Stressors and Resilience: An Integrative Model for Understanding Chronic Kidney Disease

Abstract

Alternative and Complementary TherapiesVol. 27, No. 6 Open AccessCreative Commons licenseStressors and Resilience: An Integrative Model for Understanding Chronic Kidney DiseaseJacob Hwang and Arvin JenabJacob HwangJacob Hwang, ND, is a naturopathic doctor at the Susan Samueli Integrative Health Institute, University of California, Irvine, California, USA.Search for more papers by this author and Arvin JenabArvin Jenab, ND, is the Medical Director of Naturopathic Medicine and Director of the Naturopathic Residency Program at the Susan Samueli Integrative Health Institute, University of California, Irvine, California, USA.Search for more papers by this authorPublished Online:10 Dec 2021https://doi.org/10.1089/act.2021.29358.jhwAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionChronic kidney disease (CKD) refers to persistent abnormality in kidney function present for greater than three months and classified by underlying etiology, glomerular filtration rate (GFR), and evidence of kidney damage such as albuminuria. CKD affects up to 15% of adults in the United States and is often under-recognized and underdiagnosed, with an estimated 9 in 10 adults believed to be unaware that they have CKD.1CKD is considered to be an irreversible and progressive disease, particularly at GFR less than 60 mL/min/1.73 m2. Different clinical trials have identified multiple risk factors that influence prognostic outcomes in addition to GFR and albuminuria classifications.2 Although clinical prediction tools can provide estimated risk, large variations in disease progression rates and mortality are still observed in CKD, end-stage kidney disease (ESKD), and dialysis patients.3Specific causes of CKD can be difficult to identify—although diabetes and hypertension are most associated with the onset and progression of CKD, there are a growing number of factors and influences that are being recognized as important and relevant in determining disease progression and clinical outcomes, allowing for novel strategies to be considered for the prevention and treatment of CKD and ESKD. Until recently, CKD treatment was focused on managing underlying conditions, mitigating disease-related complications, and nutritional support. However, there is growing interest and demand to consider disease management models that focus on slowing down the progression of kidney disease and reducing the risk of developing ESKD, and subsequently dialysis and kidney transplantation.Rationale for New StrategyThe current model for CKD prevention and management prioritizes early recognition of disease followed by aggressive management of underlying causes, while investing in resources to prevent and delay progression to ESKD. Prevention encompasses the screening for diseases that are at high risk for CKD development, particularly diabetes mellitus and hypertension, which generally includes recommendations for healthy lifestyle and dietary changes. Beyond preventive measures, the standard treatment approach aims to slow down CKD progression and delay dialysis transition with renin-angiotensin-aldosterone system (RAAS) inhibition through pharmacotherapy.4Despite the advances made in CKD classification and goal-oriented clinical management, treatment options have been stagnantly limited. The number of pharmaceutical medications with demonstrable effects on decreasing the rate of CKD progression or mortality has been minimal and long overdue except for the recent studies on sodium glucose cotransporter-2 inhibitors.5 The CREDENCE trial demonstrated nephroprotective effects of canagliflozin in type 2 diabetic patients.6 The nephroprotective effects of dapagliflozin on nondiabetic kidney disease were also observed in the DAPA-CKD trial due to the lack of significant outcome differences in both diabetic and nondiabetic cohorts.7The management of chronic kidney disease requires a more integrative approach, combining medications with dietary, lifestyle, and nonpharmacological treatments to delay disease progression and decrease risk of complications. The mechanisms highlighted from experimental and clinical studies8–15 provide novel insights that can guide treatment strategies by disease phenotype and other characteristics. In this article, we introduce a framework, as well as identify an expanded set of parameters, through which we may address the problem of CKD by focusing on underlying mechanisms that are involved in disease progression.We propose that the progression of CKD to ESKD can be slowed down by taking a two-prong approach, reducing the stressors that contribute to the onset and development of kidney disease, and on the other hand, enhancing kidney resilience (Fig. 1). In this context, we define kidney resilience as the kidneys' ability to withstand and adapt to physiological and biochemical stressors without sustaining damage. Thus, a proposed integrative strategy acknowledges that CKD development and progression are mediated by and dependent on the balance of stressors and physiological and biochemical resilience.Figure 1. Balance between disease stressors and kidney resilience in chronic kidney disease progression.Stressors