Stress and the Kidney

Abstract

The prevalence of CKD has increased considerably over the past 2 decades. The rising rates of CKD have been attributed to known comorbidities such as diabetes, hypertension, and obesity; however, recent research has begun to explore the degree to which social, economic, and psychological factors have implications for the prevalence and progression of CKD, especially among high-risk populations such as African Americans. It has been suggested that stress can have implications for CKD, but this area of research has been largely unexplored. One contributing factor associated with the paucity of research on CKD is that many of the social, psychological, and environmental stressors cannot be recreated or simulated in a laboratory setting. Social science has established that stress can have implications for health, and we believe that stress is an important determinant of the development and progression of CKD. We draw heavily from the social scientific and social epidemiologic literature to present an intersectional conceptual frame specifying how stress can have implications for kidney disease, its progression, and its complications through multiple stressors and pathways.

CKD is fast becoming a global health problem. The prevalence of CKD remains high, whereas the incidence of ESRD or kidney failure continues to increase.¹ If current trends continue, the global implications will be immense because the social and financial costs of care for ESRD patients are considerable. Current estimates for the United States indicate that the cost of ESRD exceeded $42 billion in 2009, more than doubling the cost in 2000.² These trends indicate that kidney disease represents a serious threat to the world’s physical and financial health.

Results from a recent study reports that nearly 6 of every 10 Americans will experience moderate kidney disease in their lifetime³; however, the burden of kidney disease is not distributed equally across the population.^4–7 The prevalence of ESRD for African Americans, for example, quadruples the corresponding prevalence for whites.^2,8,9 The disparities in ESRD, CKD, and their complications (ie, anemia, bone disease, cardiovascular disease and death) have been linked to differing rates of kidney function decline.¹⁰ It has been suggested that the accelerated rates of disease progression among populations such as African Americans and the poor can be attributed to the high prevalence rates of metabolic conditions known to impair kidney function (ie, diabetes, hypertension). But, the presence of these comorbidities does not entirely explain accelerated kidney disease progression among those most at risk.⁷

A growing segment of nephrologists has begun to examine sociologic and psychological factors potentially contributing to the incidence and progression of CKD and its complications.^9,11–19 Stress is a factor that has been studied extensively by social and behavioral scientists; however, it has remained largely unexplored in the nephrology community. As such, we draw from the social science and social epidemiologic literature to illustrate how stress can have implications for CKD initiation, progression, and complications. Figure 1 depicts a heuristic model of the multiple pathways through which stress can have implications for CKD, its progression to ESRD, and premature mortality.

Figure 1.

Heuristic model of the association between environmental factors, stress, psychological factors, behavioral factors, CKD risk factors, and CKD progression and complications.

Stress: A Brief Overview

Stress refers to an environmental, social, or internal demand that results in a psychological, physiological, or behavioral response.^20–22 These factors or stressors can lead to a state of physiological or emotional arousal that can affect physical and psychological health. Nearly 60 years ago, Selye²³ observed that long-term exposure to noxious stressors were associated with tissue damage and disease in laboratory animals. Work examining stress in humans was bolstered considerably by a study by Holmes and Rahe,²⁰ suggesting that an accumulation of major life eventswas related to illness. Literally, thousands of studies emerged from this early work, and nearly all have been founded on the premise that the accumulation of stressors tax or exceed the adaptive capacity of individual to a point where psychological or physiological responses to the stress condition can place them at risk for illness, injury, or disease.

This line of research has presented evidence, suggesting that stress can have implications for the development and progression of chronic diseases such as CKD. Stress has been shown to be associated with CKD risk factors such as hypertension, diabetes, or obesity.^13,24–27 Scientists agree that stress can have implications for CKD and health outcomes; however, research examining the relationship between stress and kidney disease has been limited. One factor contributing to the scarcity of research in this area is that stress is a multidimensional concept that can be operationalized in multiple ways.¹³

