperatures, radiant heat, and physical exertion. The use of protective clothing, although necessary, prevents sweat evaporation and normal heat dissipation, exacerbating their susceptibility to heat stress[20].

A case-crossover study of outdoor construction workers reported that each 1 °C increase in daily maximum humidity elevated the risk of accident-related injuries by 0.5% [adjusted odds ratio: 1.005 (95%CI: 1.003-1.007)][21]. Exposure to high temperatures and dehydration due to work demands have also been related to CKD of unknown origin in agricultural communities in hot regions, including Central America and Southeast Asia[22,23]. Additionally, agricultural workers in hot conditions face an increased risk of workplace injuries due to increased fatigue, reduced alertness, impaired psychomotor functions, and diminished concentration[24,25].

Heat shock proteins (HSPs) are a family of ubiquitous proteins found in a wide range of tissues across almost all organisms[26]. Discovered by Ritossa[27,28] in the 1960s in Drosophila melanogaster, HSPs play a vital role in protecting cells from various stressors, including high temperatures, chemicals, and other physiological pressures[29,30]. HSPs are classified into different groups based on their molecular weight, including HSP90, HSP70, HSP60, HSP40, and small HSPs[26,30]. These proteins primarily function as molecular chaperones, helping in maintaining cellular integrity and metabolic processes, thereby reducing stress and preserving homeostasis[31].

Studies have emphasized the crucial role of HSP27 in protecting the kidneys under adverse conditions, particularly in proximal tubular cells and collecting ducts in the renal medulla[32,33]. In addition to HSP27, HSP60 plays a remarkable role in protecting nephrons and improving the heat tolerance of the kidneys. HSP60 is predominantly expressed in the renal cortex and the corticomedullary junction, contributing to renal defense mechanisms under extreme conditions[34]. Exposure to high temperatures induces increased expression of HSP90, not only in the kidneys but also in the heart and central nervous system[35]. Both HSP70 and HSP90 are closely associated with the ability of the body to tolerate dehydration[36]. Recent research has shown that HSP90 can mitigate AKI by regulating antiapoptotic and autophagic pathways, specifically the pyruvate kinase type M2/protein kinase B and hypoxia-inducible factor-1α/BCL2-interacting protein 3 (BNIP3)/BNIP3 L pathways. This indicates that HSP90 plays a dual role: Where it not only protects renal cells but also orchestrates complex biochemical mechanisms under heat stress conditions[37].

Not only in Viet Nam but also worldwide, there remains a paucity of research on the effect of renal function in the context of increasing temperatures associated with climate change, especially as 2024 has been officially recognized as the hottest year on record. Therefore, this review focuses on the effects of heat stress induced by global climate change on renal function, emphasizing the relationship between climate change and the risk of kidney injury, particularly among vulnerable populations, through a comparative analysis of clinical features, investigative findings, manifestations, and prognostic implications. Although previous studies have documented the relationship between heat stress and kidney injury related to HSPs such as HSP27, HSP60, HSP70, and HSP90, the underlying pathophysiological mechanisms and specific roles of these HSPs are being discussed. This review aims to clarify the biological effects of HSPs on heat-induced kidney injury, with a particular emphasis on their role in regulating inflammatory responses and tubular epithelial cell damage. Remarkably, HSP70 has been demonstrated to protect renal cells from heat-induced apoptosis and mitigate thermal injury, an area that remains underexplored in previous reviews.

MOLECULAR STRUCTURE AND CANONICAL ROLES OF HSPS IN RESPONSE TO HEAT STRESS

HSPs constitute a highly conserved family of proteins essential for cellular stress response and cytoprotection, particularly within the renal system, where they maintain cellular homeostasis and structural integrity under diverse stressors, including thermal stress, toxic insults, and oxidative stress. Acting as molecular chaperones, HSPs facilitate appropriate protein folding and mitigate misfolded protein aggregation, a critical function in the densely packed renal cellular environment[38]. Upon cellular stress, HSP expression is upregulated, enabling damaged protein repair and degradation, a response indispensable for cell survival, especially in the kidneys, which are constantly exposed to potentially harmful substances filtered from the bloodstream.

Small HSPs, a subgroup predominantly located in the cytosol, lack an ATPase domain and are characterized by a conserved α-crystallin domain (ACD) flanked by variable N-terminal domains (NTDs) and C-terminal domains (CTDs). These small proteins (12-43 kDa) stabilize injured proteins, preventing misfolded protein interactions and aberrant aggregation by interacting with exposed hydrophobic residues[39].

Extensive research has revealed the dual protective and pathological roles of HSPs in kidney disease. For instance, in ischemic kidney injury, HSPs contribute to cell viability by stabilizing cellular architecture and function and inhibiting apoptosis, a programmed cell death mechanism[38,40]. Conversely, in CKDs, such as cystic kidney disease and renal malignancies, HSPs may promote cell proliferation, potentially exacerbating disease progression[41]. Extracellular HSPs can also modulate immune responses, potentially contributing to kidney injury in specific contexts. Further contributing to cellular survival during stress, particularly relevant in CKD, HSPs regulate the dynamics of stress granules[42]. Studies have also emphasized the protective role of HSPs against kidney injury due to physical exertion in heat[43]. HSPs, including HSP70 and HSP90, maintain renal cellular proteostasis by facilitating protein folding and preventing aggregation. The heat shock response, mediated by heat shock factors, upregulates HSPs, which protect renal cells by stabilizing proteins, reducing oxidative stress, and inhibiting apoptosis. Damaged proteins are degraded via the ubiquitin-proteasome pathway, thereby preserving the function of nephrons[38].

HSPs exhibit complex, context-dependent roles, acting as chaperones and antiapoptotic modulators in response to proinflammatory and prooxidative stress. Intracellular and extracellular HSPs exhibit distinct functions during injury[44], with extracellular HSPs acting as agonists for toll-like receptors (TLRs) and damage-associated molecular patterns (DAMPs), and intracellular HSPs appearing to decrease inflammation and inhibit the production of reactive oxygen species (ROS)[45]. Studies suggest a complex interplay; i.e., when HSPs induce inflammation, cytoprotection is promoted; conversely, when inflammation activates HSPs, cell death is promoted[45]. This intricate balance of HSP expression and function in the kidneys remains an active research area, crucial for developing therapeutic strategies that harness their protective effects while minimizing potential detrimental effects, such as selective activators of specific HSPs to inhibit cell proliferation and fibrosis in CKD.

HSP27

HSP27, a member of the small HSP family (12-43 kDa), is a multifunctional protein exhibiting chaperone, antioxidant, antiapoptotic, and actin cytoskeletal regulatory activities, thereby influencing diverse disease states with both protective and detrimental effects[46]. Sharing a conserved C-terminal ACD homologous to vertebrate eye lens α-crystallin[47], HSP27 was initially characterized as a heat shock-inducible protein[48] functioning as a molecular chaperone facilitating the refolding of damaged proteins[49,50]. Subsequent investigations revealed the responsiveness of HSP27 to a broader range of cellular stressors, including oxidative and chemical stress. Under conditions of oxidative stress, HSP27 functions as an antioxidant, modulating ROS levels by increasing intracellular glutathione levels and decreasing intracellular iron concentrations[51,52]. In response to chemical stress, HSP27 exerts antiapoptotic effects by interacting with both mitochondrial-dependent and mitochondrial-independent apoptotic pathways. Specifically, during Fas/FasL-mediated apoptosis, HSP27 binds to the death domain-associated protein, preventing its interaction with apoptosis signal-regulating kinase 1[53]. Moreover, HSP27 interacts with Bax and cytochrome C, inhibiting mitochondrial-dependent apoptosis[54,55]. Remarkably, HSP27 plays a prominent role in protecting against programmed cell death through caspase-dependent inhibition of apoptosis[56]. These antiapoptotic properties in response to chemical stressors have considerable implications for the efficacy of certain chemotherapeutic agents, such as doxorubicin and gemcitabine[57,58]. Finally, HSP27 regulates actin cytoskeletal dynamics during heat shock and other stress conditions, acting as both an actin polymerization promoter and an actin capping protein[59-61]. These diverse functions are rooted in the molecular structure of HSP27, as depicted in Figure 1[62-67].