and Their Effect on Kidney HealthStressors can be defined as factors that negatively affect kidney structure and function, furthering CKD progression by driving pathophysiology.8,9,16–18 Stressors can come from exogenous or endogenous sources and consist of physiological, biochemical, and mechanical influences. The effect of stressors is cumulative and can differ among patients regardless of comorbidities, gender, and age. The type and accumulation of stressors should be viewed as modifiable factors that contribute to heterogeneous CKD progression rates.19–21DiabetesDiabetes is known as the leading cause of CKD and ESKD. It can often present with hypertension due to the influence of insulin resistance on the RAAS. Elements of glomerular hyperfiltration, hyperglycemia, and advanced glycation end products (AGEs) are the source of kidney injury in diabetic nephropathy. It is often associated with proteinuria, which is a hallmark feature of diabetic nephropathy. The hyperglycemic environment of diabetes mellitus can lead to the generation of AGEs, which are glycotoxins that act as pro-oxidant compounds on cells and proteins.13Serum concentrations of AGEs are also correlated with cardiovascular risk due to mechanisms linked to endothelial dysfunction, atherosclerosis, and arterial stiffness.12,15 The resulting oxidative stress causes the initial damage on cells and tissues, which can accumulate and nullify existing antioxidant defenses. Along with glycotoxins, other endogenous and exogenous sources of oxidative stress can accumulate and cause chronic inflammation, which further promotes CKD progression.8–10HypertensionHypertension is the second leading cause of CKD and can concomitantly present with other metabolic disorders. The sustained increased arterial pressure maintained by increased RAAS activation causes endothelial dysfunction and remodeling of the afferent arteriole of the glomerulus.14,15 Since hypertension is systemic, this can lead to glomerular hypertension and eventually nephrosclerosis, which is clinically defined as hypertensive nephropathy.The endothelial damage from hypertension can cause chronic inflammation, which can alter renal hemodynamics and perpetuate end-organ damage.11 A systematic review demonstrated that intensive blood pressure (BP) control reduced mortality in CKD patients with higher albuminuria.22 The study did not show differences in renal outcomes between standard BP and intensive BP management, which suggests CKD progression is likely influenced by other factors.DysbiosisOngoing microbiome research continues to advance the understanding of microbial diversity in health and disease.23 Although the microbiome refers to the genetic makeup of the different microorganisms in a body system, dysbiosis is defined as the imbalance in the composition and metabolic capacity of the microbiota.24 Dysbiosis has been implicated in many chronic diseases such as inflammatory bowel disease, cardiovascular disease, and obesity.25–27There is a growing body of evidence identifying the important relationship between the microbiome and kidney health—in addition, the microbiome has been shown to impact factors that have a secondary influence on the kidneys including inflammation and endothelial dysfunction due to gut-derived metabolites. Dysbiosis has been observed in CKD patients whereby gut-derived protein-bound uremic toxins (PBUTs) such as p-cresyl sulfate, indoxyl sulfate, and trimethylamine N-oxide (TMAO) have been shown to accumulate due to overgrowth of proteolytic bacteria.28 The overexpression of gut-derived PBUTs is associated with impaired kidney function, likely due to downstream inflammatory effects and immune dysfunction.16,29The gut-derived PBUTs are also linked with increased cardiovascular risk, which is a leading cause of mortality in CKD patients.18 A pilot study demonstrated qualitative taxonomic variations of the blood microbiome in CKD patients, which may suggest a unique dysbiotic signature; however, this needs to be examined in a larger CKD population as various factors can influence the microbiome.30 Although it is unclear whether dysbiosis is a precipitating factor or result of CKD pathophysiology, the presence of dysbiosis contributes to the chronic inflammatory state.31Toxin BurdenThe kidneys are one of the emunctory organs involved with eliminating waste products. Due to this specific role, the kidneys are tasked with eliminating cellular metabolites and environmental toxins while fulfilling the primary role of maintaining homeostasis in the blood compartment.32,33 When the progression of CKD reaches ESKD, the ability to clear toxins is significantly impaired, which leads to retention of multiple toxic compounds responsible for uremic syndrome, cardiovascular disease, neurotoxicity, and worsening renal fibrosis.34,35Compared with uremic toxins, gut-derived PBUTs lack available treatment solutions as they are not easily filtered through dialysis and hemofiltration.18 Cumulative exposure to nephrotoxic medications, environmental toxins, and gut-derived PBUTs contributes to overall kidney disease burden by increasing inflammation and oxidative stress.9,12,13,16Diagnostic Testing OptionsBased on preclinical and clinical studies