Stress in the empirical literature has 3 forms: major life events, chronic strains, and daily hassles.²¹ Stressors categorized as major life events are occurrences that require considerable behavioral modification over a relatively short period of time (eg, death of a loved one, divorce, loss of a job). Chronic strains are persistent stressors that call for behavioral adjustment over a prolonged period of time (eg, poverty, disability). Daily hassles are stressors over the course of a day. These stressors (eg, traffic problems, interactions with rude people) are often regarded as minor; however, they can elicit physiological, psychological, and/or behavioral responses. Studies focusing on the impact of major life events or chronic strain represent the bulk of the literature examining the relationship between stress and health; however, a growing line of research has begun to examine the impact of daily hassles on health behaviors and outcomes. Much of the literature on stress and coping builds on interactional or transactional models of stress that highlight the social and cultural context of stress and coping, with each suggesting that perceptions of stressors are the primary determinants of behavior and health status.^28–30

Stress, Pathophysiology, and Kidney Disease

Results from this extensive body of research have shown that stress can have an adverse effect on illness and disease, directly through physiological effects and indirectly through behaviors and practices that have implications for health.^31,32 No study to date has developed a comprehensive stress model specifying the biologic pathways between stressors and the development and progression of CKD because most social, psychological, and environmental stressors cannot be recreated or simulated in a laboratory setting.³³ Nonetheless, results from recent studies examining the relationship between acute stress and CKD risks factors suggest some biologic pathways through which stress may be associated with CKD and its complications.

CLINICAL SUMMARY.

• Stress can have implications for kidney disease through multiple pathways.

• Intersectionality is an approach that can be useful for identifying how stress has implications for race-, gender-, and age-related disparities in kidney disease development and progression.

Many studies examining the relationship between stress and pathophysiology have focused on outcomes such as blood pressure, heart rate, and vascular reactivity.^34–41 Results from this line of research indicate that both blood pressure and heart rate increase and vascular reactivity decreases with most models of acute stress. These relationships between stress and pathophysiology are thought to be associated with alterations in the sympathetic/autonomic nervous system activity, the hypothalamic-pituitary-adrenal axis, inflammatory cytokines, and endothelin-A.^42,43 These alterations suggest that pathologic link between stress, hypertension, and CKD is possible as kidney sympathetic nerves innervate all segments of the kidney, and neural mechanisms regulate sodium and water retention.⁴⁴

It also has been suggested that stress may be linked to CKD via diabetes and insulin resistance. Environmental stressors have been found to be associated with the development of insulin resistance, metabolic syndrome, obesity, and ultimately type 2 diabetes.^45,46 The biologic link is thought to involve alterations in the neuroendocrine system including the hypothalamic-pituitary-adrenal axis (increased glucocorticoid and other stress hormones) in addition to sympathetic nervous system factors and inflammatory cytokines.^39,47

Stress also is thought to have implications in utero. The “Barker hypothesis” posits that disruption of the fetal environment or undernutrition translates into pathology. ⁴⁸ Cell division and subsequent fetal growth are influenced by products of the hypothalamic-pituitary-adrenal axis and neuroendocrine hormones. Undernutrition brought about by stress can slow cell division in a manner that adversely affects the number of cells in particular organs and, ultimately, fetal growth. These and other alterations in the fetal environment are thought to contribute to low birth weight, a factor that has been associated with metabolic syndrome, type 2 diabetes, and CKD in adult life.⁴⁹

Recent studies have also examined the extent to which genes are associated with CKD and ESRD in African Americans and other at risk groups. Genetic variants on the MYH9-APOL1 region on chromosome 22 have been found to account for the excessive risk of kidney disease among African Americans.^50–60 Recent research has shown that African Americans with the APOL1 G1 and G2 risk alleles are more likely to develop CKD and progress faster to ESRD than their counterparts with 0 or 1 risk allele.⁵¹ These genetic variants are rare in white populations, suggesting that racial disparities in kidney disease may include a genetic component. Additional research is required to determine how other CKD risk factors and gene-environment interactions have implications for individuals with an apparent genetic risk for the development of kidney disease.

In summary, stress appears to enhance sympathetic nervous system activity, increase glucocorticoid secretion, and potentially increase levels of inflammatory cytokines. These factors contribute to higher prevalence of hypertension, diabetes, and vascular disease—all major risk factors for CKD. The physiological effects may be experienced in utero, exerting early influences that may further heighten the adult risk for CKD. In patients with CKD, the levels of another hormone, renalase, that metabolizes products of the sympathetic nervous system are lower.^61,62 Therefore, it is plausible that chronic stressors result in unchecked increased sympathetic nervous system activity once CKD develops which sets in motion a vicious cycle.