Figure 1 Molecular structure of heat shock protein 27[62]. Heat shock protein 27 (HSP27) possesses three key structural regions: A less structured N-terminal domain with motifs like WDPF crucial for large oligomer assembly and chaperone function, a conserved α-crystallin domain (ACD) that forms β-sandwich dimers essential for building higher-order structures and chaperone activity, and a flexible C-terminal domain containing an IXI/V-like motif that interacts with the ACD to aid oligomerization and regulate chaperone activity. These dynamic structural features, including the ACD's role in preventing amyloid fibrillation by binding misfolded proteins, enable HSP27 to shift between various oligomeric states. This adaptability allows it to effectively bind a wide range of client proteins and prevent their aggregation, especially under stress conditions, with its function further modulated by factors like phosphorylation. This figure was adapted with Mol^* (MIT-licensed) from the Structure page for PDB ID 4MJH (CC0 1.0) on the RCSB Protein Data Bank (https://www.rcsb.org/structure/4MJH). Citation: Hochberg GK, Ecroyd H, Liu C, Cox D, Cascio D, Sawaya MR, Collier MP, Stroud J, Carver JA, Baldwin AJ, Robinson CV, Eisenberg DS, Benesch JL, Laganowsky A. The structured core domain of αB-crystallin can prevent amyloid fibrillation and associated toxicity. Proc Natl Acad Sci U S A 2014; 111: E1562-E1570. Copyright ©National Academy of Sciences 2014. Published by PNAS (Supplementary material).

HSP60

The highly conserved molecular chaperone HSP60 is critical for maintaining cellular equilibrium, particularly under stress conditions such as hyperthermia. Predominantly located within mitochondria, HSP60 assembles into a characteristic double-ring structure, formed by two heptameric rings[68,69]. Each monomer composing these rings comprises the following three distinct domains: (1) Apical, responsible for substrate binding; (2) Intermediate, essential for inter-ring communication and conformational shifts; and (3) Equatorial, housing the adenosine triphosphate (ATP) binding site[68-70]. This structural arrangement is fundamental to the function of HSP60 as a protein-folding apparatus within the mitochondrial matrix.

HSP60 collaborates with its cochaperone, HSP10 (synonymous with HSP10 or Cpn10), to facilitate the appropriate folding of newly imported mitochondrial proteins and mitigate the aggregation of misfolded polypeptides[71,72]. The ATPase activity of HSP60, localized within the equatorial domain, provides the required energy for conformational changes within the chaperone complex, driving cycles of substrate binding, folding, and subsequent release[72,73]. This ATP-dependent mechanism is essential for efficient mitochondrial protein folding and the maintenance of mitochondrial proteostasis. The interaction between HSP60 and HSP10 creates a “folding cage”, providing a sequestered environment conducive to polypeptide folding[74].

Beyond its established role in protein folding, HSP60 has been implicated in diverse cellular processes, including mitochondrial DNA replication and the import of proteins into mitochondria[74,75]. Moreover, extracellular HSP60 functions as a potent signaling molecule, stimulating both proinflammatory and anti-inflammatory responses[76]. Extracellular HSP60 can engage with pattern recognition receptors, such as TLR2 and TLR4, and CD14 on immune cells, triggering downstream signaling cascades and the release of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6[77,78]. This activation of the innate immune system by extracellular HSP60 can contribute to both protective and pathological outcomes, depending on the specific context. In hyperthermia, the release of HSP60 into the extracellular milieu may contribute to the inflammatory response observed in heatstroke and related conditions[79]. Conversely, intracellular HSP60 exerts a protective function by preventing protein aggregation and preserving mitochondrial function under heat stress[80]. This dual functionality of HSP60 as an intracellular chaperone and an extracellular signaling molecule emphasizes its complex involvement in cellular stress responses, especially those induced by hyperthermia[72,81]. This intricate interaction exemplifies the “heat shock paradox”, whereby HSPs can exert both beneficial and detrimental effects depending on their subcellular location and the specific cellular environment (Figure 2)[72,82-86].

Figure 2 Molecular structure of heat shock protein 60[82]. Each heat shock protein 60 (HSP60) monomer features three key domains: The apical domain for binding substrates and the co-chaperone HSP10, an intermediate domain acting as a hinge, and an equatorial domain responsible for adenosine triphosphate (ATP) binding and inter-ring contacts. Notably, upon ATP binding, mitochondrial HSP60's apical domains adopt an asymmetric "up/down" configuration, a crucial feature for simultaneously recruiting HSP10 and engaging client proteins, thereby coordinating the folding process. This entire ATP-dependent mechanism involves significant conformational shifts that regulate the folding chamber, enabling HSP60 to efficiently fold proteins within the mitochondria. This figure was adapted with Mol^* (MIT-licensed) from the Structure page for PDB ID 8G7M (CC0 1.0) on the RCSB Protein Data Bank (https://www.rcsb.org/structure/8G7M). Citation: Braxton JR, Shao H, Tse E, Gestwicki JE, Southworth DR. Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly. Nat Struct Mol Biol 2024; 31: 1848-1858. Copyright ©The Author(s) 2024. Published by Nature Pub. Group (Supplementary material).

HSP70

The 70 kDa HSP70 family comprises a highly conserved group of molecular chaperones essential for maintaining cellular proteostasis under both physiological and stress conditions. These proteins exhibit a modular architecture consisting of the following three principal functional domains: (1) An N-terminal nucleotide-binding domain (NBD); (2) A substrate-binding domain (SBD); and (3) A CTD. The NBD, which is responsible for ATP binding and hydrolysis, is characterized by two lobes separated by a deep cleft accommodating ATP and ADP[87-89]. This domain adopts a conserved fold, featuring a central β-sheet core flanked by α-helices, a structural motif common to other ATPases. The cyclical binding and hydrolysis of ATP to ADP drive conformational changes in the SBD and CTD, thereby modulating the interactions of HSP70 with substrate proteins[90]. This nucleotide exchange is a crucial regulatory step in the HSP70 chaperone cycle. The SBD, which is responsible for recognizing and binding unfolded or partially folded polypeptide chains, is a bipartite structure comprising a 15 kDa β-sheet subdomain and a 10 kDa α-helical subdomain. The β-sheet subdomain forms a β-barrel-like structure with protruding loops, generating a hydrophobic groove with high affinity for neutral, hydrophobic amino acid residues, which typically stretches up to seven residues[91]. This groove serves as the primary interaction site for unfolded protein segments. The predominantly α-helical CTD functions as a regulatory “lid” that controls access to the SBD. This domain, composed of five α-helices, interacts with the β-sheet subdomain of the SBD for structural stability. A specific helix forms a salt bridge and hydrogen bonds with SBD loops, effectively closing the substrate-binding pocket. The remaining helices form another hydrophobic core, further stabilizing the “lid”. The nucleotide state of the NBD dictates the conformation of the CTD as follows: ATP binding promotes an open conformation, facilitating rapid substrate binding and release, whereas ADP binding induces a closed conformation, increasing the substrate binding affinity and dwell time[88].