of different disease stressors involved in CKD progression, oxidative stress,8–10,17 chronic inflammation,16,29,31 and vascular changes11,13–15 are identified as the main driving mechanisms in CKD pathophysiology. As medical advancements continue to develop novel biomarkers and new diagnostic tests for CKD, there are commercially available laboratory test options that can quantify the effects of different disease stressors (Table 1). Clinical markers of oxidative stress from serum and urine compartments include F2-isoprostanes, coenzyme Q10 (CoQ10), glutathione, 8-hydroxydeoxyguanosine, vitamin C, vitamin E, and selenium.36–38Table 1. Overview of Potential Diagnostic Testing OptionsDiagnostic testOxidative stressInflammationVascular changesF2-isoprostanesX Coenzyme Q10X GlutathioneX 8-HydroxydeoxyguanosineX Vitamin CX Vitamin EX SeleniumX C-reactive protein XXErythrocyte sedimentation rate XXFerritin X Homocysteine XXTumor necrosis factor-α X Interleukin-6 X Insulin X Leptin X Adiponectin X Trimethylamine N-oxide X Asymmetric dimethylarginine and symmetric dimethylarginine XXPulse–amplitude tonometry XFor inflammation, conventional laboratory test options include C-reactive protein, erythrocyte sedimentation rate, ferritin, homocysteine, and proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6.31,39–41 In addition, metabolic markers such as insulin, leptin, and adiponectin can also offer further context of inflammation.42,43 Markers of dysbiosis have been investigated for different chronic diseases, but TMAO and dimethylarginines (asymmetric dimethylarginine and symmetric dimethylarginine) can specifically help assess gut–kidney axis alterations and identify dietary intake susceptible to harmful gut microbial metabolism.28,31,44–46Vascular changes can be measured through standard cardiovascular blood tests and imaging along with pulse–amplitude tonometry,47 which can be used to evaluate endothelial function and arterial stiffness. Experimental data have also highlighted gene expressions that may be of clinical value in CKD progression such as HIF, Klotho, and FGF-23.31 Continued research and validation of the discussed biomarkers are warranted before full adoption into clinical practice. In addition to different biomarkers for disease stressors, kidney function testing should incorporate estimated glomerular filtration rate (eGFR) calculations based on both serum creatinine and cystatin C. Due to multiple variables that can affect serum creatinine such as muscle mass and diet, cystatin C can help provide confirmation for kidney function.On September 2021, the National Kidney Foundation and the American Society of Nephrology joint task force has updated their recommendation to the new chronic kidney disease-epidemiology collaboration equation without race and greater use of cystatin C with creatinine to confirm eGFR.48 Compared with creatinine, cystatin C may provide improved accuracy and assessment of kidney function for certain health factors and comorbidities.49Resilience and Kidney Health PreservationConsidering the presence of multiple disease stressors and comorbidities in CKD patients, the different rates of CKD progression may be further impacted by kidney resilience. An increased number of disease stressors and reduced kidney resilience are proposed as explanation for the varying rates of CKD progression. Reduced resilience may explain why some non-CKD patients have varying rates of natural GFR decline and different rates of de novo CKD.As basic science and translational research continues to explore new therapeutic17,50 options, an appropriate action to consider contrary to conservative monitoring of disease progression is to enhance kidney resilience by optimizing metabolic pathways. Although these strategies lack strong confirmatory clinical data due to the absence of well-designed long-term studies, the totality of evidence9,10,13–16,28 has a plausible basis in physiology31 and biochemistry.18,29 This approach can also be characterized as an active prevention model, which proposes the proactive introduction and utilization of nutrients and integrative therapies to preserve kidney function and reduce disease progression.Clinical Strategies for Kidney ResilienceKidney resilience can be achieved by optimizing nutritional status, enhancing antioxidant pathways, improving mitochondrial function, modulating the immune system, and improving microvascular circulation. Poor nutritional status has been linked to less favorable outcomes in chronic diseases.51 Nutritional guidelines for CKD management have shifted to a plant-dominant low-protein diet as a favorable strategy for the preservation of kidney health.52 This is a contrast to the previous dietary recommendations of avoiding high potassium containing foods, which typically includes vegetables and fruits.The different polyphenols and phytochemicals from plant-dominant foods may be exerting an overall protective effect in ameliorating CKD progression due to lower phosphate and acid load. The low-protein limitation of 0.6–0.8 g/kg per day is still recommended due to the protective benefit of reduced intraglomerular pressure, which further alleviates the stress on kidneys. The plant-dominant dietary approach