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REVIEWS

Obesity-related cardiorenal disease: the benefits of bariatric surgery
Wiebke Fenske, Thanos Athanasiou, Leanne Harling, Christiane Drechsler, Ara Darzi and Hutan Ashrafian
Abstract | The inexorable increase in the prevalence of obesity is a global health concern, which will result in a concomitant escalation in health-care costs. Obesity-related metabolic syndrome affects approximately 25% of adults and is associated with cardiovascular and renal disease. The heart and kidneys are physiologically interdependent, and the pathological effects of obesity can lead to cardiorenal syndrome and, ultimately, kidney and heart failure. Weight loss can prevent or ameliorate obesity-related cardiorenal syndrome, but long-term maintenance of a healthy weight has been difficult to achieve through lifestyle changes or pharmacotherapy. Bariatric surgery offers both sustained weight loss and favourable metabolic changes, including dramatic improvements in glycaemic control and symptoms of type 2 diabetes mellitus. Procedures such as Roux-en‑Y gastric bypass offer immediate multisystemic benefits, including bile flow alteration, reduced gastric size, anatomical gut rearrangement and altered flow of nutrients, vagal manipulation and enteric hormone modulation. In patients with cardiorenal syndrome, bariatric surgery also offers renoprotection and cardioprotection, and attenuates both kidney and heart failure by improving organ perfusion and reversing metabolic dysfunction. However, further research is required to understand how bariatric surgery acts on the cardiorenal axis, and its pioneering role in novel treatments and interventions for cardiorenal disease.
Fenske, W. et al. Nat. Rev. Nephrol. 9, 539–551 (2013); published online 6 August 2013; doi:10.1038/nrneph.2013.145

Introduction
Over the past three decades, the prevalence of obesity (defined as a BMI ≥30 kg/m2) has reached pandemic levels and poses a major threat to modern public health. In 2008, approximately 500 million people worldwide were considered to be clinically obese, a figure expected to rise to 700 million by 2015.1 Obesity-related metabolic syndrome now affects approximately 25% of the adult population, and at least 2.8 million adults die each year owing to obesity and obesity-related cardiovascular disease.1,2 The close physiological interdependence of the heart and kidneys is well recognized; these organs share responsibility for haemodynamic stability and end-organ perfusion via the tight-knit control of cardiac output, volume status and vascular tone. Key medi­ ators of the cardiorenal system include the sympathetic nervous system, the renin–angiotensin–aldosterone system (RAAS), local vasodilators such as nitric oxide (NO), adenosine, prostaglandins and the natriuretic peptides. A functional disturbance in either the heart or kidney consequently elicits a cascade of mediators that affect the other organ, explaining why renal failure frequently accompanies cardiac dysfunction and vice versa. This complex is referred to as cardiorenal syndrome, an indicator of poor prognosis frequently observed in patients with obesity. Cardiorenal syndrome can be defined as disorders of the heart and kidney whereby acute
Competing interests The authors declare no competing interests.

or chronic dysfunction in one organ induces acute or chronic dysfunction of the other (Table 1).3–6 Although weight loss and metabolic modulation produce beneficial effects on both cardiac and renal function,7 the availability of effective therapeutic strat­ egies for sustained weight loss and management of metabolic dysfunction remains limited.8 However, with the success of emerging bariatric surgical interventions, 9 weight loss and metabolic enhancement have become a novel therapeutic option for obesity-associated cardiac and renal disease.7,10 Previous articles have focused on the potential ameli­ or­ating effects of bariatric surgery on either cardiac11,12 or renal function.13,14 In this Review, we concentrate on the cardiorenal interface, and analyse the complex pathological mechanisms by which obesity might affect physio­ logical cardiorenal interactions. In addition, we discuss the potential roles of surgically induced weight loss and metabolic enhancement in the prevention and treatment of obesity-related cardiorenal syndrome.

Obesity-related cardiorenal dysfunction
The complex association between obesity and cardio­ renal function is made up of a multitude of pathological processes (Figure 1).

Department of Internal Medicine, Endocrine and Diabetes Unit (W. Fenske), Department of Medicine, Division of Nephrology (C. Drechsler), University Hospital Würzburg, Oberduerrbacherstr 6, 97080 Würzburg, Germany. Department of Surgery and Cancer, Imperial College London, 10th Floor, Queen Elizabeth the Queen Mother Building, St Mary’s Hospital, Praed Street, London W2 1NY, UK (T. Athanasiou, L. Harling, A. Darzi, H. Ashrafian). Correspondence to: H. Ashrafian h.ashrafian@ imperial.ac.uk

T2DM and metabolic syndrome Patients who are overweight or obese account for ~80–90% of all cases of type 2 diabetes mellitus (T2DM).

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VOLUME 9  |  SEPTEMBER 2013  |  539