HSP70 interacts with extended peptide segments and partially folded proteins, preventing aggregation and promoting appropriate folding. In the absence of the substrate, HSP70 is typically in an ATP-bound state with low intrinsic ATPase activity. Upon the emergence of nascent polypeptide chains from ribosomes, the SBD recognizes and interacts with the exposed hydrophobic amino acid sequences. This reversible interaction stimulates the ATPase activity of HSP70, thereby accelerating ATP hydrolysis to ADP, which triggers the closure of the C-terminal lid and tight binding of the peptide chain. J-domain co-chaperones, such as HSP40 in eukaryotes and DnaJ in prokaryotes, further stimulate the ATPase activity of HSP70 and deliver unfolded proteins. After the completion of protein synthesis, a nucleotide exchange factor, such as GrpE in prokaryotes and BAG1 and HSPBP1 in eukaryotes, stimulates ADP release and ATP binding, opening the lid and releasing the appropriately folded protein[92]. The released protein can then fold spontaneously or be transferred to other chaperones, such as HSP90, for further processing, a transfer often mediated by the HSP70/HSP90 organizing protein[93].

Beyond protein folding, HSP70 participates in other cellular processes, including assisting in transmembrane protein transport by stabilizing partially unfolded proteins for translocation across membranes. Posttranslational modifications, such as phosphorylation, can modulate the function of HSP70 by altering its interactions with substrates and cochaperones[94-96]. HSP70 plays a vital role in the cellular stress response, protecting cells from stressors such as thermal and oxidative stress, which induce protein denaturation and aggregation. By transiently binding to exposed hydrophobic residues, HSP70 prevents aggregation and inhibits irreversible misfolding. Under low ATP conditions, a characteristic of severe stress, HSP70 binding is prolonged, suppressing aggregation. Recovery from stress involves ATP binding and nucleotide cycling, enabling substrate release and refolding. Studies in thermophilic anaerobes suggest a redox-sensitive binding regulation based on oxidative stress[97,98]. HSP70 is also involved in protein degradation through interaction with the carboxyl terminus of Hsc70-interacting protein, an E3 ubiquitin ligase, thus targeting damaged or misfolded proteins for ubiquitination and proteasomal degradation[99].

Furthermore, HSP70 also directly inhibits apoptosis through multiple mechanisms, including inhibiting apoptosome complex formation, thereby preventing caspase activation[100]. Moreover, HSP70 interacts with the endoplasmic reticulum (ER) stress sensor protein inositol requiring kinase 1-α, thus protecting cells from ER stress-induced apoptosis by modulating X-box binding protein-1 (XBP-1) mRNA splicing and subsequent upregulation of XBP-1 target genes[101,102]. Although not involved in Fas-ligand-mediated apoptosis (regulated by HSP27), the antiapoptotic functions of HSP70 emphasize its importance in cellular survival. This direct apoptosis inhibition provides an evolutionary perspective because HSP70 predates the apoptotic machinery, suggesting the coevolution of apoptotic pathways with preexisting HSP-mediated protection. Studies in mice demonstrate that administration of exogenous recombinant human HSP70 can improve lifespan, learning, and memory[102].

In the context of hyperthermia and its effect on renal function, the cytoprotective roles of HSP70 are particularly important. Elevated temperatures induce protein denaturation and aggregation in renal cells, compromising function and potentially resulting in cell death. HSP70 mitigates these effects by preventing protein aggregation, promoting refolding, and preserving cellular proteostasis, which is crucial in the metabolically active and stress-susceptible kidney. Research has demonstrated HSP70 upregulation in renal cells in response to heat stress, protecting against heat-induced damage[103]. The antiapoptotic function of HSP70 also protects renal cells from heat-induced apoptosis, preserving renal tissue integrity. Several studies further emphasize the protective role of HSP70 in the kidney under hyperthermic conditions. HSP70 overexpression protects against ischemia-reperfusion injury, a condition exacerbated by heat stress, through reduced oxidative stress, decreased inflammation, and apoptosis inhibition[104,105]. HSP70 also protects against heat-induced AKI by maintaining mitochondrial function and reducing tubular cell damage[106]. In heatstroke models, HSP70 induction correlates with improved renal function and reduced mortality[105,107,108]. These findings emphasize the crucial role of HSP70 in protecting renal function during hyperthermia. Further studies have demonstrated that HSP70 plays a vital role in maintaining the integrity and function of renal tubular epithelial cells under heat stress by reducing oxidative stress and inflammation[107,109]. Moreover, HSP70 has been shown to attenuate hyperthermia-induced kidney injury by modulating the expression of proinflammatory cytokines such as TNF-α and IL-1β[110-112]. These studies collectively emphasize the vital role of HSP70 in protecting renal function during hyperthermia by preserving cellular proteostasis, inhibiting apoptosis, reducing oxidative stress, and modulating inflammation (Figure 3)[91,113-117].

Figure 3 Molecular structure of heat shock protein 70[113]. Heat shock protein 70 (HSP70) is a molecular chaperone with two main domains: An N-terminal nucleotide-binding domain (NBD) (approximately 44 kDa) and a C-terminal substrate-binding domain (SBD) (approximately 25-30 kDa), connected by a flexible, conserved linker that facilitates allosteric communication. The NBD consists of two lobes creating a deep cleft for adenosine triphosphate (ATP) binding and hydrolysis, exhibiting a structural fold similar to actin. The SBD is characterized by a β-sandwich subdomain that forms a peptide-binding groove and an α-helical lid that covers the bound substrate. The crucial chaperone function of HSP70 relies on ATP-dependent conformational changes: ATP binding to the NBD leads to an open SBD lid and low substrate affinity, while ATP hydrolysis promotes lid closure and high-affinity substrate binding, enabling HSP70 to act as a molecular machine in protein folding. This figure was adapted with Mol^* (MIT-licensed) from the Structure page for PDB ID 1S3X (CC0 1.0) on the RCSB Protein Data Bank (https://www.rcsb.org/structure/1S3X). Citation: Sriram M, Osipiuk J, Freeman B, Morimoto R, Joachimiak A. Human Hsp70 molecular chaperone binds two calcium ions within the ATPase domain. Structure 1997; 5: 403-414 Copyright ©2002 Elsevier Science Ltd. Published by Elsevier Inc (Supplementary material).

HSP90

The highly conserved HSP90 family, present in almost all organisms except archaea, comprises the following five subfamilies: (1) Cytosolic HSP90A; (2) ER-localized HSP90B (GRP94 in humans); (3) Chloroplast HSP90C; (4) Mitochondrial TNFR-associated protein; and (5) Bacterial high-temperature protein G (HtpG)[29]. Although HtpG is found in most bacteria and exerts modest effects on growth at high temperatures, it is not essential under nonstressful conditions, unlike its eukaryotic counterparts. Eukaryotic HSP90 subfamilies are believed to have evolved from an HtpG-like ancestor[29]. Although TNFR-associated protein is most closely related to HtpG, it probably evolved independently of the other eukaryotic subfamilies (HSP90A, HSP90B, and HSP90C) during early eukaryotic evolution, with a proposed role in protecting against oxidative stress-induced apoptosis[29,118]. GRP94 functions in ER protein quality control, interacting exclusively with clients in secretory pathways or on the cell surface, and is strongly induced by ER stress conditions such as glucose starvation and tunicamycin exposure[119]. In particular, it has been suggested that cytosolic HSP90A and chloroplast HSP90C evolved from the ER-localized HSP90B group[29].

