A Scoping Review of Life-Course Psychosocial Stress and Kidney Function

Increased exposure to maternal psychosocial stress during gestation and adverse neonatal environments has been linked to alterations in developmental programming and health consequences in offspring. A programmed low nephron endowment, among other altered pathways of susceptibility, likely increases the vulnerability to develop chronic kidney disease in later life. Our aim in this scoping review was to identify gaps in the literature by focusing on understanding the association between life-course exposure to psychosocial stress, and the risk of reduced kidney function. A systematic search in four databases (PubMed, ProQuest, Wed of Science, and Scopus) was performed, yielding 609 articles. Following abstract and full-text review, we identified 19 articles meeting our inclusion criteria, reporting associations between different psychosocial stressors and an increase in the prevalence of kidney disease or decline in kidney function, mainly in adulthood. There are a lack of studies that specifically evaluated the association between gestational exposure to psychosocial stress and measures of kidney function or disease in early life, despite the overall evidence consistent with the independent effects of prenatal stress on other perinatal and postnatal outcomes. Further research will establish epidemiological studies with clear and more comparable psychosocial stressors to solve this critical research gap.


Introduction
Kidney disease is a rapidly growing global health problem, both as a direct cause of morbidity and mortality as well as an important risk factor for cardiovascular disease [1,2]. The global all-age mortality rate from chronic kidney disease (CKD) increased 41.5% (95% Confidence Interval (CI): 35.2, 46.5) between 1990 and 2017. The global prevalence of CKD in 2017 was 9.1% (95% CI: 8.5, 9.8) after controlling for two primary comorbidities affecting kidney function: hypertension and diabetes. These trends indicate that CKD represents a serious threat to global public health and the economy [1,2]. Therefore, identifying preventable risk factors is essential for reducing CKD burden [3].
Stress-related psychosocial factors have repeatedly been associated with different non-communicable diseases, with studies linking stress to poorer kidney function [4,5], and prenatally, psychosocial stressors have been associated with adverse perinatal outcomes, including low birth weight, small for gestational age, and preterm birth [6,7]. However, the contribution of psychosocial stress to kidney development and diseases [8,9] has remained relatively unexplored.
The Developmental Origins of Health and Disease (DOHaD) hypothesis [10] postulates that adverse exposures during pregnancy or long before conception can result in poor fetal growth and impair normal development and organogenesis [6,11]. Nephrogenesis,

Materials and Methods
We followed the methodology by Arksey and O'Malley [15] and reported according to the guidelines for scoping reviews (PRISMA-ScR) [16].
The research question was: "What is the contribution between exposure to psychosocial stress and kidney development and diseases?". Search strategy results are defined in Table 1  We defined 'psychosocial stressor' as a life situation that creates an unusual or intense level of stress that may contribute to the development or aggravation of mental disorder, illness, or maladaptive behavior (i.e., divorce, the death of a child, prolonged illness, unwanted change of residence, a natural catastrophe, or a highly competitive work situation), in accordance with the American Psychological Association definition [17]. In addition, other psychosocial stressors were included according to the diagnostic and statistical manual of mental disorders DSM-IV-TR Axis IV in nine groups: problems with primary support groups, problems related to the social environment, educational problems, occupational problems, housing problems, economic problems, problems with access to health care, problems related to interactions with the legal system/crime legal charges, other psychosocial and environmental problems [18].
We excluded studies where the study population consisted of subjects with non-communicable disease (diabetes mellitus, hypertension, obesity or cancer) history. Additionally, conference abstracts, letter, notes, and comments were excluded.
The PRISMA flow diagram depicting the article selection process is shown in Figure  1 Data were extracted using a predesigned form and included the year of publication, author, study design, country, population and settings, outcomes studied, primary results and conclusions.