diabetes mellitus. Nephrol. In fact. 18. 2. N. they do not have insulin resistance. amyloidosis 4 5 *Estimated glomerular filtration rate <60 ml/min/1. B.25 However. vasculitis. visceral adipose tissue promotes direct renal compression. demonstrates insulin resistance and increased cardiometabolic risk. 27–29 However.35. which is published under an open-access license by SAGE-Hindawi Access to Research.19 Metabolically healthy patients with obesity have less fatty infiltration of the liver and skeletal muscle than do metabolically abnormal obese individuals matched for BMI. dyslipidaemia or hypertension. This adipocyte load might also increase left ventricular wall stress and result in left ventricular dilatation. but also by the increased fat mass itself.nature.41 Furthermore. metabolic dysfunction. Table adapted from Shah. 920195 (2011). end-stage renal disease (ESRD)26 and accelerated atherosclerosis in obese patients with T2DM. Abbreviation: CRS.com/nrneph . due to increased metabolic activity of the excess adipocytes. resulting in a significantly higher incidence of nephrotic syndrome and ESRD.73 m2. still under debate. End-organ effects of T2DM Microvascular and macrovascular disease are leading risk factors for cardiovascular complications. and account for their high risk of death from cardiovascular disease. All rights reserved www.30 Obesity-related glomerulo­ pathy leads to glomerular changes that are distinct from those seen in diabetic nephropathy.REVIEWS Key points ■■ The global epidemic of obesity and metabolic syndrome is associated with both renal and cardiovascular disease ■■ The physiological interdependence of the kidneys and heart leads to pathology in both organs as a consequence of obesity and metabolic dysregulation— termed cardiorenal syndrome ■■ Bariatric surgery offers long-term weight reduction and profound improvements in metabolic dysfunction. 540  |  SEPTEMBER 2013  |  VOLUME 9  © 2013 Macmillan Publishers Limited. impairing both vascular (vasa recta) and renal tubular (loop of Henle) function. Int. K. including the resolution of type 2 diabetes mellitus and decreased cardiovascular risk ■■ The renoprotective and cardioprotective effects of bariatric surgery ameliorate renal and cardiac failure through weight-dependent and weight-independent mechanisms leading to improved organ perfusion and improved metabolic function ■■ Increased knowledge of the mechanisms through which bariatric surgery acts on the cardiorenal axis could lead to future advances in the management of obesity-related cardiorenal disease ■■ Functional metabolic and endocrinological phenotyping might increase the efficiency of identifying patients with obesity who are at high risk of cardiorenal complications and might benefit from early bariatric management high interindividual and intraindividual variability in the body composition–metabolism relationship. & Greaves. obesity-related cardiomyopathy is not confined to the ventricles.15 and severe obesity (BMI ≥35 kg/m 2 ) increases this risk 93-fold. a subgroup of patients with normal weight and little subcutaneous fat. 31–34 as well as promoting RAAS activation.38–40 A similar remodelling process might also occur in the right ventricle.24.9 kg/m2) have a fivefold higher risk of T2DM than do those with a BMI <20 kg/m. and also has a much more aggressive disease course than diabetic nephro­ pathy. Whether this relationship is causative or not is. diabetic cardiomyopathy and heart failure are important risk factors for cardiac morbidity and mortality in patients with obesity.42 Overweight women (BMI 25. inflammation. Affected patients are at increased risk of progressive heart failure and sudden cardiac death. J. about 30% of patients with obesity are considered metabolically healthy.31 Furthermore. renal damage in these patients is not only mediated by vascular disease and hypertension. particularly in the presence of pulmonary arterial hypertension secondary to obesity-related obstructive sleep apnoea. but a markedly increased visceral fat mass. which in severe cases can be accompanied by systolic dysfunction.37 Diabetic cardiomyopathy is typically characterized by increased preload and afterload values. which has independent adverse effects on the progression of chronic kidney disease (CKD). myocardial infarction and pulmonary ooedema) secondary to acute renal failure Left ventricular hypertrophy and diastolic heart failure secondary to renal failure Sepsis. which is discussed below in more detail.16 Despite the strong association between excess body adiposity and T2DM. not all obese individuals will develop T2DM. cardiorenal syndrome.20–23 leading to the suggestion that insulin resistance and metabolic syndrome are associated with non­ alcoholic fatty liver disease (NAFLD).0–29.24 emphasising the multifaceted nature of the obesity phenotype and the Table 1 | Classification of cardiorenal syndrome based on the aetiology of dysfunction109 CRS type 1 2 3 Name Acute cardiorenal syndrome Chronic cardiorenal syndrome Acute renocardiac syndrome Chronic renocardiac syndrome Secondary cardiorenal syndrome Description Acute worsening of cardiac function leading to acute kidney injury Chronic abnormalities in cardiac function leading to chronic kidney disease* Acute worsening of renal function contributing to cardiac dysfunction Chronic abnormalities in renal function leading to heart disease Systemic condition causing simultaneous dysfunction of the heart and kidney Example Acute decompensated heart failure and subsequent worsening of renal function Congestive heart failure Uraemic cardiomyopathy (arrhythmias. therefore. mechanical atrial stretch and subsequent dilatation contribute to an increased risk of atrial fibrillation and stroke (Table 2).36 Aside from atherosclerotic disease. compensatory eccentric left ventricular hypertrophy and decreased diastolic compliance.17 Conversely. 2011. ~40% of patients with hepatic steatosis are not insulin resistant. that is.