HSP90A is the largest, most widespread, and best-investigated subfamily, often exhibiting multiple paralogous genes (e.g., HSP90AA/1 and HSP90AB/1 in vertebrates) resulting from recent duplication events, which share overlapping functions with some paralogue-specific roles[120]. In general, HSP90 functions as a highly abundant, ATP-dependent homodimeric chaperone[121,122]. Constituting 1%-2% of the cytosolic proteome under normal conditions and increasing to 4%-6% under stress[123], it is crucial for the folding, stabilization, and functional maturation of diverse client proteins[122]. This chaperone participates in various cellular processes, including signal transduction, protein degradation, and stress response pathways[124,125]. HSP90 client proteins include transcription factors, kinases, receptors, and other structurally diverse molecules[126]. Using ATP hydrolysis at the NTD, HSP90 facilitates appropriate client protein folding and prevents aggregation[121,126]. Each subunit of the homodimer comprises the following three domains: (1) The NTD (approximately 25 kDa) for ATP and drug binding and cochaperone interaction; (2) The middle domain (approximately 40 kDa) for client and cochaperone binding; and (3) the CTD (approximately 12 kDa) mediating dimerization and further cochaperone and client interactions[121,127-130]. The NTD adopts a two-layer sandwich fold, forming the ATP-binding pocket[127]. HSP90 interacts with numerous client proteins, affecting the conformation of complexes involved in diverse processes, including RNA polymerase II function, telomere maintenance, kinetochore activity, snoRNA processing, phosphatidylinositol 3-kinase-related kinase activity, RNA-induced silencing complex function, and proteasomal degradation[131]. Although essential for maintaining cellular homeostasis and metabolism, HSP90 dysregulation, particularly in cancer cells, can promote carcinogenesis, making it a therapeutic target for certain cancers[132]. In response to environmental stress, HSP90 expression often doubles in eukaryotes, frequently involving both constitutively expressed and inducible cytosolic isoforms. Inducible transcription is regulated by heat shock factor 1, which activates numerous genes in response to stress[133,134]. The capacity of HSP90 to interact with such a diverse range of client proteins stems from the molecular structure of HSP90, as illustrated in Figure 4[114,116,117,135,136].

Figure 4 Molecular structure of heat shock protein 90[135]. Heat shock protein 90 functions as a homodimer, with each monomer comprising three key domains: An N-terminal domain (NTD) that binds adenosine triphosphate (ATP), a middle domain involved in client protein and co-chaperone interactions, and a C-terminal domain primarily responsible for dimerization. The NTD can form a 'molecular clamp', and ATP binding to the NTDs induces their transient dimerization, driving significant conformational changes between open and closed states, a process crucial for client protein activation and the overall chaperone cycle. This dynamic, ATP-dependent mechanism, regulated by co-chaperones, enables HSP90's flexible multi-domain architecture to interact with a wide range of client proteins, facilitating their proper folding, maturation, and stabilization. This figure was adapted with Mol^* (MIT-licensed) from the Structure page for PDB ID 8AGI (CC0 1.0) on the RCSB Protein Data Bank (https://www.rcsb.org/structure/8AGI). Citation: Tassone G, Mazzorana M, Mangani S, Petricci E, Cini E, Giannini G, Pozzi C, Maramai S. Structural Characterization of Human Heat Shock Protein 90 N-Terminal Domain and Its Variants K112R and K112A in Complex with a Potent 1,2,3-Triazole-Based Inhibitor. Int J Mol Sci 2022; 23: 9458. ©2022 by the authors. Published by MDPI (Supplementary material).

To summarize, although all these HSPs act as molecular chaperones, they differ considerably in their sizes, structures (especially ATPase domains), primary subcellular localizations, specific client protein repertoires, reliance on co-chaperones, and distinct roles in other cellular processes such as apoptosis, immune signaling, and cytoskeletal dynamics. HSP27 is a small, versatile chaperone with antioxidant and antiapoptotic roles. HSP60 is primarily a mitochondrial protein chaperone. HSP70 is a general and robust chaperone involved in nascent protein folding to degradation, and stress response. HSP90 is a more specialized chaperone vital for the maturation and stability of key signaling proteins.

RENAL FUNCTION RESPONSES TO HEAT SHOCK AT THE ORGANISMAL LEVEL

Heat stress profoundly affects renal function through a complex interaction between inflammatory and noninflammatory mechanisms. These mechanisms, triggered by factors such as strenuous muscle work, increased metabolic demands, and activation of the renin-angiotensin-aldosterone (RAA) system, can initiate a cascade of events culminating in a spectrum of renal dysfunction, ranging from transient changes in GFR to severe conditions such as AKI and potentially contributing to the progression of CKD. These pathways are often intertwined, generating a complex feedback loop that can considerably compromise kidney health.

Non-inflammatory pathways primarily involve physiological responses to fluid loss and circulatory changes, operating independently of direct immune system activation. A central component of this response is the precise regulation of fluid balance orchestrated by the antidiuretic hormone (ADH) and RAA system. Dehydration resulting from sweating, a crucial thermoregulatory mechanism in hot environments, triggers the release of ADH from the posterior pituitary gland[137]. ADH exerts its effects on the renal collecting ducts, increasing water reabsorption by promoting the insertion of aquaporin-2 water channels into the apical membrane of principal cells[138]. This increased water reabsorption causes a remarkable reduction in urine volume and a corresponding increase in urine osmolality, potentially exceeding 1000 mOsm/L[139]. Although this mechanism is crucial for maintaining fluid homeostasis during periods of dehydration, the resulting excessive urinary concentration can considerably predispose individuals to nephrolithiasis (formation of kidney stones). Supersaturation of urine with minerals such as calcium oxalate, calcium phosphate, and uric acid increases the thermodynamic driving force for crystal nucleation, growth, and aggregation, ultimately resulting in the formation of calculi within the renal tubules and collecting system[140]. The reduced urine volume further exacerbates this risk by decreasing the dilution capacity for these minerals and prolonging the contact time between crystals and the tubular epithelium (Figure 5)[137-146].

Figure 5 Non-inflammatory pathways of renal function in heat shock conditions. Non-inflammatory pathways of heat-induced renal dysfunction are primarily driven by fluid loss and circulatory changes. Dehydration triggers the release of antidiuretic hormone, increasing water reabsorption and concentrating urine, which can lead to nephrolithiasis. The renin-angiotensin-aldosterone system is activated, causing vasoconstriction that can reduce renal blood flow and glomerular filtration rate, potentially leading to acute kidney injury. Reduced urine output increases the risk of urinary tract infections and pyelonephritis. Based on a summary of the findings from references. (+): Activate; (-): Inhibit.

Concurrent with ADH release, the decrease in extracellular fluid volume and the subsequent reduction in renal perfusion pressure activate the RAA system. This hormonal cascade is initiated by the release of renin from juxtaglomerular cells in the kidneys, which are sensitive to changes in renal perfusion pressure and sympathetic nerve activity[143]. Renin, an aspartyl protease, cleaves angiotensinogen, a circulating protein produced by the liver, to angiotensin I. Angiotensin I is subsequently converted into angiotensin II by angiotensin-converting enzyme, primarily in the pulmonary vasculature. Angiotensin II exerts a multitude of effects that contribute to renal dysfunction in the context of heat stress and exertion. It causes vasoconstriction of both afferent and efferent arterioles in the glomeruli, although the effect on the efferent arteriole is typically more pronounced. This differential vasoconstriction causes an increase in glomerular filtration pressure, which initially helps maintain GFR. However, sustained vasoconstriction, particularly in the setting of dehydration, can remarkably reduce renal blood flow and GFR, predisposing individuals to prerenal AKI[142]. Angiotensin II also stimulates the release of aldosterone from the adrenal cortex, a mineralocorticoid hormone that promotes sodium and water reabsorption in the distal nephron, further contributing to fluid retention and potassium excretion[144]. Although this sodium and water retention is vital for restoring blood volume, it can also contribute to electrolyte imbalances and further concentrate the urine, exacerbating the risk of nephrolithiasis. Moreover, the reduced urine output resulting from RAA system activation can increase the risk of retrograde urinary tract infections (UTIs) by reducing the flushing action of urine and facilitating bacterial ascent from the lower urinary tract to the kidneys. Ascending UTIs can result in pyelonephritis, a serious kidney infection characterized by inflammation of the renal parenchyma, which can cause permanent kidney damage and potentially progress to CKD if left untreated[141]. These hormonal and hemodynamic adjustments represent the key non-inflammatory pathways of renal function in heat shock conditions, which are summarized in Figure 5[137-146].