may also be promoting greater gut microbiome diversity, reducing the risk of dysbiosis and accumulation of gut-derived PBUTs. Nutritional counseling and nutrient therapies can replete and correct deficiencies, electrolyte imbalances, and other factors related to disrupted energy balance and metabolism caused by CKD.31,53 Recommendations can be further individualized by analyzing micronutrient status to identify targeted nutrient therapies.54To address oxidative stress, simply improving antioxidant stores and reducing pro-oxidants through optimizing nutritional status may not be adequate. As one of the most energy-demanding human organs and having the second highest amount of mitochondrial content and oxygen consumption, the kidneys have increased susceptibility to oxidative stress and mitochondrial dysfunction.55 Mitochondrial dysfunction is characterized as decreased adenosine triphosphate production, altered cellular function, and loss of mitochondrial homeostasis. Antioxidants such as CoQ10, alpha lipoic acid, N-acetylcysteine, and resveratrol50 can help sequester reactive oxygen species and ameliorate mitochondrial dysfunction.As a contributor and byproduct of increased oxidative stress, mitochondrial dysfunction is also observed in other chronic degenerative disease processes.17 Ameliorating mitochondrial dysfunction can help attenuate oxidative stress damage and improve cellular metabolic resilience in the kidneys. Chronic inflammation in CKD is triggered by oxidative stress, AGEs, gut-derived PBUTs, and metabolic abnormalities. Addressing the cause of inflammation can be difficult since CKD typically exists in a state of inflammatory milieu and immune dysfunction. Providing adequate antioxidants and mitochondria-targeted nutrients are foundational treatments needed to dampen the oxidative stress burden.Controlling hyperglycemia and dietary intake of heat-treated foods can decrease the accumulation of AGEs.12,13 Promoting a healthy gut microbiome should involve an adherence to a plant-based diet,52 probiotics, prebiotics, and synbiotics to lower the concentration of gut-derived PBUTs and other uremic toxins56,57 associated with dysbiosis. A nutraceutical option such as omega-3 fatty acids at 2.4 g daily for 12 weeks58–60 has been shown to lower inflammation markers and proinflammatory cytokines in hemodialysis patients.Ultimately, oxidative stress and chronic inflammation induce harmful vascular changes mediated by immune dysfunction. The treatment approaches for oxidative stress, mitochondrial dysfunction, inflammation, and vascular changes are similar as the therapeutic options have overlapping benefits. Vascular changes occur when uncontrolled inflammation promotes immune dysregulation, leading to a loss of immune homeostasis responsible for appropriate immune cell recruitment and coordinated tissue repair.61The immune dysregulation leads to kidney injury and fibrosis, the clinical consequence of CKD progression. Botanical and herbal medicine offers potential adjunctive treatment options that addresses immune dysregulation in CKD. Both Astragalus membranaceus62–64 and Cordyceps sinensis or Cordyceps militaris65–67 have been studied in CKD populations and demonstrated results in reducing renal fibrosis, proteinuria, and stabilizing GFR.Although these results may be promising, these treatment options require confirmation and replication in future randomized controlled trials. Nonetheless, the overall safety profile of these multimodal treatment options is relatively safe and should be considered in an integrative treatment strategy. So, although decreasing stressors through diet, lifestyle, disease management, and pharmacotherapy are all very important, enhancing metabolic resilience allows the kidneys to be more tolerant of existing stressors, reducing the risk of damage and the rate of progression of CKD.ConclusionA new framework for understanding CKD will undoubtedly offer opportunities for the development and application of novel clinical strategies and disease management models that combine integrative approaches with current and standard medical treatments. Although major causes for CKD have been clearly identified, treatment options for slowing disease progression have been limited. Furthermore, the varying disease progression rates observed in CKD and ESKD populations warrant new perspectives on characterizing and quantifying the heterogeneous disease trajectories.Both preclinical and clinical studies have evaluated the effectiveness of integrative therapies by demonstrating preliminary evidence of enhanced clinical outcomes in CKD patients, irrespective of primary etiologies and contributing comorbidities, supporting the novel model that presents CKD as a balance between disease stressors and kidney resilience. Future disease management models for CKD must include an integrative, multidisciplinary, and whole-person approach to address the broader determinants of health and target mechanisms that drive the disease, while protecting the kidneys and preventing CKD progression to end-stage renal disease and delay dialysis initiation.Author Disclosure StatementNo competing financial interests exist.Funding InformationNo funding was received for this article.