Dietary aspects, including some dietary patterns have also been identified as possible risk factors for CKD.
Chronic Kidney Disease: Detection and Evaluation - American Family Physician
Obesity influences the development of CKD, among other factors, by predisposing to diabetic nephropathy, hypertensive nephrosclerosis and focal and segmental glomerulosclerosis. In a multicentric cohort study ELSA-Brasil , which included 15, Brazilian adults, the observed rate of excess weight was high, affecting This article discusses the pathophysiology aspects of the association between obesity and kidney disease, discussing the most important aspects and the most current evidence of this association.
Overweight and obesity have increased incidence and prevalence worldwide.
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In the United States, it is estimated that one third of adults are overweight and one third are obese. In the last 15 years, a steady increase in the number of obese patients undergoing dialysis has been observed. The association between increased waist circumference, high blood pressure, high fasting glucose and dyslipidemia constitutes the condition known as metabolic syndrome, which is associated with high cardiovascular risk. Several renal disorders are associated with overweight, obesity and metabolic syndrome, as summarized in Table 1. Overweight and obesity are associated with hemodynamic, structural and histopathological alterations in the kidney, as well as metabolic and biochemical alterations that predispose to kidney disease, even when renal function is normal in the conventional tests.
A series of events is triggered by obesity, including insulin resistance, glucose intolerance, hyperlipidemia, atherosclerosis and hypertension, all of which are associated with increased cardiovascular risk. The association between CKD and dyslipidemia has also been described, but its causes are still unknown. Insulin action resistance, present in CKD, reduces the activity of lipoprotein lipase, which may be implicated in the pathophysiology of dyslipidemia in CKD. Obesity leads to increased renal tubular sodium reabsorption, impairing pressure natriuresis and causing volume expansion due to the activation of the sympathetic nervous system SNS and the renin-angiotensin-aldosterone system RAAS.
Compression also occurs in the kidneys, especially when visceral obesity is presente.
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The increase in sodium reabsorption and consequent extracellular volume expansion is a central event in the development of SAH in obesity. Some evidence suggests that an increase in sodium reabsorption occurs in some segments in addition to the proximal tubule, possibly in the loop of Henle.
Glomerular hyperfiltration, associated with increased blood pressure and other metabolic alterations such as insulin resistance and DM, finally result in kidney damage and reduced GFR 3 , 7 , 8. The sympathetic nervous system SNS activation also contributes to obesity-related hypertension. There is evidence that renal denervation reduces sodium retention and hypertension in obesity, suggesting that SNS activation induced by obesity increases blood pressure mainly due to the sodium retention stimulus, rather than vasoconstriction.
The mechanisms that lead to SNS activation in obesity are not yet fully understood, but several factors have been proposed as triggers for this stimulus, including hyperinsulinemia, hyperleptinemia, increased levels of fatty acids, angiotensin II levels and baroreceptor reflex alterations.
An increased production of endothelin-1 has also been described in obese subjects, which further contributes to the elevation of blood pressure levels and consequently to renal dysfunction. Adipose tissue accumulation, especially in visceral adiposity, causes kidney compression, and a consequent increase in intrarenal pressure. The excess of retroperitoneal adipose tissue involves the kidneys and penetrates the renal hilum up to the medulla, causing compression of the renal medulla and increased hydrostatic pressure of the renal interstitial fluid.
Excess visceral fat also increases the intra-abdominal pressure, causing further renal compression. As the kidneys are surrounded by a capsule, which has low compliance, extracellular matrix accumulation can further exacerbate intrarenal compression and increase the hydrostatic pressure of the interstitial fluid. This increase in intrarenal pressure, in turn, compresses the loop of Henle and peritubular capillaries vasa recta , which reduces the flow of fluids through the renal tubules leading to sodium reabsorption by them.
Another important factor in the pathophysiology of obesity renal complications is the so-called "lipotoxicity", which refers to the disorders caused by the exacerbated metabolism of fatty acids in non-adipose tissue, such as skeletal muscle, pancreatic islets, myocardium and possibly the kidneys. In "overnutrition" states, the supply of fatty acids to the tissues exceeds the metabolic needs, leading to a compensatory increase in their oxidation. The increase in fatty acid metabolism leads to the production and release of several substances harmful to the cells, such as the products of lipid peroxidation and triglycerides, which can induce apoptosis and fibrosis in non-adipose tissues.
Inflammation itself is a risk factor for renal function loss. There is also evidence that obesity itself increases albumin excretion, which progressively increases with obesity severity and, in rare cases, can lead to nephrotic syndrome. Focal and segmental glomerulosclerosis FSGS is the type of glomerulonephritis most often associated with obesity. The morphological findings include glomerulomegaly, predominance of perihilar variant and mild podocyte fusion.
The association between obesity, MS and nephrolithiasis has been observed in some studies, mainly due to increased serum uric acid levels in obese individuals. Although obesity represents a major risk factor for the development of cardiovascular disease, some studies have shown that obesity is a protective factor in individuals with end-stage CKD undergoing dialysis , 8 , 31 perhaps because malnutrition is associated with higher mortality when compared to obesity.
However, even in patients undergoing dialysis, visceral obesity is associated with increased risk of coronary calcification and adverse cardiovascular events.
The incidence of obesity has been increasing worldwide and is an important risk factor for kidney disease. There is evidence that obesity alone can lead to the development of kidney diseases, including chronic kidney disease, glomerulopathy and nephrolithiasis. The pathophysiology of obesity-related kidney disease includes anatomic and hemodynamic alterations in the renal system. More studies are required to better understand the association between obesity and kidney disease. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
Lancet ; Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Obesity and chronic kidney disease. J Ren Nutr ;SS Early diagnosis saves life: focus on patients with chronic kidney disease. Kidney Int Suppl ; Prevalence of chronic kidney disease and associated risk factors--United States, J Bras Nefrol ; Is obesity a major cause of chronic kidney disease?