Beyond these noninflammatory hormonal responses, strenuous muscle work in hot environments initiates a cascade of inflammatory events that can further compromise renal function. Strenuous muscle work dramatically increases metabolic demands, requiring a corresponding increase in oxygen and nutrient delivery to the working muscles. In hot environments, thermoregulation through sweating causes decreased blood volume and potentially reduced cardiac output, which can compromise oxygen delivery to muscles. This mismatch between oxygen supply and demand can cause muscle ischemia, cellular stress, and potential muscle injury[147]. The sympathetic nervous system is activated in response to this physiological stress, resulting in increased heart rate, peripheral vasoconstriction, and the release of catecholamines such as epinephrine and norepinephrine[148]. This sympathetic activation can contribute to further renal vasoconstriction and reduced renal blood flow, further exacerbating the risk of kidney injury. Muscle injury also triggers the release of DAMPs, which are intracellular molecules released into the extracellular space upon cellular damage. DAMPs activate the innate immune system by binding to pattern recognition receptors on immune cells, initiating an inflammatory cascade[149].

The increased metabolic rate associated with both exercise and the inflammatory response further elevates cellular oxygen demand, potentially exacerbating tissue hypoxia, especially in the kidneys, which have inherently high metabolic activity due to their role in filtration and reabsorption[150]. The RAA system is further activated by this metabolic stress and reduced renal perfusion, generating a positive feedback loop that further compromises renal perfusion and increases the risk of kidney injury. Muscle injury can also cause hyperuricemia due to the release of purines from damaged muscle cells[151]. Elevated uric acid levels can further impair renal blood flow and contribute to inflammation and oxidative stress in the kidneys through various mechanisms, including activation of the renin-angiotensin system, induction of endothelial dysfunction, and stimulation of inflammatory cytokine production[152-154].

The combination of muscle injury, hypoxia, and metabolic stress triggers a systemic inflammatory response characterized by the release of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6[155]. These cytokines contribute to systemic inflammation and can directly affect renal function by altering renal hemodynamics, increasing vascular permeability, and promoting leukocyte infiltration into the kidneys[156]. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) to manage pain associated with muscle injury can further exacerbate renal dysfunction by inhibiting prostaglandin synthesis, which is vital for maintaining renal blood flow, especially in the context of dehydration and RAA activation[146]. Prostaglandins, especially prostaglandin E2 and prostacyclin, play a critical role in maintaining renal vasodilation and counteracting the vasoconstrictive effects of angiotensin II and sympathetic activation. The inhibition of cyclooxygenase enzymes by NSAIDs reduces prostaglandin production, resulting in unopposed vasoconstriction and increased risk of renal ischemia and AKI. Inflammation also induces the expression of HSPs, a family of highly conserved proteins that act as molecular chaperones, protecting cells from stress and facilitating protein folding and repair[157]. Nevertheless, HSPs can also act as DAMPs, further amplifying the inflammatory response and contributing to tissue damage[158,159]. The complex interaction between the protective and proinflammatory roles of HSPs in the context of heat stress and kidney injury requires further investigation to completely elucidate their contribution to renal pathophysiology (Figure 6)[146,155-168].

Figure 6 Inflammatory pathways of renal function in heat shock conditions. Heat stress-induced muscle injury, hypoxia, and metabolic stress trigger a systemic inflammatory response, releasing pro-inflammatory cytokines that can directly impair renal function. Nonsteroidal anti-inflammatory drugs used for pain management can exacerbate renal dysfunction by inhibiting prostaglandin synthesis, which is crucial for maintaining renal blood flow. Heat shock proteins, though protective, may also act as damage-associated molecular patterns (DAMPs), amplifying inflammation. Based on a summary of the findings from references. (+): Activate; (-): Inhibit.

The effects of heat stress on renal function are not solely attributable to either inflammatory or noninflammatory mechanisms but rather represent a complex and dynamic interaction between these pathways. Dehydration and circulatory changes trigger noninflammatory responses involving ADH and the RAA system, which can predispose the kidneys to injury. Concurrently, muscle work, increased metabolism, and the resulting inflammatory response further exacerbate renal stress through cytokine release, hypoxia, and potentially the NSAID use. This combined insult can result in a spectrum of renal dysfunction, ranging from transient decreases in GFR to severe AKI and potentially contributing to CKD progression in susceptible individuals. Therefore, understanding these complex interactions is vital for developing effective preventive and therapeutic strategies to alleviate the risk of kidney complications associated with heat stress and physical exertion. Proper hydration, appropriate electrolyte replacement, careful consideration of NSAID use, and strategies to minimize muscle injury are essential for maintaining kidney health in these challenging conditions.

THE COMPREHENSIVE EFFECT OF HEAT STRESS ON RENAL FUNCTION: FROM AKI TO CHRONIC CONDITIONS

Heat stress and AKI

Heat stress considerably increases the core body temperature, particularly when accompanied by dehydration. This physiological response results in increased vascular resistance and reduced blood volume, exacerbating conditions that may contribute to kidney disorders. AKI is among the most severe consequences and is commonly defined as a sudden decline in renal function[43,160,161]. Studies have demonstrated a clear association between heat stress and AKI, indicating that individuals exposed to high temperatures for as little as 6 h face a significantly elevated risk of acute kidney failure[162]. For instance, Xu et al[162] reported that patients exposed to high-temperature conditions for 6 hours had a markedly higher risk of AKI, affecting a total of 1815 individuals. Similarly, Chapman et al[163] observed that hyperthermia and dehydration considerably increased the risk of AKI in a cohort of 30 adults. Epidemiologically, studies demonstrate a clear relationship between increasing temperatures and kidney issues, wherein a Brazilian study observed a 0.9% increase in kidney disease hospitalizations per 1 °C temperature increase[11], and an Australian study linked remarkable emergency visits and hospital admissions to heat, with several cases being kidney-related[10].

Heatstroke is often accompanied by electrolyte imbalances, as evidenced by a study involving individuals with exertional heatstroke, in which 91% developed AKI along with various electrolyte disturbances, including hyponatremia and hypokalemia[164,165]. Reduced levels of serum potassium, phosphate, and magnesium are frequently associated with increased urinary excretion, suggesting tubular dysfunction. Additional contributing factors include sodium and potassium loss through sweat as well as respiratory alkalosis, which may result in decreased serum phosphate levels.

The trend of the increasing incidence of nephrolithiasis can be attributed to climate change-related temperature increases[166,167]. Heat stress and dehydration elevate urinary solute concentrations and simultaneously reduce urine volume, thereby increasing the probability of stone formation[168]. Clinical investigations continue to demonstrate that elevated temperatures and dehydration can result in the production of acidic, concentrated urine, facilitating urate crystallization and subsequent tubular damage[169].