Results
A total of 19 articles were identified an included in this review. Our main finding was the lack of human studies focusing on gestational exposure to psychosocial stress; this was mostly assessed in animal studies. The majority of epidemiologic studies examined adult psychosocial stressors (most often assessed by socio economic status (SES)) and reported inverse relationships with CKD status or kidney function, but this was not consistent across all studies: there were significant associations between low socioeconomic status with CKD, especially among women and African Americans [19][20][21][22][23]. Adjei et al. reported associations between stress at work/home and increased albuminuria and CKD risk [24]. Other psychosocial stress such as goal-striving stress (GSS) and stress-related Data were extracted using a predesigned form and included the year of publication, author, study design, country, population and settings, outcomes studied, primary results and conclusions.

Results
A total of 19 articles were identified an included in this review. Our main finding was the lack of human studies focusing on gestational exposure to psychosocial stress; this was mostly assessed in animal studies. The majority of epidemiologic studies examined adult psychosocial stressors (most often assessed by socio economic status (SES)) and reported inverse relationships with CKD status or kidney function, but this was not consistent across all studies: there were significant associations between low socioeconomic status with CKD, especially among women and African Americans [19][20][21][22][23]. Adjei et al. reported associations between stress at work/home and increased albuminuria and CKD risk [24]. Other psychosocial stress such as goal-striving stress (GSS) and stress-related disorders were associated with rapid kidney function decline (RKFD) after adjusting for demographics, health behaviors, risk factors, and the burden of discrimination [3,25,26]. In contrast, higher optimism was associated with lower odds of CKD and lower odds of RKFD [27].

Study Designs and General Characteristics
Articles included n = 2 cross-sectional studies [19,24], n = 1 retrospective cohort [20], n = 8 prospective cohort studies [3,19,[21][22][23][25][26][27][28] and n = 8 animal model studies [29][30][31][32][33][34][35][36]. The epidemiological studies included data for adults with different age distributions, ethnic compositions and who lived in both urban and rural areas. Seven of the studies were carried out in the United States (Jackson Heart Study, Healthy Aging in Neighborhoods of Diversity across the Life Span HANDLS study, Life Course Socioeconomic Status Study), one in Korea (KoGES study), Sweden (SCREAM project), and Ghana-Netherlands-Germany-United Kingdom (Research on Obesity & Diabetes among African Migrants RODAM study). Table 2 summarizes the results of these studies, starting with epidemiological studies followed by experimental studies. Socioeconomic factors, including area socioeconomic status and social class were associated with CKD and may account for some observed racial disparities

Socioeconomic status (SES)
Chronic kidney disease (CKD) High SES was associated with lower risks for CKD, although the results were not linear.

Crews et al., 2010
n = 2375 Healthy Aging in Neighborhoods of Diversity Across the Lifespan (HANDLS) Study

Individual-level SES, race
Chronic kidney disease (CKD) Individual-level poverty (low SES) was associated with prevalent CKD among African Americans, but not among whites Among African Americans, low SES was independently associated with a nearly twofold greater risk of CKD when compared with higher   Prenatal CORT exposure reduced nephron endowment and caused albuminuria in male and female offspring; however, CORT-exposed male offspring were hypotensive in a salt-loading challenge, indicating that renal changes (that are normally associated with increased blood pressure) were being overridden by other factors

Kidney Outcomes
Kidney function among population-based studies included baseline and repeated measures of serum/plasma creatinine and urinary albumin. The primary outcomes were the prevalence or incidence of CKD and CKD progression assessed through the estimated glomerular filtration rate (eGFR) decline [3,26,27]. GFR was estimated for using either the "Modification of Diet in Renal Disease (MDRD) Study" [19,20,22] or the Chronic Kidney Disease Epidemiology Collaboration equation models [3,[24][25][26][27]37].
In animal studies, a variety of post-mortem renal histopathology analyses (estimation of the total number of glomeruli per kidney by stereological counting [31,32,34,35] and α-adrenergic receptors α-ARs), plasmatic and urinary creatinine samples [37], renal inflammatory and metabolic biomarkers [30,36] were carried out in exposed and control groups to examine stress-induced effects. Prenatal exposure to glucocorticoids resulted in postnatal growth restriction [34], with significant reduction in the kidney weight and total nephron number, increased mean arterial pressure, presence of albuminuria, and the expression of receptors in the renin-angiotensin system and apoptotic gene markers in offspring [34,35].
The experimental studies in postnatal exposure (prepuberal age) to physical immobilization, maternal separation, or transportation stress models showed significantly lower values of kidney weight, and glomerular volume density in the stressed group [31,32], as well as sensitization to arterial hypertension after angiotensin II infusion [33], exaggerated gene expression immune response (IL-1β and T cells) [36], reduced alfa-adrenergic receptor (α-AR) density in renal vasculature [29], and cardiorenal metabolic alterations [30].