Social Determinants, Stress, and Kidney Disease

Scientists agree that kidney disease risk can vary by population, and this variance is reflected in the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation used to estimate the glomerular filtration rate (GFR), a value indicating how well the kidneys are functioning. Specifically, the CKD-EPI formula uses serum creatinine levels along with patient characteristics (age, gender, and race) to calculate GFR [GFR = 141 × min (Scr/κ, 1)^α× max(Scr/κ, 1)^−1.209 × 0.993^Age × (1.018 if female) × (1.1.59 if African American)].⁶³ Social science literature has established that stress is associated with each of the individual characteristics included in the CKD-EPI formula. As such, stress can have implications for kidney disease and its progression to kidney failure through multiple stressors and pathways.

Stress and Age

Kidney disease has been thought to be a function of aging because kidney function decreases as individuals get older. However, the relationship between age and kidney disease appears to vary by group because African Americans experience kidney failure at younger ages and have greater incidence rates of ESRD at each decade of life compared with any other racial/ethnic group.^9,10 It has been asserted that the progression of aging can vary by race, gender, socioeconomic status, and/or other sociodemographic characteristics, and some researchers suggest that stress can be attributed, in part, to the early onset of health conditions associated with old age, but the relationship between stress, aging, and health conditions has not been examined extensively. One explanation for the limited research in this area is that both aging and stress can be dynamic and the mechanisms associated with each can change as individuals get older. A life course approach offers a potential fruitful line of research, an optimal opportunity to identify critical points in the life course where stress has the most adverse effects and to understand the impact that the duration of stress has on health outcomes including CKD and ESRD.^64,65 The life course approach incorporates 3 primary conceptual models (ie, critical period models, pathway models, and accumulation models) to account for temporal ordering of exposure variables and their inter-relationships.⁶⁶ Cumulative disadvantage theory and weathering hypothesis are 2 theories associated with the life course approach that are useful for situating stress as a determinant of kidney disease.

Cumulative disadvantage theory highlights how early social and economic advantage or disadvantage shape the health outcomes of socially defined groups over time.^67–71 Early life experiences set in motion a chain of risk or protective factors for short- and long-term outcomes. Some people have little or no stress in their life, and this advantage may compound over time to produce health benefits, whereas others have endured and continue to endure stress because of social or environmental factors. These social, environmental, and/or economic disadvantages also accumulate over time and may be potentially associated with CKD or ESRD.⁷²

The weathering hypothesis states that the health status of African Americans begins to decline prematurely in early adulthood.⁷³ The earlier health declines are a result of long-term and compound exposure to unfavorable social and environmental conditions.⁷³ The weathering hypothesis provides a framework to assist in advancing our understanding of how stress contributes to disparities in the initiation of health conditions such as CKD or ESRD by elucidating how social environmental stressors can adversely affect health over time.^74,75 Often, minorities experience life differently in the United States because of a large amount of social and structural inequalities that limit social, economic, and health-promoting opportunities that create stress, which can contribute to early onset of age-related diseases such as CKD and premature mortality.^13,31,76,77

Stress and Gender

Gender disparities in kidney disease have been noted in nephrology literature as men have been shown to have a higher incidence and prevalence of ESRD.⁷⁸ Men tend to have an earlier onset of ESRD, thereby starting dialysis at younger ages.⁷⁹ A small line of research has attempted to identify biologic sources of men’s elevated risk for kidney disease and kidney failure, but the results have not been definitive.^80,81 An emphasis on biologic differences suggests the nephrology community has focused primarily on sex differences rather than gender differences. Although “sex” and “gender” have been used interchangeably in a significant segment of the health science literature, these terms refer to different mechanisms and processes. Sex differences involve rigid classification (ie, male, female) by reproductive organs and their function and secondary sex characteristics. Gender distinctions involve categories (ie, masculine, feminine) based on psychological and behavioral outcomes that are shaped by the surrounding cultural and social environment. Stress can be linked to gender disparities in kidney disease because stressors arise from one’s social location and can have implications for health behaviors. Gender identities, roles, and relations are diverse and mediate health behaviors and practices^82,83; thus, it is critical to examine how genders intersect with other identities and experiences to accurately explain health behaviors and health outcomes. An important source of stress is how people define themselves and the gendered roles they play in their families and communities.^84–88