Sustained weight loss after surgery may reduce glomerular hyperfiltration. leading to hyperglycaemia and hyperinsulinaemia. Furthermore. Hyperglycaemia increases the activation of protein kinase C and stimulates both the sorbitol–aldose reductase pathway (wherein glucose is reduced to sorbitol.44.45 Furthermore. no change Obesity Bariatric surgery/ weight loss or or or or or or or or or or Dyslipidaemia and atherosclerosis Obesity leads to dyslipidaemia through impaired adipo­ cyte fatty acid trapping and excessive adipocyte lipo­ lysis. Metabolic surgery can reverse systemic hypertension. . reduce albuminuria and improve renal function. decreases. These changes promote the release of endothelin‑1 and lead to vasoconstriction and athero­ sclerosis. which is converted to fructose) and the RAAS. which can lead to renal artery stenosis. metabolic surgery might also improve cardiac function via the actions of hormones such as GLP‑1 and ghrelin and the adipokines leptin and adiponectin. RAAS.REVIEWS Decreases Direct nephrotoxic effects Proteinuria Kidney function GFR Improves Glomerulosclerosis. The network of interactions between obesity. By modulating the entero-cardiac axis. and also increases the generation of advanced glycation end products and reactive oxygen species (ROS). Metabolic effects of T2DM Metabolic changes resulting from both hyperglycaemia and insulin resistance also have deleterious effects on cardiovascular health. ultimately downregulating the PI3K pathway and the vasoprotective effects of NO. resolution of type 2 diabetes mellitus and systemic hypertension might reduce progression or even reverse chronic kidney disease. paracrine and inflammatory signalling. 43 Insulin resistance affects a number of signalling pathways. 46 These changes in lipid profile potentiate the direct and indirect mechanisms of endothelial injury. All rights reserved . and eventually atherosclerotic plaque formation (Figure 1). increased. vascular smooth muscle cell proliferation. renin–angiotensin–aldosterone system. GFR. glomerular filtration rate. endocrine. including subendothelial macrophage uptake of LDL (resulting in the formation of foam cells).46 Increased cardiovascular risk and atherogenic dyslipidaemia might develop even in patients with a normal BMI (>21 kg/m2)46. improve systolic and diastolic function and precipitate reverse cardiac remodelling leading to improvement of obesityassociated cardiomyopathy. decreased. hypoxia Obesity Insulin resistance Systemic inflammation Adipokines/ leptin Sympathetic activity Dyslipidaemia and atherosclerosis Arterial hypertension Metabolic surgery Endothelial dysfunction Atherosclerosis Arterial stiffness and vasoconstriction Coronary artery disease Direct cardiotoxic effects RAAS Renal blood flow Na+ reabsorption Volume overload Preload Sympathetic activity Vasoconstriction Afterload Cardiac function Improves Figure 1 | Mechanisms of obesity-related cardiorenal syndrome and the beneficial effects of metabolic surgery.48–50 Renal atherosclerosis.28 The hyperinsulinaemia associated with T2DM produces sympathoexcitatory and Na2+-retaining effects. increased levels of small dense LDL particles. Abbreviations: .51 High-grade Table 2 | Obesity and weight modification on heart function Parameter Haemodynamic variable Cardiac output Peripheral vascular resistance Blood pressure Diastolic function Systolic function Ejection fraction Structural characteristics Left ventricular mass Left ventricular volume Left atrial volume Abbreviations: . and decreased NATURE REVIEWS | NEPHROLOGY VOLUME 9  |  SEPTEMBER 2013  |  541 © 2013 Macmillan Publishers Limited. is an independent risk factor for the progression of cardiovascular disease and results in renal vascular hypertension and ischaemic nephropathy. levels of HDL cholesterol. . volume overload Type 2 diabetes mellitus Endothelial injury. leading to a rise in blood pressure. while leaving the MAPK pathway un­ affected. which lead to further stimulation of the MAPK pathway and a reduction in NO production. hyperfiltration Sympathetic activity Na+ reabsorption. defective PI3K signalling impairs glucose uptake. cardiac and renal impairment comprises a complex multisystemic dialogue including neurohormonal. increases. ­ .47 who present with a combination of elevated serum triglyceride levels.

all of which negatively affect vascular reactivity. inducing systemic vaso­ constriction.56.107 Furthermore. insulin. these effects of aldo­ sterone might occur both directly and independently of angiotensin II.108 Results from animal models demonstrating the protective effect of antioxidant administration have also highlighted the role increased oxidative stress in both cardiovascular and renal injury. by activating fatty acid oxidation.61 This inflammation is further characterized by increased levels of circulating C‑reactive protein. postinfarction myocardial hypertrophy is mediated by leptin.75 Leptin is secreted by adipocytes at levels that are in direct proportion to adipose tissue mass. endothelial function. cardiovascular events and progression of renal disease. chronic hyperleptinaemia potentiates renal fibrosis and produces glomerulosclerosis and proteinuria in both normal-weight rats and mice with metabolic syndrome as a result of chronic feeding of a high-fat diet.63–65 IL‑6. renal fibrosis. skeletal muscle lipid oxidation and adipocyte differentiation. High aldosterone levels also promote inflammation and oxidative stress in the renal and cardiac vessel wall. and can be reversed by leptin receptor blockade.76. which react with NO.59 Obesity is also often associated with low-grade chronic inflammation.102 However. promote hypertension by increasing renal sympathetic activity 78–80—a mechanism linking sympathetic hyperactivity to cardiorenal deterioration.95. reduced production of adiponectin in patients with obesity confers an increased risk of cardiovascular disease (Figure 1). ROS and platelet-activating factor. and contribute to cardiovascular fibrotic changes and hypertrophy. mesangial proliferation and podocyte dysfunction.97.REVIEWS atherosclerotic lesions in the renal artery might decrease renal perfusion and impair renal function. leptin produces direct negative inotropic effects (Figure 1).54–57 Elevated circula­ ting levels of free fatty acids. which promotes vasoconstriction and renal Na2+ retention.98 The role of apelin in obesity-related hypertension is not yet fully understood.87 Leptin induces the proliferation. leading to increased catecholamine levels and obesity-related hypertension. lead to a state of sympathetic dominance.94 Furthermore.109 www. differentiation.81–83 Leptin increases oxidative stress by stimulating production of ROS. VEGF) and decreases adiponectin release. which exa­ cerbates hypertension and potentiates the cycle of further atherosclerosis.96 Under normal conditions. might produce chronic cardiac sympathetic overstimulation and reduce parasympathetic drive. or baseline blood pressure. 100 Adiponectin promotes insulin sensitivity. resistance to the hypotensive effects of apelin might develop in the long term. These two parameters are also markedly reduced in patients who are overweight or obese. and when combined with obesity related sympathetic overactivity. which suggests that local production of angiotensin in this tissue might be controlled at the adipocyte level.58 Reduced beat-to-beat heart rate variability and decreased parasympathetic activity is a powerful predictor of death after myocardial infarction. renal and cerebrovascular disease. 62 tumour necrosis factor (TNF). PAI‑1. leptin and angio­ tensin II potentiate these effects. reducing circulating triglyceride levels and subsequently altering adenylate cyclase function.99 Adiponectin is a 244 amino acid protein. which is attributed to local hypoxia within the expanding adipose tissue60 that stimulates the expression and secretion of cytokines (such as leptin.101 By heightening NO synthase activity and NO production. apelin.88–93 In rats.86 Furthermore. promo­ting myocyte growth. However.66–68 transforming growth factor β. promoting renal Na2+ and water retention and increasing aldosterone production. as the antiproteinuric influence of angiotensin II inhibition can be reversed by aldosterone infusion. haptoglobin and serum amyloid A.70 Furthermore.K+-ATPase activity. the levels of which are inversely correlated with fat mass in adults and—uniquely—reflect the metabolic activity of adipo­ cytes. apelin decreases blood pressure and prevents hypertension by inducing vaso­ dilatation.71–73 and has been independently associated with death from coronary heart disease in apparently healthy men and women. activating angiotensin II.52 hypertension independently of BMI. this hormone exerts cardioprotective effects. which are found in patients with obesity whose hypothalamus and smooth muscle cells are resistant to the anorectic actions of leptin. These inflammatory cytokines have profound vaso­ active effects leading to the release of prostanoids. angiotensin II and angiotensinogen receptors. bradykinin.84 decreasing its bioavailability and increasing Na+. as well as tubulointerstitial inflammation. leuko­ trienes.104–106 Subsequent increases in circulating angiotensinogen levels serve both as a cause and mediator of adipocyte hyper­ trophy. and acts under physiological conditions on hypothalamic neuro­ peptide Y and agouti-related peptide neurons to reduce food intake. glomerulosclerosis. and reducing ROS generation.85. or high circulating apelin levels might enable this protein to cross the blood–brain barrier and act in the central nervous system to stimulate sympathetic outflow and increase blood pressure in individuals with obesity.103 Sympathetic activation and inflammation The sympathetic nervous system is an important regulator of metabolic and cardiovascular function. insulin resistance.74. and functional activation of myelocytic progenitor cells as well as primitive haemo­poietic and progenitor cells in the heart. IL‑8 and IL‑10. and a diminished response to heart rate variation and blood pressure.69.34. and promote athero­sclerosis.77 Elevated circulating leptin levels. hypertrophy and sub­ sequent cardiac dysfunction. 53 An obesity-related reduction in baroreceptor sensitivity.com/nrneph  © 2013 Macmillan Publishers Limited. All rights reserved . Elevated leptin levels also predict the develop­ment of 542  |  SEPTEMBER 2013  |  VOLUME 9 RAAS activation in adipose tissue White adipose tissue abundantly expresses renin. and a concomitant rise in central sympathetic outflow increases arterial stiffness.nature. inducible NO synthase. the presence of this proinflammatory cytokine profile might be a powerful predictor of (and aetiological contributor to) cardiovascular.