Discussion
The literature search for this review focused on exposure to psychosocial stress and kidney function, and consistent with prior reviews [8,25], we note that a growing body of evidence supports a link between lifetime stressors and CKD risk or kidney function decline. However, we note that there is an important gap in research for studies that examined earlylife or prenatal stress. Only two animal studies and one epidemiological study indirectly addressed this research question [33,36,38]. Specifically, we found no studies addressing psychosocial determinants of kidney health in early childhood, an area that remains a critical research need [39]. We included studies that reported associations between different psychosocial stressors (low socio-economic status, racial discrimination, migration, etc.) and poorer kidney health outcomes in previously healthy adult populations.
Individuals can be exposed to psychosocial stressors through different pathways, including poverty, low socioeconomic status, life events, pregnancy-related stressors, racial discrimination, and the presence of stress factors related to living conditions and the geographic area. These psychosocial stress factors have previously been associated with adverse perinatal effects that include low birth weight, small for gestational age, prematurity, neurodevelopment, metabolic, cardiovascular, and respiratory alterations [6,7,[40][41][42][43]. Additionally, it is essential to acknowledge that exposure to chemical substances may have a synergistic effect in perinatal outcomes when pregnant women are co-exposed to psychosocial stressors and other environmental toxicants, both individually and at a community level [44][45][46]. As is the case for preterm birth, wherein concomitant exposure to adverse life events (e.g., poverty, racism, inequitable access to healthcare) as well as an individual's exposure to environmental toxicants (e.g., air pollution, metals, some pesticides, or phthalates), may also damage developing kidneys, reducing nephron endowment over the life course [38,47,48]. Co-exposures, or studies where psychosocial stress may be the result of other life events such as starvation, were outside the scope of this review.
Different biological mechanisms that enhance disease and frailty in adulthood have been described to explain early-life exposure to biologic and psychosocial stressors [49]. Specifically, regarding kidney development, nephrogenesis culmination between gestational weeks 34 and 36, together with nephron maturation in the early postnatal period, are critical windows of susceptibility [9]. Several studies demonstrated that low birth weight (<2500 g), prematurity and delayed intrauterine growth are associated with CKD in adulthood, secondary to elevated blood pressure, microalbuminuria presence and reduced estimate glomerular filtration rate [50,51], because low birth weight correlates linearly with nephron number in children and adults [12,52].
From a neuroendocrine and epigenetics perspective, there is evidence suggesting that fetal, placental and maternal factors, associated through the multiple-hit hypothesis, influence the development of antenatal distress and adverse offspring outcomes by different pathways [12,53]. An adverse environment induces the long-lasting hyper-reactivity of physiological survival systems: stress responses on the maternal and fetal hypothalamicpituitary-adrenal (HPA) axis [54][55][56], immune and inflammatory responses [57,58], and energy-conserving responses [59]. Particularly, exposure to maternal-fetal undernutrition or psychosocial stress for a certain organ can impair growth, resulting in a permanently reduced number of normally functioning units (e.g., nephrons, cardiomyocytes, pancreatic insulin-secreting B cells) [60]. At the same time, reduced functional capacity can limit the ability of the organ to adapt to an increased functional load imposed postnatally, and increase the risk for later life kidney disease, heart failure, and diabetes [61]. Specifically, current evidence shows that the developmental programming of chronic conditions, such as diabetes, cardiovascular disease, obesity, and depression, has a transgenerational effect [11,62] through the excessive expression of the glucocorticoid-responsive transcription factor called nuclear-receptor related 1 protein (NURR1) with environmental stress interactions during early life [63].