Health behaviors are used in daily interactions to help people negotiate social power and social status, and these same health practices can either undermine or promote health.⁸⁵ Enacting gender through the interpretation and choice of coping behavior can both privilege and harm population groups.⁸⁹ In addition to examining the types and sources of stress that affect health, it is critical to consider how people respond to and cope with stress.^90,91

The methods chosen to cope with stressors are largely dictated by the nature of the problem. Modifiable and controllable stressors often are addressed with more problem-focused coping behaviors, whereas chronic, uncontrollable, and seemingly immutable situations often elicit more emotion-focused responses.⁹⁰ The resources at peoples’ disposal shape their coping responses.⁹¹ Self-constructs and identity are important mediators of the association between stressful experiences and responses to stressors. These intrapersonal factors have important implications for health. Symbolic interactionism emphasizes the intrapersonal meaning construction process that shapes the coping process.⁹¹ This meaning is dynamic and evolves over time.

Some of the ways that men and women try to demonstrate their gender identity may change over the life course as the fundamental meaning of masculinity and femininity and the salience of different aspects of gender change over the life course. It is critical to consider how gendered notions, stressors, and strains change over time, particularly in relation to pressures to engage in key health behaviors that adversely affect CKD.^83,92,93

Stress and Race

General interest in health disparities has raised the profile of research examining racial differences in the incidence, prevalence, and progression of kidney disease. The risks for CKD and ESRD among African Americans are considerably greater than other racial/ethnic groups.^{2,5,6,8,9,14,15,94,95} Explanations for racial disparities in CKD or ESRD have been primarily biological as they have been attributed to high levels of diabetes, hypertension, and obesity among African Americans.¹³ Health scientists recognize that the primary risk factors for CKD and ESRD are largely preventable and a growing segment of the nephrology community have begun to consider how factors such as stress contribute to the excess risks for kidney disease among African Americans.

Social scientists have highlighted a number of social environmental stressors encountered by African Americans and other marginalized racial groups. Recent epidemiologic research has shown that living in racially segregated, unstable, and poverty-stricken areas have consequences for the general health and well-being of residents.^96–99 Economic deprivation has been a central component in epidemiologic studies including African Americans, and results have indicated that socioeconomic factors at the individual and community levels can have implications for kidney disease.^{6,16,18,19,95,100}

It has been suggested that the primary stressors for African Americans are economic^101,102; however, race-related stress can involve other factors such as racial discrimination, institutionalized racism, and prejudice.^77,103 It has been nearly 40 years since the end of the civil rights movement, yet African Americans continue to report encounters with individuals and institutions that they believe to be racially motivated.^104–108 Repeated exposures to interactions perceived to be discriminatory or racist, such as unfair treatment on the job, in the housing market, or at public events can elicit a physiological response, regardless of the intentions of others involved or the accuracy of the perception.^76,109–111 Further, institutional racism, redlining, and race-based residential segregation are associated with African Americans being more likely than their white counterparts to live areas plagued by substandard educational resources, inadequate housing, family disruption, general disorder, pollution, and violence.^112–114 Recent studies have shown that being exposed to discrimination and racism are related to CKD risk factors such as elevated blood pressure,^110,115 and exposure to these stressful experiences adversely affects CKD progression and complications.