Occupational exposure, at-risk populations, and AKI incidence

The effect of heat stress on kidney health in vulnerable populations, detailing systemic and organ-specific clinical manifestations, investigation findings, and prognosis supported by scientific literature. Outdoor workers exposed to prolonged high temperatures and physical exertion may present with fever, dizziness, dehydration, fatigue, and hypotension, often exhibiting flank pain, reduced urine output, and peripheral edema. Studies typically reveal elevated creatinine and blood urea nitrogen (BUN) levels, decreased estimated GFR (eGFR), and proteinuria, resulting in a high risk of AKI and CKD[163,170]. Agricultural laborers face similar systemic symptoms along with flank pain and oliguria, with studies showing electrolyte disturbances and elevated creatinine levels, predisposing them to a high risk of nondiabetic CKD due to chronic dehydration[168,169]. Occupational heat exposure poses a severe risk, with United States agricultural workers facing a 20-fold higher heat-related mortality. AKI risk increases considerably after just six hours of heat exposure[162] and can affect up to 91% of patients affected by exertional heatstroke[164,165]. Kitchen workers experience dehydration, fatigue, and dizziness, with oliguria and lower limb edema indicating kidney strain, evidenced by reduced eGFR and proteinuria, resulting in a remarkably increased risk of AKI[171]. Brick manufacturing workers exposed to extreme heat may exhibit heat exhaustion, fatigue, and muscle pain, with flank pain and oliguria, with studies often showing elevated BUN and creatinine levels and reduced eGFR, indicating a high probability of latent CKD[170]. Marathon runners can experience dehydration, muscle cramps, and heat exhaustion, with potential flank discomfort and urinary urgency; investigations may reveal electrolyte imbalances and elevated creatinine levels, typically indicating transient AKI[172]. Elderly individuals, vulnerable because of impaired thirst and thermoregulation, may present with dizziness and altered mental status along with hypertension and oliguria, with investigations often showing reduced creatinine clearance, elevated N-terminal pro B-type natriuretic peptide levels, and electrolyte imbalance, resulting in rapid CKD progression and increased mortality[173-175]. Pregnant women may experience fatigue, hypotension, and dizziness, with proteinuria, pedal edema, and gestational hypertension, with studies indicating decreased eGFR, elevated liver enzyme levels, and proteinuria, thereby increasing the risk of preeclampsia and pregnancy-related AKI[176]. Finally, immunocompromised individuals may present with persistent fever and increased infection susceptibility, including recurrent UTIs and hematuria, wherein investigations may show elevated C-reactive protein levels, leukopenia, and increased creatinine levels, indicating a high risk of renal deterioration and multiorgan failure[177]. These findings emphasize the diverse and considerable effects of heat stress on kidney health in these vulnerable populations (Table 1)[163,170-179].

Table 1 Effect of heat stress on renal function in high-risk populations: Clinical, investigation, manifestations, and prognostic implications.

High-risk populations	Systemic clinical manifestations	Organ-specific clinical manifestations	Investigation	Prognosis	Ref.
Outdoor workers	Fever, dizziness, dehydration, fatigue, and hypotension	Flank pain, reduced urine output, and peripheral edema (renal and cardiovascular systems)	Elevated creatinine and BUN levels, decreased eGFR, and proteinuria	High risk of AKI and CKD, and recurrent hospitalizations	Chapman et al[163], Gallo-Ruiz et al[170]
Agricultural laborers	Fatigue, intense thirst, and heat exhaustion	Flank pain and oliguria (renal system)	Electrolyte disturbances, elevated creatinine levels, and proteinuria	High risk of nondiabetic CKD; repeated AKI episodes due to chronic dehydration	Wesseling et al[178], Nerbass et al[179]
Kitchen workers (chefs)	Dehydration, fatigue, and dizziness	Oliguria and lower limb edema (renal system)	Reduced eGFR and proteinuria	2.8-fold increased risk of AKI compared with the general population	Koh[171]
Brick manufacturing workers	Heat exhaustion, fatigue, and muscle pain	Flank pain and oliguria (renal system)	Elevated BUN and creatinine levels and reduced eGFR	High probability of latent CKD due to prolonged heat exposure	Gallo-Ruiz et al[170]
Marathon runners	Dehydration, muscle cramps, and heat exhaustion	Flank discomfort and urgency of urination (renal system)	Electrolyte imbalance and elevated creatinine levels	Transient AKI; reversible with prompt management	Tidmas et al[172]
Elderly individuals (aged ≥ 65 years)	Impaired thirst sensation, dizziness, and altered mental status	Hypertension, cardiac insufficiency, and oliguria (cardiovascular and renal systems)	Reduced creatinine clearance, elevated N-terminal pro B-type natriuretic peptide levels, and electrolyte imbalance	Rapid CKD progression; higher risk of hospitalization and mortality	Glaser et al[173], Johnson et al[174], Tran et al[175]
Pregnant women	Fatigue, hypotension, and dizziness	Proteinuria, pedal edema, and gestational hypertension (renal and cardiovascular systems)	Decreased eGFR, elevated liver enzyme levels, and proteinuria	Increased risk of preeclampsia, intrauterine growth restriction, and pregnancy-related AKI	Moronge et al[176]
Immunocompromised individuals	Persistent fever, fatigue, and increased infection susceptibility	Recurrent urinary tract infections and hematuria (renal system)	Elevated C-reactive protein levels, leukopenia, and increased creatinine levels	High risk of renal deterioration; susceptibility to multiorgan failure	Leon et al[177]

AKI: Acute kidney injury; BUN: Blood urea nitrogen; CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration rate.

Table 2[7,171,173,180,181] summarizes five key studies investigating the relationship between heat stress and kidney injury across diverse populations and settings. Despite differences in the study design, all studies underscore the detrimental effect of occupational heat exposure on kidney health. For instance, Koh[171] focused on kitchen workers in Malaysia and found a medium heat stress risk, with 38.7% of workers reporting heat-related symptoms, indicating a potential dehydration-linked kidney strain. Furthermore, Venugopal et al[180] investigated industrial workers in India and emphasized the high prevalence of urogenital discomfort and productivity loss, particularly among those in physically demanding, unorganized sectors. In contrast, Chapman et al[7] conducted a controlled laboratory trial in healthy adults, revealing that short-term heat exposure remarkably elevated the sensitive urinary biomarkers of AKI [e.g., neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7), and tissue inhibitor of metalloproteinases-2 (TIMP-2)], even without overt symptoms. Although the study by Chapman et al[7] presents certain methodological limitations-most particularly a relatively small sample size (n = 13) and the absence of obvious clinical manifestations of AKI, such as consistent alterations in serum creatinine levels or GFR-its scientific contributions remain important. The study demonstrated meaningful elevations in sensitive urinary biomarkers of AKI, including NGAL, IGFBP7, and TIMP-2, even in the absence of clinical symptoms. Remarkably, it was among the first to document a divergent response between IGFBP7 and TIMP-2, suggesting a predilection for proximal tubular stress or injury under conditions of concurrent hyperthermia and dehydration. Importantly, this study lays a foundation for future investigations aimed at better characterizing the complex interaction between climate-induced thermal strain and renal pathophysiology, along with informing the development of early diagnostic and prognostic strategies for populations exposed to occupational or environmental heat stress. Both Johnson et al[181] and Glaser et al[173] provided broader population-level insights, wherein Johnson et al[181] emphasized the mechanisms linking AKI and chronic kidney injury with climate-driven dehydration and heatstroke, and Glaser et al[173] highlighted the epidemic emergence of nontraditional CKD in rural agricultural communities across Central America, South Asia, and Africa. Common across all studies is the recognition that heat stress, particularly in vulnerable and labor-intensive settings, poses a substantial and underrecognized threat to kidney health, although they differ in methodology, biomarkers used, and the depth of mechanistic exploration.