through cardiac and renal fatty infiltration and dis­ ordered biological signals. Hyperinsulinaemia leads to increased uric acid synthesis as well as reduced renal excretion of both uric acid and Na2+. VOLUME 9  |  SEPTEMBER 2013  |  543 . The direct mechanisms underlying this inter­ action are unclear but are probably mediated by a reduction in glomerular filtration rate (GFR). Bariatric procedures might offer a unique opportunity to disrupt crosstalk between the cardiovascular and renal systems.144 Roux-en‑Y gastric bypass (RYGB) powerfully modulates postoperative levels of this toxin.138–140 In patients with metabolic syndrome. insulin resistance. This algorithm clarifies the role of bariatric surgery in the treatment of chronic cardiorenal syndrome in patients with a BMI of 35–40 kg/m2 and obesity-related comorbidities (such as T2DM). Emerging evidence indicates that cardiorenal syndrome is derived from the accumulation of uraemic toxins.118 obesity 119 and NAFLD.143 However. activation of the RAAS. inflammatory cytokines and modulators of renal function. humoral factors (such as natriuretic peptides) released from the heart.109.110 endothelial dysfunction. insulin resistance. prohypertrophic agents (such as angiotensin II and endothelin‑­­ 1) and biochemical inducers of apoptosis such as inter­ leukins and other inflammatory cytokines. and renal dynamic and histo­ logical changes associated with metabolic syndrome can be ameliorated by treatment with xanthine oxidase inhibitors. Surgery might also be considered for patients with a BMI of 30–35 kg/m2 who have obesity-specific renal or cardiac disease.134 The resulting rise in serum uric acid levels after fructose ingestion is likely to have a key role in promoting the development of metabolic syndrome. 124–126 In humans. In the acute setting. metabolic syndrome. primary cardiac or renal disease should be managed supportively. abrupt. the increased oxidative stress and proinflammatory environment produced by high uric acid levels stimulates synthesis of C‑C motif chemokine 2 (also known as monocyte chemoattractant protein 1) and increases levels of IL‑6 and TNF. Furthermore.136 and activation of the RAAS. such as anti-diuretic hormone. determining the relative contribution of obesity to cardiac and renal disease via the cardiorenal axis will require increased scrutiny and further research using in vitro and in vivo models to reveal important mechanistic information. and might be considered a hallmark of today’s obesity epidemic. primary and secondary cardiorenal decompensation.114–117 dyslipidaemia.112 and is an independent predictor of 1‑year mortality in patients with acute myocardial infarction. the most common form of chronic liver disease. including coronary artery disease.131. including the highly protein-bound molecule indoxyl sulphate. in addition to a multitude of beneficial metabolic effects. the conventional view of this association as a simple epiphenomenon has evolved into a more complex understanding of the dual role of serum uric acid levels as a consequence of hypertension and metabolic syndrome. fibrogenic and oxidative stress inducing effects.120 as well as kidney dysfunction 121–123 and metabolic syndrome as a whole.113 Serum uric acid levels are a strong independent predictor of hypertension.128–130 Hence. cardiomyo­ p athy and primary renal disease.132 stimulation of vascular smooth muscle cell proliferation.120 inhibition of endothelial NO synthase (which reduces NO bioavailability).132 The rise in consumption of fructose over the past three decades correlates temporally with the rise in the prevalence of metabolic syndrome. Similarly. reciprocal renal effects are produced on the myocardium secondary to anaemia. expression of vaso­ active and inflammatory mediators. NATURE REVIEWS | NEPHROLOGY © 2013 Macmillan Publishers Limited. and their interaction. All rights reserved Cardiorenal syndrome The inherent crosstalk between the kidneys and heart can result in cardiorenal syndrome.133 One unique aspect of fructose ingestion. but also as an independent risk factor for metabolic syndrome. and this change is associated with profound shifts in the patient’s gut flora.131. These changes can lead to acute.120. or in patients with a BMI of ≥40 kg/m2 (morbid obesity).141 leading to a possible mechanism though which uric acid contributes to the pathogenesis of NAFLD. chronic.142 The added pathological effects of obesity on the cardio­ vascular and renal systems. respectively (Table 1). as the hyper­ tension. Uric acid production occurs in the liver and small intestine as a result of the activity of xanthine oxidase.135 The detrimental effects of hyper­ uricaemia include generation of mitochondrial oxidative stress. before consideration of surgical intervention. thereby breaking the vicious cycle of pathology and its sequelae that leads to both renal failure and heart failure.127 Previous studies report that the relationship between serum uric acid levels and cardiometabolic disease is observed not only in individuals with hyperuricaemia.REVIEWS Hyperuricaemia Hyperuricaemia is an important obesity-related risk factor for a number of cardiovascular conditions.145 Treatment of cardiorenal disease We propose an algorithm for the management of obesityrelated cardiorenal disease (Figure 2). which has prohypertrophic. heart failure and renal dysfunction can be worsened by obesity-related systemic inflammation. stroke111 and heart failure.137 Furthermore. accumulation of uraemic toxins. but also in those with uric acid levels in the normal to high-normal range. several studies have demonstrated a strong relationship between serum uric acid levels and NAFLD. The decline in GFR is partly due to a reduction in renal blood flow and other cardiac failure signals to the kidneys including sympathetic activation. in comparison with the intake of glucose and other dietary sugars. is that it rapidly contributes to depletion of ATP and increases the generation and release of uric acid by hepatocytes. which correspond to types 1–5 cardiorenal syndrome. uric acid in serum is the metabolic end product of purine degradation. T2DM. which is regarded as the hepatic manifestation of metabolic syndrome. which often presents as worsening renal function in patients with heart failure. are also likely to accentuate the severity of cardio­ renal syndrome.