Regarding the developmental programming field, human studies are limited due to challenges in the inherent temporal lag between an adverse event during pregnancy and the occurrence of an associated clinical phenotype. Therefore, animal models are critically important in exploring possible mechanisms for kidney development under controlled conditions and in discrete developmental periods [64]. The correct assessment of the timing of psychosocial stress exposure in pregnancy may be key to determining potential fetal programming effects [64], because in humans and species such as sheep, nephrogenesis is largely completed before birth, whereas in rodents, rabbits, and pigs, nephron formation and completion continue in the postnatal period [65,66]. Furthermore, many psychosocial stressors cannot be recreated or simulated in a laboratory setting.
The results of animal studies subject to different stress models report that prenatal and postnatal exposure to glucocorticoids is associated with: a reduced renal reserve [31,32,34,35,67,68], changes in the vascular response to vasoconstrictors [29,69], activity increase in the renin-angiotensin-aldosterone system and its renal and brain receptors [31,35], change in molecular pathways that regulate the kidney transcriptome [36,70], alterations of the immuno-inflammatory processes [71] and modifications in the baroreceptors response [29,35,72]; each of these factors jointly contributes to altered kidney development and the potentially increased risk of later life arterial hypertension and CKD [34,53,73]. Additionally, recent evidence suggests a transgenerational transmission of these alterations through epigenetic mechanisms such as chromatin remodeling and modifications of non-codifying RNA [11,52].
During pregnancy, psychosocial stressors may contribute to the persistence of disparities of adverse birth outcomes across specific socioeconomic and ethnic groups. Higher levels of psychosocial stress may be associated with lower SES populations, where food insecurity, greater financial strain, and job strain are more prevalent compared to higher SES groups [74]. Perceived stress and depression may also be higher among non-white women as a result of racial discrimination [28]. The Cumulative Disadvantage Theory highlights how early social and economic advantage or disadvantage shapes the health outcomes of socially defined groups over time [8]. However, Luneyra et al. concluded that life stressors were negatively associated with prevalent CKD at baseline in the Jackson Heart Study cohort. It is important to understand the underlying factors driving the unexplained disparities in CKD outcomes among African Americans; therefore, future studies should delineate the potential role of biological markers in the relationship between psychosocial factors and kidney health [33], while recognizing genetic factors associated with CKD in risk groups such as African Americans. This review has some limitations. The search strategy used terms that included different psychosocial stress factors. However, it is not an exhaustive list that includes all possibilities and interactions with others biological, genetics, quality of healthcare systems, maternal comorbidities, family support, and environmental factors to address their cumulative effects in the nephron endowment. We only included studies published in English between 2007 and 2020, carried out in high-income countries. Due to the heterogeneity of articles identified, we could not find a definitive answer to our research question. We did not formally evaluate the level of evidence of the studies because this was not the main goal of our scoping review. It is also important to highlight that some of the epidemiological evidence arose from a single cohort study (the Jackson Heart Study), although applied different metrics for the evaluation of psychosocial stressors. Our findings provide a guide for future prospective epidemiological studies or controlled experimental trials that interrogate the causal roles of psychosocial early-life stress and kidney function, considering the timing of outcome and exposure in the critical windows of susceptibility, and other risk factors such as the dehydration and sex effects [3,12,25].
Finally, findings between studies can also vary considerably depending on the methodological approaches to measuring psychosocial stress. Self-report questionnaires may be biased due to either over-or under-reporting. By measuring clinical parameters, e.g., cortisol levels, blood pressure or heart rate, it is possible to better evaluate the response to stress [75,76], although not always feasible.

Conclusions
Epidemiological evidence in adult populations shows the association of different psychosocial stressors on kidney function, and the overall evidence in animal studies is consistent with the independent effects of prenatal psychosocial stress on perinatal and postnatal outcomes. We conclude that there is an important gap to fill with human studies between exposure to psychosocial stress during pregnancy and kidney outcomes.