Adv Ren Replace Ther ; The effect of obesity on chronic kidney disease. J Ren Nutr ; Obesity, weight gain, and the risk of kidney stones. JAMA ; Am J Kidney Dis ; Patients who were nondippers and those who were reverse dippers had an increased risk of renal death and cardiovascular events Table 5. Only 2 studies 28 , 29 have previously compared the prognostic role of ABPM and office BP measurement in this population. The current study confirms the greater predictive value of ABPM and extends this observation to a more heterogeneous population including women and non-US patients.
Chronic Kidney Disease: Detection and Evaluation
In contrast to previous studies, our results demonstrate that the predictive role of ABPM is independent of other risk factors, such as diabetes mellitus, cardiovascular disease, proteinuria, hemoglobin level, and GFR. Of interest, the lack of predictive value of office BP measurement, as well as office BP target level, raises concerns regarding the adequacy of recommendations of hypertension guidelines that are derived mainly from expert opinion and post hoc analyses rather than randomized trials. Among the components of ABPM, nighttime systolic BP was a stronger predictor than daytime systolic BP for both end points, with an increased risk for the renal end point occurring for daytime SBP higher than mm Hg and an increased risk for the cardiovascular end point occurring for nighttime SBP higher than mm Hg.
The analysis with continuous variables confirmed the data obtained with the categorization of BP in quintiles. Interestingly, our data suggest that caution should be exercised with excessively low daytime SBP values because of the potential increase in cardiovascular risk Figure 2. The analysis of daytime and nighttime BP target levels provides another important finding of our study. International guidelines 1 - 3 , 35 do not provide specific thresholds for daytime and nighttime BP for patients with CKD. To determine whether achieving these goals implies a favorable risk factor profile or is causally associated with good outcomes will require randomized controlled trials.
Our results therefore suggest that the ABPM target levels recommended for patients with essential hypertension can be reasonably used in patients with CKD. This study also provides evidence that the lack of physiological BP decline during nighttime predicts important clinical outcomes in CKD, as described in a non-CKD population.
Interestingly, this analysis also confirmed the poor predictive role of office BP measurement, as it was ineffective in discriminating risk profile across dipping categories. Previous small, retrospective studies reported 41 - 44 the relationship between altered circadian pattern of BP and more rapid decline in renal function in specific subgroups of patients with CKD; however, none of these studies used important clinical end points such as ESRD, death, or cardiovascular events.
More recently, Redon et al 45 evaluated the risk of renal death in a small number of patients with CKD stages 3 and 4. However, the population studied was scarcely representative of a typical CKD population because diabetic patients, those with previous cardiovascular disease, and those with more advanced CKD were excluded. This selection bias led to an event rate in these patients much lower than that in the current study and in the cohort evaluated by Agarwal and Andersen, 28 therefore making the study by Redon et al somewhat underpowered. Only 1 study has investigated the effect of nondipping on cardiovascular outcome.
Analyzing a cohort of US veterans, Agarwal and Andersen 29 found that nondipping was associated with increased cardiovascular risk, but its predictive role disappeared after adjusting for other risk factors with the use of propensity scores. In contrast, our study found that an abnormal dipping pattern was a strong predictor of renal and cardiovascular outcomes, even after adjusting for the main demographic and clinical factors influencing dipping status.
The current study has some limitations. First, our study included few diabetic patients and was racially homogenous. A larger study with a more diverse population would allow generalization of our findings to patients with diabetes and nonwhite individuals. Second, ABPM data are based on a single set of measurements, which can lead to some imprecision, in particular, for dipping status. The third limitation relates to treatment of hypertension. The IDACO investigators demonstrated that use of antihypertensive drugs removed the significant association between cardiovascular events and daytime BP.
Finally, patients with true normotension were excluded, which may explain the difference with the IDACO study. The prediction of renal and cardiovascular risk among patients with CKD treated according to BP measured in physicians' offices was better with ABPM, in particular, nighttime BP and an abnormal dipping pattern. In contrast, office BP measurement was prognostically less informative.
Interventional studies based on ABPM rather than office BP measurement are urgently required in this high-risk population. Author Contributions: Dr Minutolo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Statistical analysis : Agarwal, Borrelli, and Chiodini. Administrative, technical, and material support : Zamboli and De Nicola. All Rights Reserved. Figure 1. View Large Download. Table 1. Demographic and Clinical Characteristics of Patients.
The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease Study. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the Irbesartan Diabetic Nephropathy Trial: clinical implications and limitations.
Prevalence and clinical correlates of white coat hypertension in chronic kidney disease. Effects of age on hypertensive status in patients with chronic kidney disease. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension.
Changing the timing of antihypertensive therapy to reduce nocturnal blood pressure in CKD: an 8-week uncontrolled trial. Prediction of mortality by ambulatory blood pressure monitoring versus screening blood pressure measurements: a pilot study in Ohasama. Prognostic value of ambulatory and home blood pressure compared with office blood pressure in the general population: follow-up results from the PAMELA study. Ambulatory blood pressure and year risk of cardiovascular and noncardiovascular mortality: the Ohasama study.
Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin Outcome Study. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Progression of diabetic nephropathy—is diurnal blood pressure rhythm as important as absolute blood pressure level?
LOW BP TARGET IN CKD PATIENTS: SAFETY AND BENEFITS
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