bariatric surgery might lead to symptomatic improvement in all stages of obesity-related cardiomyopathy. 171–173 By contrast. Acute obesity associated CRS (type 1 or type 3) should be managed primarily with supportive renal and cardiac therapy in order to successfully treat the acute pathology. the hybrid RYGB is considered by some units as the ‘gold standard’ bariatric procedure in appropriately selected patients. The individuals who are most widely accepted to have an indication for bariatric surgery are patients seen in a multidisciplinary obesity unit who are morbidly obese (BMI >40 kg/m2) or those who have a BMI ≥35 kg/m2 and life-changing or life-threatening obesity-related comorbid­ ities. Patients with lower BMIs (>30 kg/m2) may also be considered for surgical intervention where specific obesity-related cardiomyopathy or nephropathy is present. However. However. patients may be considered for early surgical intervention. GLP‑1 is cardio­ protective. controlled Swedish Obese Subjects (SOS) trial demonstrated that bariatric operations are not only effective compared with medical treatment (in terms of the reduction in weight over 20 years in patients with obesity). pancreas. particularly in patients with pre-­existing systolic dysfunction and long-­ standing morbid obesity.151 Furthermore. the anatomical rearrangement of the upper gastrointestinal tract in patients after RYGB provokes several pleiotropic physio­ logical effects (summarized by the acronym BRAVE: bile flow alteration. These procedures are now primarily performed using minimally invasive laparoscopic techniques.9. lifestyle. These beneficial effects are partly ascribed to a reduction in systemic hypertension (Table 2). and levels of this hormone are upregulated after bariatric surgery. are safe and have an operative mortality not dissimilar to that of laparo­scopic cholecystectomy. GLP‑1 is a satiety hormone produced by duodenal cells. Surgical intervention can improve diastolic function and precipitate reverse remodelling of the heart.g. the underlying cause should be sought and treated before consideration for surgical intervention. Each type of bariatric surgery is associated with a unique benefit and risk profile that should guide the choice of procedure for each individual patient.152 decrease obesity-related disease.154 544  |  SEPTEMBER 2013  |  VOLUME 9  © 2013 Macmillan Publishers Limited. and can improve left ventricular systolic function even in patients with severe heart failure who are awaiting a heart transplant.165. in order to reduce the risk of disease progression.153 and increase life expectancy. In secondary. particularly in the long term.8. two pivotal hormones that are modulated by gastric bypass surgery. However. glucagon-­ like peptide‑1 (GLP‑1) and ghrelin.146 Various types of surgical procedures have. given its low morbidity and profound metabolic effects. the SOS study results demonstrated a decrease in cardiovascular morbidity and mortality in patients 20 years after gastric bypass. Abbreviation: CRS. and early molecular data suggesting the presence of an ‘enterocardiac’ hormonal axis through which such procedures can alter the metabolic milieu independently of their effects on body weight.157–159 The BRAVE effects occur almost instantaneously after gastric bypass surgery. anatomical gut rearrangement and altered flow of nutrients. type 2 nephropathy or diabetes mellitus cardiomyopathy CRS type 4 Chronic renocardiac syndrome CRS type 5 Secondary cardiorenal syndrome BMI >40 kg/m2 CRS type 2 Chronic cardiorenal syndrome Treat underlying pathology Consideration for bariatric surgery Figure 2 | Proposed algorithm for the management of patients with obesity-related cardiorenal syndrome.168 Changes in postprandial gut hormone release might also improve cardiac function after bariatric surgery. glucagon (produced in the pancreas). obesity-related e.com/nrneph Positive effects of bariatric surgery Decreased cardiovascular risk Weight loss seems to be a simple answer to most obesityrelated health problems. cardiorenal syndrome.156. been developed to achieve efficient and sustained weight loss in patients with excess weight. particularly in patients with dilated cardiomyo­ pathy or left ventricular systolic dysfunction.REVIEWS Primary cardiac Primary renal support and therapy support and therapy Acute disease successfully managed CRS type 1 Acute cardiorenal syndrome CRS type 3 Acute renocardiac syndrome BMI >30 kg/m2 BMI >35 kg/m2 with obesitywith obesity-related specific pathology comorbidities e.160–162 Reduced cardiovascular disease Bariatric surgery has beneficial effects on both structural and functional cardiac status. where CRS has reached a chronic (type 2 or type 4) stable state.166 Whether these postsurgical changes in the heart are a direct consequence of the weight reduction or an in­ direct response to the metabolic and endocrine changes and reduction in adipose tissue mass is the subject of ongoing debate. also modulate cardiac function. and brain) act as inotropes by activating cardiac membrane adenylate cyclase.151 but also improve quality of life. enterocardiac and entero­ renal axes independently of the weight-reducing effects of this surgery. when performed in a centre of excellence. these patients can be considered for metabolic surgical intervention in order to reduce the risk of disease progression.nature. production of the appetite-stimulating hormone www.163.150. and enteric gut hormone modulation)156 that modulate the enteroinsular. independently of baseline BMI. Once stabilized. and have key roles in the enterocardiac axis (Figure 1).143.164 Furthermore.167 However. these data are now supported by cardiac imaging studies demonstrating that bariatric surgery results in improved postoperative cardiac geometry. type 5 CRS.g.155 By bypassing the duodenum. Patients should be considered for surgery if BMI >40 kg/m2 or if BMI >35 kg/m2 with obesity-associated co-morbidities such as type 2 diabetes mellitus. bypass and hybrid surgeries (Box 1). By enhancing myocardial glucose uptake. therefore.169 Hormones such as secretin (produced in the duodenum).170 Moreover. All rights reserved . These procedures are termed bariatric surgeries.143. vagal manipulation. which. reduction of gastric size. and vasoactive intestinal peptide (produced in the gut. Bariatric procedures can be divided into three broad categories based on their mechanism of action: restrictive.147–149 The prospective. behavioural and pharmacological weight-loss strategies provide limited efficacy.

