Keywords

Nephrolithiasis core; Body temperature; Ambient temperature; Kidney stone; Stone formation mechanism

Introduction

Higher ambient temperature has been postulated to increase rate of kidney stone formation, with increased adverse effects of high daily temperatures on stone formation [1]. A recent case report showed an elevated prevalence of kidney and urethral stones among the high-heat exposed steelworkers in Southern India [2]. Chronic high heat exposure, heavy workload, and dehydration were factors contributing to heat strain. For example, the south-eastern U.S. kidney “stone belt” is described as the warmer regions in the southern United States with a risk ratio ≥ 1.2 relative to the Northeast. The “stone belt” is projected to move northward into the Midwest in conjunction with the steady upward trend in global temperature on almost a yearly basis [3,4]. Considering the rise in warmer climate, further studies on the effect of chronic heat exposure on stone formation are necessary, given the resultant consequences on quality of life, employment, and disability.

Literature Review

The literature has largely focused on the effects of ambient temperature on kidney stone formation. There continues to be a lack of literature on the role of core body temperature on nephrolithiasis. A retrospective study of a large clinical dataset of 2,545,835 measurements from 228,574 patients from 2013-2018 assessed the role of core body temperature in urinary stone formation [5]. The study hypothesized that patients with history of nephrolithiasis would have a lower core body temperature compared to non-urinary stone-forming patients. Their hypothesis was based on the Ostwald ripening phenomenon which describes coalescence of small particles into larger particles as a process that is inversely dependent on temperature. After matching the patients, they found no significant differences in demographics, medical history, and medication history between cohorts [5]. When compared to 14,208 matched controls, 7104 patients with a history of kidney stones had a higher mean oral temperature [5]. Lastly, according to the binary logistic regression, higher core temperature was predictive of history of kidney stones [5]. Several explanations for this phenomenon emerged, for instance, extreme sympathetic nervous system-mediated renal vasoconstriction has been proposed to contribute to hypoxic insult in warm ambient temperature [6]. The alternative has been proposed as a possible contributor; stone formers may experience behavioural or autonomic phenomena that dysregulate homeostasis of set-point of core body temperature [4]. In addition, thermoresponsive receptor potential channels undergoing conformational change in response to minimal changes over a long period of time may contribute to the cumulative risk of nephrolithiasis [7]. In summary, this study provided a novel perspective to the field by utilizing a dataset that provided sufficient statistical power to demonstrate a statistically significant difference in core body temperature. Further studies are required to help define the pathophysiological connection between nephrolithiasis formation and core body temperature.

In addition to these explanations, it may be helpful to consider the effect of core body temperature on the immunomodulatory that contribute to stone formation and elimination. Components of the immune system may behave differently in the setting of homeostasis and in changes of thermal elements. Sato et al. tested the effect of increasing the core temperature on kidney disease with a mice heat stress model [8]. The mild increase in temperature by 1°C correlated with worsening albuminuria, renal tubular injury, and interstitial infiltration of monocytes and macrophages [8]. The study also found that the kidney injury had a prominent inflammatory component with associated reduction in ATP levels and evidence of mitochondrial oxidative stress [8]. In the event of heat stress, kidney injury is markedly worsened, even with minimal change of core temperature. In reptiles, temperature influences the induction of reproductive activity and also influences morphological, physiological, and behavioural traits [9,10]. Warner et al. used chemical manipulations to study the effect of incubation temperature and turtle gonadal sex [10].

Given the involvement of inflammation in cell injury contributing to papillary dysfunction, future analysis of migratory inflammatory cells in the setting of elevated core temperature would be necessary to further understand their role in kidney stone formation. Umekawa et al. showed that renal tubular cells exposed to calcium oxalate monohydrate crystals had increased expression of a c-c chemokine MCP-1 (CCl2) which induced recruitment and migration of monocytes and macrophages [11,12]. Okada et al. investigated the transcriptome of urinary stone formation and elimination in mice using gene selection with microarray technique [13]. Their mouse model showed that macrophage migration within inflammation and immune reactivity contributed to stone formation and elimination [13]. In a subsequent study, Okada et al. performed a microarray pathway analysis to further characterize macrophage-related factors in the prevention of crystal formation in murine kidneys [14]. They concluded that inflammation-related genes of renal tubular cells activated from crystal formation could induce monocyte-macrophage migration and phagocytosis via interaction of CD44 with osteopontin and fibronectin [14].

In addition to the role of immunomodulatory and core temperature in nephrolithiasis, there is also evidence suggesting an effect of gut microbiota in nephrolithiasis [15,16]. Ambient temperature also has demonstrated to be an important factor in shaping phenotypic plasticity of microbiome [17]. Literature on the effect of core temperature on gut microbiota, however, remains limited. Khakisahneh et al. hypothesized that the gut microbiota plays a role in regulating phenotypic plasticity in an environment with constant fluctuations [17]. The study concluded that the plasticity of host thermoregulation was associated with dynamic changes in gut microbial profiles in response to repeated high or low ambient temperatures [17]. Future studies are needed to further characterize the effect of gut microbiota in stone formation in the setting of core body temperature.

Discussion

As mentioned in the recent paper, patients with history of kidney stones were found to have elevated mean oral temperature compared to matched controls. This raises questions about the pathophysiological process of stone growth, aggregation, and adhesion. It is important to study the association of core body temperature and stone formation mechanisms. In review, physiochemical processes of supersaturation and crystallization are required for crystal formation. The transition to stone formation requires crystal growth and aggregation in which modulators of low molecular weight, such as citrate, attach to larger particles. High molecular weight substances, such as urinary macromolecules may also function via various modes of action. Proteins like glycosaminoglycan may coat crystal surfaces and prevent stone formation. Ironically, osteopontins do the opposite-they bind and promote crystallization which further contributes to adhesions of crystals to tubular cells [18]. Continued adhesions of crystals can lead to their retention and entrapment. It’s logical to think that crystalluria followed by stone formation would be impacted by a change in body temperature. The role of temperature on these mechanisms remains largely understudied.

Conclusion

In summary, urinary stone formation is associated with elevated ambient temperature. Currently, only one study investigated the relationship between core body temperatures with history of nephrolithiasis. This study suggested that a thermodynamic process is not the sole driving force of stone formation given the elevated core body temperature in patients with a history of kidney stones, contrary to their initial hypothesis of involvement of Ostwald ripening. Further studies exploring the pathophysiological processes of bio-mineral formation within the context of changes in core body temperature aimed at stone prevention are required. This would ultimately help reduce healthcare costs associated with kidney stones and improve the quality of life of our patients.

References

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