Table 2 Summary of representative studies on heat stress and kidney injury.

Ref.	Study design and population characteristics	Primary methods for heat stress assessment	Primary methods for kidney injury/health assessment	Key findings related to kidney injury/health
Koh[171], 2024	A cross-sectional descriptive study was conducted among kitchen workers in Kampar, Malaysia	WBGT, thermal work limit, ambient temperature, humidity, questionnaire, workload observation	Urinalysis dipstick (10 parameters: Leukocytes, nitrites, glucose, potential of hydrogen, protein, ketones, specific gravity, blood, bilirubin, and urobilinogen) preshift and postshift; self-reported kidney-related symptoms	In a study conducted across 14 kitchen settings in Kampar, WBGT was recorded at 27.2 ± 1.0 °C, exceeding the recommended action level of 25 °C. These findings classify kitchen workers as being at a medium risk of heat stress. A total of 38.7% of kitchen workers reported symptoms of heat-related illness, with excessive sweating (45.1%), thirst (25.8%), and fatigue (24.2%) being the most commonly reported symptoms. Prolonged exposure to such heat stress conditions may increase the risk of dehydration-related kidney injury, particularly among workers with inadequate fluid intake or preexisting health conditions
Venugopal et al[180], 2016	A cross-sectional descriptive study was conducted among 442 workers across 18 organized and unorganized workplaces in India	WBGT measurements, work intensity judgment by an industrial hygienist, HOTHAPS questionnaire on perceived heat exposure, and coping	Self-reported heat-related health effects via the HOTHAPS questionnaire, including urogenital symptoms	A comprehensive evaluation of 18 Indian workplaces, spanning both organized and unorganized sectors, found that most workers were exposed to heat levels exceeding the recommended WBGT thresholds. Those engaged in physically demanding outdoor tasks reported more heat-related health issues, including skin rashes, dehydration, heat syncope, and urogenital discomfort. Statistical analysis revealed considerable associations between workload intensity and adverse health outcomes (χ² = 23.67, P ≤ 0.001), as well as between heat exposure and decreased productivity (χ² = 15.82, P ≤ 0.001). Heat-induced fatigue, illness-related absenteeism, and income loss were major concerns, particularly in the unorganized sector. The findings emphasize the persistent threat of occupational heat stress year-round
Chapman et al[7], 2020	A quasi-randomized crossover experimental trial was conducted involving 13 healthy adult participants	Controlled laboratory exercise (2 hours) in heat (39.7 °C, 32% relative humidity) under 4 conditions (control, water, cooling, and water + cooling); core temperature, skin temperature, body weight loss	Urinary AKI biomarkers (albumin, NGAL, IGFBP7, and TIMP-2) pre-exercise, post-exercise, 1-hour post-exercise, and 24-hour post-exercise	This study is the first to report the distinct urinary biomarker responses of IGFBP7 and TIMP-2 following physical exertion under heat stress conditions. These findings indicate site-specific kidney injury, probably affecting the proximal tubules, where IGFBP7 is predominantly secreted. Occupational heat stress, particularly when accompanied by hyperthermia and dehydration, was found to remarkably elevate AKI biomarkers such as urinary albumin, NGAL, and IGFBP7 in the absence of thermoregulatory interventions such as hydration and cooling
Johnson et al[181], 2019	This review examines the current literature on the effect of increasing global temperatures on kidney health, focusing on heat-related acute kidney disease and CKD, nephrolithiasis, and Urinary tract infections. Data were drawn from studies involving vulnerable populations such as outdoor workers and elderly individuals, particularly in tropical and low-resource settings	Environmental monitoring (e.g., WBGT), heat stress indices (such as predicted heat strain and humidex), and physiological monitoring of workers (e.g., core temperature, heart rate, and dehydration levels)	Monitoring serum creatinine levels and estimated glomerular filtration rate; performing urinalysis to detect proteinuria, hematuria, or crystalluria; and measuring urinary biomarkers such as leukocytes or indicators of tubular injury, electrolyte sodium, and potassium	Global temperature rise and renal implications: The global rise in temperature has led to more frequent extreme heat events, increasing health risks. The kidneys are vital for thermoregulation and fluid-electrolyte balance. However, they are highly vulnerable to damage from heat-related stress. Heat-induced AKI: High ambient temperatures can increase the core body temperature, cause dehydration, and increase plasma osmolality. Both clinical and subclinical heatstroke contribute to AKI through rhabdomyolysis, inflammation, and renal hypoperfusion. CKD linked to heat stress: Repeated heat exposure and dehydration can cause progressive tubular damage, resulting in CKD. This may account for the increasing CKD rates in hot regions, especially among laborers with poor access to cooling and hydration
Glaser et al[173], 2016	This review provides a global perspective with particular emphasis on rural agricultural communities residing in hot-climate regions	Review of existing literature; analysis of temperature trends in CKD epidemic regions	Discussion of CKD of nontraditional origin epidemics; proposed pathophysiology of heat stress nephropathy	A novel form of CKD, unrelated to traditional causes such as diabetes and hypertension, has been increasingly identified among populations exposed to repeated occupational heat stress and inadequate hydration. This condition, often referred to as CKD of nontraditional origin, has shown geographic clustering in hot, rural regions such as Central America, South Asia, and parts of Africa, primarily affecting manual laborers with limited access to rest, shade, and clean water. Climate change is believed to exacerbate the problem through rising temperatures and more frequent extreme heat events, along with reduced water availability

AKI: Acute kidney injury; CKD: Chronic kidney disease; HOTHAPS: High Occupational Temperature Health and Productivity Suppression; IGFBP7: Insulin-like growth factor-binding protein 7; NGAL: Neutrophil gelatinase-associated lipocalin; TIMP-2: Tissue inhibitor of metalloproteinases-2; WBGT: Wet-bulb globe temperature.

Heat stress and CKD

Recurrent episodes of AKI, particularly those induced by heat-related illnesses, can considerably contribute to the pathogenesis and progression of CKD. Prolonged exposure to high ambient temperatures and chronic dehydration remain pivotal drivers of this serious condition. Numerous epidemiological and occupational health studies have increasingly documented CKD prevalence in hot-climate regions, even among individuals without traditional risk factors such as diabetes and hypertension, indicating a novel climate-sensitive nephropathy[173,177]. For instance, a study conducted in Taiwan demonstrated a higher incidence of CKD among individuals exposed to heat injury (HI). Recent epidemiological evidence has further emphasized the critical role of AKI, a common complication of HI, in mediating the progression to CKD. HI episodes frequently result in both dehydration and rhabdomyolysis, which are potent triggers for AKI. Importantly, recurrent or unresolved AKI episodes can initiate a cascade of pathological changes, including interstitial fibrosis, tubular atrophy, and maladaptive repair, ultimately causing nephron loss and chronic renal dysfunction. These repeated injuries compromise renal resilience and render the kidneys more susceptible to subsequent insults, thus generating a pathophysiological continuum from AKI to CKD. Furthermore, HI may act as both the initial insult and an accelerant of this progression, particularly in individuals with comorbid conditions such as hypertension, diabetes mellitus, and heart failure-factors independently associated with increased CKD risk. Therefore, instead of viewing prolonged heat exposure as a direct and isolated risk factor for CKD, it should be understood within the broader context of recurrent HI-induced AKI, which plays a pivotal role in the transition from acute to chronic kidney damage[182].

A study conducted in Taiwan demonstrated that patients exposed to high ambient temperatures over extended periods-either continuously or intermittently at an increased risk of developing CKD, with an incidence rate of 8.83% compared with 4.38% after 13 years of follow-up[182].