8 of days after the surgery). biliopancreatic diversion with or without duodenal switch. ■■ Examples: laparoscopic adjustable gastric banding.1% in patients undergoing bilio­ pancreatic diversion with or without duodenal switch.160 The long-term effects of this type of bariatric surgery are mediated by alterations in fat metabolism and adipo­ kine secretion.183. a dramatic improvement in glycaemic control is observed within days of the surgery. the antidiabetic effect of RYGB was attributed to absolute weight reduction.187 The mechanisms whereby RYGB induces resolution of T2DM can be categorized according to the organ systems NATURE REVIEWS | NEPHROLOGY © 2013 Macmillan Publishers Limited. Some procedures have management profiles that may require regular review. and reduces left ventricular wall stress. 190 gut microbiota modulation. In Roux-en‑Y gastric bypass. ileal interposition ■■ Advantages: Immediate and long-lasting metabolic enhancement and resolution of disease. ■■ Disadvantages: Beneficial effects may occur in association with weight loss and therefore are not always immediate. gastric banding and vertical banded gastroplasty.192 Persistent early changes include the powerful gut hormone effects that occur almost immediately after RYGB surgery and persist for many months thereafter.182 A meta-analysis of 221 studies found that resolution of T2DM occurred in 80. future studies must aim to standardize changes in biochemical markers according to a measure of preoperative and postoperative BMI. myocardial hypertrophy and blood pressure. ghrelin resistance in the setting of hyperghrelinaemia has been implicated as a precipitating factor in cardiac failure (Figure 1).160 Early postsurgical resolution of T2DM is thought to occur via manipulation of vagal nerve signalling and changes in gustatory neurohormonal signalling. in studies showing that 74–83% of patients with a preoperative diagnosis of T2DM remained free from the disease 14 years after bariatric surgery.178 However. 145 a shift in metabolite profiles191 and a reduction in inflammation. The role of gastric bypass surgery in reversing or ameliorating T2DM was first identified in the 1980s. Some cases have led to conditions such as nesidioblastosis. Ghrelin promotes vasodilatation and reduces susceptibility to (as well as improving tolerance of) coronary artery disease. Some procedures such as the biliopancreatic diversion have malabsorbtive effects that require intense nutritional monitoring and follow-up.188. sleeve gastrectomy ■■ Advantages: Procedures can be performed in a short time while offering durable metabolic benefits.180. in which they exert their principal actions (Figure 3).197 VOLUME 9  |  SEPTEMBER 2013  |  545 .183 Initially. This class of operations has been traditionally termed ‘malabsorptive’ procedures.189 alterations in bile metabolism.185 Furthermore.143. which suggests that at least some of these metabolic effects occur as a result of the absolute weight reduction.179 To determine whether adipokine levels modulate the cardioprotective effects of bariatric surgery above and beyond absolute weight reduction.136 In turn. decreases plasma leptin levels and promotes adipo­nectin production. the foregut is bypassed but 95% of the small bowel is left intact.180 By contrast. although the evidence for malabsorption remains generally unquantified (with the some specific exceptions).135.194 adding support for weight-independent amelioration of insulin resistance and improvement of T2DM control after RYGB surgery.193 Two randomized controlled trials194. however.186 In fact. adjustable gastric band).176 Gastric bypass surgery also modulates adipokine release. these changes might lead to reductions in inflammatory mediator release.174 Infusion of ghrelin in patients with heart failure significantly improves the cardiac index. they have a typically longer operative time with a higher degree of complexity requiring multiple gastrointestinal anastomoses.184 and has a far more potent effect on T2DM than is observed in patients who achieve similar amounts of weight reduction by nonsurgical means. despite resulting in similar weight reductions.181.143. the increased surgical morbidity and mortality associated with this procedure has limited its uptake. Partial ileal bypass aims to reduce cholesterol absorption from the distal ileum. the reader should note that similar changes in adipokine profiles and inflammation can be observed following chronic starvation. partial ileal bypass. 30% of patients had normal blood sugar levels and no longer required anti­ diabetic pharmacotherapy by the time of hospital discharge (an average 2.195 have demonstrated the pronounced efficacy of this form of bariatric surgery compared with medical treatment of T2DM up to 2 years after the procedure.3% of patients who underwent gastric bypass. long before any pronounced weight loss occurs. ■■ Example: Roux-en‑Y gastric bypass ■■ Advantages: These procedures carry the benefits of both full bypass and restrictive operations that can offer immediate weight-independent metabolic benefits and longer term weight-dependent disease resolution effects. Restrictive procedures Restrictive procedures.REVIEWS ghrelin (by P/D1 cells in the stomach) is upregulated after nonrestrictive bariatric procedures. only half of medically treated patients with T2DM attained adequate glycaemic control. the cost of treatment and regular follow-up is high and pharmacological treatment is poorly adhered to in this setting. Bypass procedures These procedures bypass a segment of the small intestine. Biliopancreatic diversion aims to reduce the absorption of fats and other nutrients. stroke volume and left ventricular ejection fraction. Hybrid procedures Hybrid procedures offer a combination of restriction and bypass to restrict food intake by creating a small gastric pouch. which limit the amount of food that can be consumed by surgically reducing the size of the stomach. RYGB and biliopancreatic diversion improve blood sugar levels more effectively than do other bariatric procedures.149.197 caloric restriction and weight loss. after RYGB. re-intervention and modification (for example. they also demonstrate the powerful metabolic benefits of bypass procedures. One study in particular revealed the results were statistically independent of patients’ baseline BMI. such as sleeve gastrectomy. which leads to metabolic changes. This figure reached 95. which avoids many of the adverse effects of other bypass procedures. However. ■■ Examples: jejunoileal bypass. All rights reserved Box 1 | Types of bariatric procedure Careful postoperative nutritional follow-up of all patients after bariatric surgery is vital (and should be standard practice). ■■ Disadvantages: As with bypass procedures.177. ■■ Disadvantages: Typically longer procedures with higher degree of complexity requiring multiple gastrointestinal anastomoses.196. intimal hyperplasia.175 Moreover. Improved glycaemic control Despite substantial advances in the management of T2DM.