Stress, Intersectionality, and Kidney Disease: An Intriguing Avenue of Inquiry

Scientists agree that stress can have implications for health outcomes like kidney disease. However, the relationship between stress and chronic diseases like CKD has not been pursued extensively and few efforts to explain these relationships can explain how age, gender, and race pattern health outcomes. One factor contributing to the paucity of research in this area is that stress is a factor that has been conceptualized and operationalized in manner with limited utility for explaining racial disparities in CKD. Psychological research often presents stress as an acontextual psychological construct with universal mechanisms and pathways^28,89; yet, characteristics (eg, race, ethnicity, life stage) that are socially meaningful in their societal context^85,116,117 shape what aspects of life are deemed stressful. Stress appraisals have traditionally been based on subjective perceptions of threat, controllability, change, and other characteristics, but critiques of this approach argue that these measures conflate appraisals of events with reactions to these events.⁹¹ It has been critical to distinguish the social patterns of inequality from the cultural structure of shared meanings of stressful experiences.¹¹⁸ The social origins of meaning, particularly how meanings of stressful experiences are constructed over time, are essential to understand how stress has implications for disease risk. How people negotiate structural and cultural constraints is essential to explaining the mechanisms and pathways that connect stress and chronic diseases like CKD.^13,91,118 Although it is certainly shaped by intrapersonal factors, meaning is a social product of the connotations that stimuli have for individuals and interpersonal relationships. Thus, it is not simply the objective social arrangements that act as stressors, but the subjective interpretation of these stressors that shape physiological and behavioral responses that can affect kidney disease risk, progression, and mortality.^91,118

There may be systematic social causes of stress and psychological and physiological aspects of strain that vary by socially meaningful characteristics and social determinants of health.¹¹⁹ Stressors that arise from one’s unique position in social systems with unequal distributions of resources, opportunities, life chances, power, privilege, and prestige are best examined through an intersectional lens.¹²⁰ Social status can shape how people construct meaning¹¹⁸ and provide access to social, political, and economic resources that can be used to cope with stressors.^121–123 Understanding group differences in health outcomes such as kidney disease includes considering how social determinants of health intersect to shape people’s lives and experiences.^13,123–125 Poverty, poor educational opportunities, underemployment and unemployment, incarceration, and social and racial discrimination all vary by socially defined characteristics and also influence the capacity of individuals to achieve and maintain good health.^{123,125–127} Intersectionality is a perspective that examines how socially defined and socially meaningful characteristics are inextricably intertwined, ^84,117,128 thereby enabling scientists to consider multiple pathways through which stress has implications for disparities in the development and progression of kidney disease.

Over the past few years, the number of studies examining the relationship between nonbiologic factors and kidney disease has grown as a larger segment of the nephrology community has been interested in identifying and addressing modifiable risk factors.¹²⁹ The study of factors, such as stress, is relatively new; however, we believe that this line of research can provide unique insights into the development and progression of CKD and ESRD. Methodologic development, however, is one area in need of considerable attention. Many of the factors discussed here, including stress, are measured with indices that are limited. Stress and environmental measurement development are critical for the development of testable intersectional models that specify why and how determinants of health combine to increase risk and the conditions through which environmental stressors “get under the skin.” Psychonephrology is a promising line of research because it has the potential for the development of biopsychosocial models through which seeming incommensurable relationships can be tested. Biopsychosocial model development can encourage researchers to give greater attention to the complexities associated with the multiple environments in which individuals are embedded. As such, future studies can explore pathways through which gene and social environmental factors interact to have implications for CKD development and progression. Empirical models emerging from this line of work may require scientists to use statistical methodology that accounts for multiple levels and unobserved factors simultaneously. Genetic predisposition along with economic, social, and psychological factors, including stress, can interact to have a detrimental impact on the health of individuals. As such, it may be necessary to use techniques such as structural equation and/or latent class models that enable scientists to observe how multiple stressors and pathways can have implications for the development of kidney disease and progression to kidney failure.

The results from this line of work can have implications for clinical or policy-oriented segments of the nephrology community. Identifying how stress affects group-specific processes associated with kidney disease would enable health care providers and public health officials to develop culturally and context-specific interventions to help reduce disparities in CKD development and progression in the short term and eliminate them in the long term. Stress has emerged as a critical determinant of health and a central barrier to the effective management of the risk and progression of illnesses associated with CKD (eg, diabetes, hypertension).^130–133 Increasingly, stress management is being included in state-of-the-art interventions to prevent, manage, and reduce the risk of illnesses associated with CKD.^134–138 Future research should similarly incorporate stress management in CKD prevention, management, and treatment interventions, and it will be important for these studies to incorporate an intersectional lens to most effectively understand and address how stress and other determinants of CKD are patterned.