Emerging global data further support the need to widen the geographic focus when evaluating heat stress-related kidney disease. In Latin America, particularly along the Pacific Coast of Central America, a phenomenon termed CKD of nontraditional causes has been recognized, affecting thousands of sugarcane and agricultural workers. A landmark study in El Salvador demonstrated that 20%-30% of male laborers in the sugarcane industry developed CKD, with recurrent subclinical AKI episodes believed to play a causative role[181,183]. Chronic heat exposure has been shown to contribute to the development of CKD, with a reported prevalence of 20%-30% among Salvadoran sugarcane workers[181,183] and an estimated 2300000 outdoor workers in the United States at risk[7]. The combination of heat exposure, insufficient hydration, and limited rest periods creates a hazardous environment that results in both AKI and long-term nephron damage.

Pathophysiologically, repeated AKI episodes induce nephron dropout, promote renal interstitial fibrosis, and impair tubular regeneration capacity. This sequence results in maladaptive repair processes, progressive glomerulosclerosis, and a decline in renal functional reserve. Studies in animal models and human histopathology confirm that heat stress leads to glomerular hypoperfusion, increased oxidative stress, and microvascular rarefaction, all of which accelerate renal parenchymal scarring[169,178].

Additionally, a pivotal study conducted in Nicaragua reported a remarkable association between outdoor manual labor and CKD incidence, with workers from brick manufacturing facilities exhibiting elevated creatinine levels and reduced eGFR after heat wave exposure[184]. Similarly, in South Asia, particularly India and Sri Lanka, agricultural workers and construction laborers in hot, humid environments exhibited an alarming increase in CKD prevalence, a trend increasingly related to heat stress[179,185]. Studies further suggest that low-income and middle-income countries in tropical and subtropical regions are witnessing a rapid increase in heat-related CKD prevalence, particularly among outdoor laborers such as agricultural workers, construction workers, and migrant laborers[186,187]. In addition to physical stress, a thermoregulatory imbalance contributes to reduced renal perfusion and activation of neurohormonal pathways such as the RAA and ADH systems. These responses, although compensatory in the short term, impose further strain on renal microcirculation, potentiating hypoxia and ischemia-reperfusion injury[180]. Recent evidence also suggests that HSPs, particularly HSP70 and HSP90, play a protective role by stabilizing cellular proteins and facilitating the repair of damaged renal tubular epithelial cells. Nevertheless, chronic dysregulation of HSP expression under sustained heat exposure may paradoxically contribute to maladaptive cellular remodeling and fibrosis. The burden is not merely limited to rural and agricultural populations because studies have also documented increased AKI incidence in kitchen workers, brick makers, foundry workers, and even marathon runners. For instance, a United States cohort study estimated that > 2300000 outdoor workers may be at risk for CKD due to heat exposure[7].

Older adults represent another vulnerable population. During a heat wave, individuals aged ≥ 65 years experienced a disproportionate increase in hospitalizations and mortality, with renal dysfunction being a key contributor. Reduced thirst sensation, impaired renal concentrating ability, and baseline comorbidities exacerbate susceptibility to heat-induced AKI[174]. Alarmingly, even pregnant women have demonstrated increased vulnerability. Heat exposure in pregnancy has been associated with hypertension, proteinuria, preeclampsia, and gestational AKI, emphasizing the need for special workplace and environmental protection. The cumulative evidence underscores the need for integrative public health policies addressing hydration strategies, workplace cooling systems, and surveillance programs targeting high-risk populations[188,189]. Global nephrology communities are now recognizing heat stress as a key environmental determinant of CKD. In this context, multisectoral collaboration - between health, labor, climate, and urban planning sectors-becomes imperative.

Future directions

Considering the growing effects of global warming on kidney health, future research should emphasize integrative approaches to mitigate the burden of heat stress-induced renal dysfunction. Clinically, it is imperative to develop risk stratification models that combine environmental exposure data, patient comorbidities, and physiological parameters to proactively identify high-risk individuals, particularly outdoor workers, elderly individuals, pregnant women, and those with preexisting CKD.

From a mechanistic perspective, further investigation of the protective role of HSPs (HSP27, HSP60, HSP70, and HSP90) is warranted to clarify their contributions in maintaining renal cellular homeostasis under thermal stress. Identifying reliable biomarkers-such as NGAL, IGFBP7, and TIMP-2-may facilitate earlier detection and monitoring of kidney injury in vulnerable populations.

A truly effective response to heat stress-induced kidney injury requires a deeply integrated, multidisciplinary framework that brings together both core and complementary disciplines. Nephrologists play a vital role in clarifying the underlying pathophysiological mechanisms of heat-induced kidney injury and optimizing clinical management, including the identification and validation of early biomarkers for heat-related renal dysfunction. Environmental scientists contribute by improving the accuracy of localized heat exposure forecasting, quantifying the effects of urban heat islands, and characterizing environmental cofactors that exacerbate renal stress. Public health professionals are integral to the design and implementation of targeted interventions, including population-level heat adaptation strategies, early warning systems, and occupation-specific safety guidelines for vulnerable outdoor workers. In parallel, other specialties provide essential extensions to this foundation. Surgical and transplant teams are crucial for managing irreversible kidney failure, especially in resource-limited regions. Obstetricians address heat-related renal risks in pregnant women, a uniquely susceptible population. Geriatricians manage age-related renal vulnerability and tailor interventions for elderly individuals. Artificial intelligence improves early detection and personalized risk stratification through real-time data integration. Stem cell therapies hold promise for renal tissue regeneration in the aftermath of cumulative injury. Furthermore, traditional and complementary medicine may support functional recovery through culturally appropriate, integrative strategies that promote hydration, reduce oxidative stress, and improve physical and mental resilience. The synergy among these diverse disciplines not only strengthens diagnostic, prognostic, and preventive efforts but also advances equitable, long-term functional recovery-strengthening the need for holistic, climate-adaptive kidney health systems in a warming world.

On a broader scale, interdisciplinary efforts must focus on the integration of heat-related kidney protection into clinical guidelines, occupational health policies, and national public health programs. The implementation of heat alert systems, hydration strategies, and education campaigns is vital to reducing the incidence of heat-related AKI and chronic kidney injury. Collaborative research frameworks across nephrology, environmental science, and public health will be essential to address this emerging global health challenge.

CONCLUSION

This review underscores heat stress-intensified by the ongoing rise in global temperatures, as exemplified by 2024 being the hottest year on record-as a significant and multifactorial contributor to renal pathology, including AKI, CKD, and nephrolithiasis. The pathophysiological mechanisms implicated include dehydration, electrolyte disturbances, and activation of neurohormonal pathways such as the RAA system and ADH axis. At the molecular level, HSPs exhibit a dual role: While they provide cytoprotection under transient stress, their dysregulation during prolonged exposure may promote maladaptive cellular responses, inflammation, and fibrosis. Vulnerable populations-including outdoor laborers, the elderly, pregnant individuals, and those with pre-existing renal impairment disproportionately affected. In light of these findings, there is an urgent need for integrated clinical and public health responses. This includes increased clinical vigilance, risk stratification, and targeted education, as well as policy interventions aimed at environmental risk mitigation, occupational safety reform, and public health preparedness. Furthermore, the development and implementation of early detection tools, such as validated renal biomarkers, and the promotion of interdisciplinary research are critical to advancing preventive strategies. A globally coordinated effort across clinical, policy, and research domains is essential to address the escalating burden of heat-related kidney disease and mitigate its anticipated impact on global health systems.

ACKNOWLEDGEMENTS

We are grateful to Can Tho University of Medicine and Pharmacy in Can Tho City (Viet Nam) for their time and efforts in this study.