the most severe form of NAFLD. Through these mechanisms. management of hypertension and appetite control. which is characterized by pancreatic β‑cell hyper­ trophy. restrictive bariatric procedures. and stimulate insulin release before the post­prandial rise in blood glucose.209 and inflammation. might contribute to this process. In addition to weight loss. Bariatric surgery might be associated with a histological improvement in steatosis. the failure of RYGB surgery to reverse obesity-induced β‑cell hypertrophy. and indirectly through improved glycaemic control. and the role of surgery in modulating other complications of NAFLD (such as T2DM and cardiovascular disease).156. perhaps through bile-acid-mediated enhancement of hepatocyte function. and development of ESRD is yet to be fully determined.212 Surgically induced weight reduction has an even more pronounced effect in this setting. ­.nature. All rights reserved Autonomic nervous input Hypertension control Appetite control Autonomic nervous input Hypertension control Bariatric surgery Heart failure Diabetic cardiomyopathy Obesity-related cardiomyopathy Cardioprotection Improved geometry Beneficial adipokine profile Beneficial or inotropic gut hormone profile Improved glycaemic control Chronic renal failure Renoprotection Albuminuria Cardiorenal crosstalk Improved systemic perfusion Enhanced systemic metabolic profile Systemic and uraemic toxins Figure 3 | The mechanisms by which bariatric surgery induces resolution of cardiac and renal disease.207 Improved renal function Weight loss has been associated with a decrease in protein­ uria in patients both with and without renal impairment. do not confer the same renoprotective effects as RYGB.com/nrneph © 2013 Macmillan Publishers Limited. surgery is likely to have potential benefits in this setting in terms of ameli­ orating several systemic metabolic disturbances that contribute to the pathogenesis of NAFLD. the difference in albuminuria between these two time points is not statistically significant and no changes have been observed in levels of urea and creatinine. and can even worsen GFR and renal plasma flow. or by a combination thereof.198.214 a phenomenon that is not observed following nonsurgical weight loss strategies. 219 Surgically induced renoprotection www. Of particular interest are the incretin (insulin-stimulating) effects of RYGB and biliopancreatic diversion. islet hyperplasia and increased β‑cell mass.210. as well as for preventing 546  |  SEPTEMBER 2013  |  VOLUME 9  .199 In fact.215 Despite these findings. required to elucidate the role of bariatric surgery in these patients.204 and terminal liver failure. when compared with the levels in obese patients who did not undergo such procedures. Further research is. and improves renal function in patients with pre-existing glomerular hyper­filtration.211 and improving hepatic metabolism.202 cirrhosis. inflammation and fibrosis in patients with nonalcoholic steato­ hepatitis. or the persistence of changes in gut hormone signalling even after substantial weight reduction. Weight reduction and amelioration of metabolic disturbances are the mainstays of therapy for NAFLD. decreased.206 however.207 decreasing dyslipidaemia208. autonomic nervous system modulation. but might represent ‘autobionic’ (that is. or the creatinine clearance rate. therefore. that of surgery-related weight loss) on renal dysfunction. this capacity of RYGB to promote both insulin production and insulin sensitivity has led to a number of cases of hyperinsulin­ aemic hypoglycaemia (nesidioblastosis). Incretin hormones decrease insulin resistance via increasing insulin sensitivity in the liver and muscle. Bariatric surgery might resolve both cardiac disease and renal disease through multifaceted actions with effects on cardiorenal crosstalk.203 hepatocellular carcinoma. the independent effects of weight loss per se (and.217 Emerging evidence suggests that the largest postRYGB reductions in albuminuria and GFR occur in patients with obesity and concomitant metabolic syndrome or T2DM. bariatric surgery modulates obesity-related metabolic dysfunction to induce direct cardiac and renal benefits. bariatric surgery might mitigate NAFLD by normalizing insulin resistance and serum uric acid levels. Furthermore.161 The SOS trial results revealed a significant and persistent decrease in uric acid levels at both 2 years and 10 years of follow-up in patients who underwent bariatric surgery. Abbreviations: . However. are still poorly understood.200. The potential role of bariatric surgery in the treatment of NAFLD is complex and the underlying mechanisms are not fully understood. despite its beneficial effects on glycaemic control. via both direct effects on the heart and kidneys. in particular.213.218.212.201 Reversal of nonalcoholic fatty liver disease T2DM and NAFLD per se are not an indication for bariatric surgery in patients with a BMI <35 kg/m2. such as vertical band gastroplasty. the majority of the available evidence of this benefit comes from retrospective or nonrandomized studies. but these changes return to baseline by 12 months.216 Crucially.161. the replacement or boosting of physiological functions by the rearrangement and manipulation of existing tissue or organs)161 augmentation of pancreatic β‑cell function. increased. progression of CKD.205 However.160 The mechanisms underlying this effect of RYGB surgery are not yet fully elucidated.REVIEWS the progression of NAFLD to fibrosis. the benefits of bariatric surgery in patients with NAFLD who are at high risk of liver cirrhosis.213 Furthermore. although RYGB surgery is associated with significant reductions in obesity-related albuminuria at 12 months and 24 months of follow-up.219 Early post-RYGB improvement in glomerular hyperfiltration also occurs in obese patients without T2DM.

