Obesity and Kidney Disease: Hidden Consequences of the Epidemic

Kövesdy, Csaba P.; Furth, Susan L.; Zoccali, Carmine

doi:10.17140/npoj-3-e007

Cited by 35 publications

(47 citation statements)

References 84 publications

(114 reference statements)

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“…The processes by which obesity leads to CKD are not fully understood. While the development of comorbidities such as diabetes and hypertension may explain a large proportion of the renal complications of obesity (10), there appear to be other factors involved. These include renal hemodynamics, endocrine factors, inflammation, oxidative stress, and the recently identified concepts of fetal programming and epigenetics.…”

Section: Pathophysiologic Mechanisms Of Ckd In Obesitymentioning

confidence: 99%

“…Independent of diabetes and hypertension, obesity increases microalbuminuria, which potentiates renal damage (4). Obesity affects renal hemodynamics such that when renal vasodilation occurs, renal perfusion increases and hyperfiltration results (10). Compounding this is the inappropriate activation of the renin-angiotensin aldosterone system in obese individuals (16), partly as a consequence of hyperinsulinemia and insulin resistance (11).…”

Section: Renal Hemodynamics and Endocrine Factorsmentioning

confidence: 99%

“…It contains various cell types, including macrophages and other inflammatory cells (11). In obesity, there is an up-regulation of proinflammatory adipocytokines such as resistin and leptin, and decreased secretion of the antiinflammatory cytokine IL-10 and chemokine adiponectin, further exacerbating the proinflammatory milieu (10,11,17). TNF-a, IL-6, and IL-8 are released, recruiting additional macrophages (18).…”

Section: Inflammation and Oxidative Stressmentioning

confidence: 99%

“…TNF-a, IL-6, and IL-8 are released, recruiting additional macrophages (18). The net result is a low-grade inflammatory state that promotes renal oxidative stress, glomerular inflammation, and tubulointerstitial fibrosis (10,11). In addition, lipids themselves can exert toxic effects.…”

Section: Inflammation and Oxidative Stressmentioning

confidence: 99%

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DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

et al. 2018

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Chronic kidney disease (CKD) is a global epidemic, and its major risk factors include obesity and type 2 diabetes. Obesity not only promotes metabolic dysregulation and the development of diabetic kidney disease but also may independently lead to CKD by a variety of mechanisms, including endocrine and metabolic dysfunction, inflammation, oxidative stress, altered renal hemodynamics, and lipotoxicity. Deleterious renal effects of obesity can also be transmitted from one generation to the next, and it is increasingly recognized that offspring of obese mothers are predisposed to CKD. Epigenetic modifications are changes that regulate gene expression without altering the DNA sequence. Of these, DNA methylation is the most studied. Epigenetic imprints, particularly DNA methylation, are laid down during critical periods of fetal development, and they may provide a mechanism by which maternal-fetal transmission of chronic disease occurs. Our current review explores the evidence for the role of DNA methylation in the development of CKD, diabetic kidney disease, diabetes, and obesity. DNA methylation has been implicated in renal fibrosis-the final pathophysiologic pathway in the development of end-stage kidney disease-which supports the notion that demethylating agents may play a potential therapeutic role in preventing development and progression of CKD.-Larkin, B. P., Glastras, S. J., Chen, H., Pollock, C. A., Saad, S. DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease.

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Section: Pathophysiologic Mechanisms Of Ckd In Obesitymentioning

confidence: 99%

Section: Renal Hemodynamics and Endocrine Factorsmentioning

confidence: 99%

Section: Inflammation and Oxidative Stressmentioning

confidence: 99%

Section: Inflammation and Oxidative Stressmentioning

confidence: 99%

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DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

et al. 2018

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“…2 The prevalence of both these diseases is increasing with the global epidemic of obesity, diabetes, hypertension, and an aging population. 3,4 Approximately half of all patients with heart failure have heart failure with preserved ejection fraction (HFpEF), and there are no treatments available that have conclusively been shown to reduce mortality or to…”

mentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study

Whittaker

Kragh

Hartleib‐Geschwindner

et al. 2019

Clinical Translational Sci

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Excessive activation of the mineralocorticoid receptor (MR) underlies the pathophysiology of heart failure and chronic kidney disease. Hyperkalemia risk limits the therapeutic use of conventional MR antagonists. AZD9977 is a nonsteroidal, selective MR modulator that may protect nonepithelial tissues without disturbing electrolyte balance. This phase I study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AZD9977 in healthy volunteers. Twenty‐seven male participants aged 23–45 years were randomized 3:1 to receive oral AZD9977 or placebo for 8 days (with twice‐daily dosing on days 2–7), in dose cohorts of 50, 150, and 300 mg (AZD9977, n = 6 per cohort; placebo, n = 3 per cohort). Adverse events occurred in 4 of 18 participants receiving AZD9977 (22.2%) and 6 of 9 receiving placebo (66.7%), all of mild or moderate severity; none were serious or led to withdrawal. AZD9977 was rapidly absorbed, with median time of maximum concentration of 0.50–0.84 hours across dose groups. Area under the curve and maximum concentration were approximately dose proportional but elimination and accumulation terminal half‐life increased with dose. Steady‐state was reached after 3–4 days, with dose‐dependent accumulation of 1.2–1.7‐fold. Renal clearance was 5.9–6.5 L/hour and 24–37% of AZD9977 was excreted in the urine. Serum aldosterone levels increased dose dependently from days −1 to 7 in participants receiving AZD9977, but serum potassium levels and urinary electrolyte excretion were unchanged. AZD9977 was generally well‐tolerated with no safety concerns. Exploratory outcomes suggested reduced hyperkalemia risk compared with MR antagonists. These findings support further clinical development of AZD9977.

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Kidney cachexia or protein‐energy wasting in chronic kidney disease: facts and numbers

Koppe

Fouque

Kalantar-Zadeh

2019

J cachexia sarcopenia muscle

159

105

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Background Weight loss and homeostatic disturbances of both energy and protein balances are characteristics of several illnesses including cancer, heart failure, and chronic kidney disease (CKD). Different definitions have been used to describe this deleterious process. The term protein‐energy wasting (PEW) has been proposed for CKD patients by the International Society of Renal Nutrition and Metabolism . Methods We searched the publication in Medline from February 2008 to September 2018 using PEW or cachexia in their title. Results Since its inception, the term PEW has been exceptionally successful, highlighted by 327 original publications referenced in PubMed over 10 years. Using this classification, several studies have confirmed that PEW is among the strongest predictors of mortality in CKD patients [hazard ratio of 3.03; confidence interval of 1.69–5.26 in 1068 haemodialysis patients and 1.40 (1.04–1.89) in 1487 non‐dialysed patients across PEW stages 0 to 4]. Based on this classification, prevalence of PEW is 28% to 54% among 16 434 adults undergoing maintenance dialysis. PEW prevalence increases when renal function declines, that is, from <2% in CKD stages 1–2 to 11–54% in CKD stages 3–5. A more general definition of cachexia for all chronic diseases proposed by the Society on Sarcopenia, Cachexia and Wasting Disorders was also published concurrently. In the CKD area, we found 180 publications using ‘cachexia’ underlining that some confusion or overlap may exist. The definitions of PEW and cachexia are somewhat similar, and the main difference is that a loss of body weight >5% is a mandatory criterion for cachexia but supportive for PEW. Conclusions The recent understanding of cachexia physiopathology during CKD progression suggests that PEW and cachexia are closely related and that PEW corresponds the initial state of a continuous process that leads to cachexia, implicating the same metabolic pathways as in other chronic diseases. Despite the success of the definition of PEW, using a more uniform term such as ‘kidney disease cachexia’ could be more helpful to design future research through collaborative groups of researchers with focus on cachexia.

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Obesity and Kidney Disease: Hidden Consequences of the Epidemic

Cited by 35 publications

References 84 publications

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study

Kidney cachexia or protein‐energy wasting in chronic kidney disease: facts and numbers

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