Nephrol.. D.220. 1. Nelson. 2154–2169 (2003).222 As such. together with the amount of weight loss. NATURE REVIEWS | NEPHROLOGY © 2013 Macmillan Publishers Limited. Obesity-related cardiorenal syndrome. weight reduction and the effects of surgical intervention. Dial. Diabetes Obes. and the elevated risk of cardiovascular and renal dysfunction in patients with obesity remains unclear. to fill the gaps in our understanding of the pathophysiology of obesity-associated comorbidities. because creatinine production is proportional to muscle mass. J. 41. & Dietz. High Blood Pressure Research. with complete resolution of glomerulonephritis in one individual. particularly in complex organ systems such as the kidney and heart. “renal disease”. http:// www. Diet Assoc. Cardiol. therefore. adipose tissue distribution and the extent. Sjöström. gastric bypass surgery might delay the need for dialysis and/or kidney transplantation in patients with CKD. 725–728 (2003). although other factors (such as reductions in levels of circulating inflammatory cytokines. H. et al. et al. in the context of translational clinical trials. dyslipid­ aemia and T2DM. P . House. what effect this improvement has on the progression of renal disease and its associated mortality. the study was small. M. & Sloand. AND “bariatric surgery”.224 However. Conclusions Obesity-related cardiorenal disease results from the complex interplay of several shared elements.REVIEWS is. We also do not completely understand the multifaceted pheno­ type of obesity.223. therefore. These pathophysiological elements can now be successfully treated with bariatric surgery. 3. Increased study of bariatric surgery and its effects on the cardiorenal axis might.who.. 59–63 (2010). 357. Brinkworth. Ford. to fully assess the relationships between obesity. 1416–1420 (2010). proteomic and post-transcriptional variations that predispose patients to obesity and metabolic syndrome. Engl. E. “nephropathy”. J. J. Coll. D. H. J. Future research must focus on improving our knowledge of the intermediary physiological factors and genotypic.. 356–359 (2002). McCullough. hypertension and hyperlipidaemia and. Effects of bariatric surgery on mortality in Swedish obese subjects. We also searched the reference lists of identified articles for further relevant papers. alone and in combination. are needed to manage and develop the next generation of interventions and procedures to treat obesity-related. Review criteria A search for original articles published between 1953 and 2013 and focusing on obesity-associated comorbidities. 7. and of increased metabolic activity (rather than obesity itself). and Epidemiology and Prevention. N. I. RYGB also improves renal function in patients with obesity who already have CKD. et al. W. 9. JAMA 287. J. Renal function following long-term weight loss in individuals with abdominal obesity on a very‑low‑carbohydrate diet vs highcarbohydrate diet. World Health Organisation Fact Sheet No. the contributions of altered crosstalk between muscle and fat. (Greenwich) 12. 6. if so. “cardiorenal”. renal and cardiac dysfunction and the effects of bariatric surgery was performed in MEDLINE and PubMed. we do not yet fully appreciate the extent to which the deleterious effects of obesity are modulated by differing genetic and physiological mechanisms. L.. including hypertension. S. 8. the assessment of renal end points is hampered in a number of studies by their use of differing GFR assessment modalities and failure to control for pre­ operative BMI. autonomic disturbance. A. Metab. despite early research into this field. S. on postsurgical renal and cardio­ v ascular end points requires further clinical and mechanistic investigation. J.int/mediacentre/factsheets/fs311/ en/index. Why is chronic kidney disease the “spoiler” for cardiovascular outcomes? J. and could even have a role in improving comorbidities before transplantation in patients who are morbidly obese and undergoing dialysis. 25. “cardiac disease”. However. Thirdly. particularly with regard to the influence of body composition.222 One study in 45 patients with CKD and various renal pathol­ ogies demonstrated improvement or stabilization of CKD in nine patients. W. 557–570 (2009). Transplant. Finally. & Clifton. In addition. although encouraging evidence supports the existence of improved renal and cardiac outcomes after bariatric surgery. but the renoprotective effects of RYGB seemed to be very convincing. Sarnak. M. “cardiomyopathy”. cardiorenal disease. M. J. which improves both cardiovascular and renal outcomes and offers a unique method to concomitantly manage both systemic diseases via effects on cardio­ renal crosstalk. As such. D. Bisognano.html (2013). Med. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease. as yet. Giles. full-text papers. A. Both systems biology and mechanistic studies. Antonetti. Puterbaugh. All rights reserved VOLUME 9  |  SEPTEMBER 2013  |  547 . 11. the role of bariatric surgery in managing cardiorenal disease in patients who are only moderately obese or of normal weight is. changes in body composition should be examined. 4. G. Clin. location and composition of individual fat deposits. multisystem. WHO.221 Interestingly. the extent to which surgery modulates the need for dialysis. Hypertens. 2. Noakes. the influence of preoperative obesity duration. the reduction in muscle mass associated with weight loss makes serum creatinine levels an unreliable marker of GFR. a number of compelling clinical questions remain un­ answered. or the choice of bari­ atric procedure. 311: Obesity and Overweight [online]. 5. partly mediated by improved glycaemic control and blood pressure reduction. Secondly.. A. renal transplantation or cardio­vascular interventions and affects overall survival and quality of life is yet to be fully delineated. Circulation 108. Am. 633–638 (2010). 741–752 (2007). The emperor’s tailors: the failure of the medical weight loss paradigm and its causal role in the obesity of America. total fat mass. Firstly. identify important mechanisms that underpin the effects of weight changes on cardiorenal syndrome and spearhead the next generation of interventions for multisystem metabolic disorders. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. 110. renal lipotoxicity and oxidative stress) are also implicated. P . J. R. Definition and classification of Cardio-Renal Syndromes: workgroup statements from the 7th ADQI Consensus Conference. Buckley. Am. Moreover. unknown. Clinical Cardiology. The search terms used were “obesity”. Future studies should determine whether weight loss improves renal function independently of its effects on T2DM. All articles identified were English-language.

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