Obesity-Related Cardiorenal Disease

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Obesity-related cardiorenal disease: thebenefits 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 type2 diabetes mellitus. Procedures such as Roux-enY 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. etal. Nat. Rev. Nephrol. 9, 539551 (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 30kg/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 reninangiotensinaldosterone 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 (Table1).36 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 (Figure1).
Department of Internal Medicine, Endocrine and Diabetes Unit (W.Fenske), Department of Medicine, Division of Nephrology (C.Drechsler), University Hospital Wrzburg, Oberduerrbacherstr 6, 97080 Wrzburg, Germany. Department of Surgery and Cancer, Imperial College London, 10th Floor, Queen Elizabeth the Queen Mother Building, St Marys 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 ~8090% of all cases of type2 diabetes mellitus (T2DM).
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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, including the resolution of type2 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 compositionmetabolism relationship.

End-organ effects of T2DM Microvascular and macrovascular disease are leading risk factors for cardiovascular complications, end-stage renal disease (ESRD)26 and accelerated atherosclerosis in obese patients with T2DM, and account for their high risk of death from cardiovascular disease. 2729 However, renal damage in these patients is not only mediated by vascular disease and hypertension, but also by the increased fat mass itself, which has independent adverse effects on the progression of chronic kidney disease (CKD).30 Obesity-related glomerulo pathy leads to glomerular changes that are distinct from those seen in diabetic nephropathy, and also has a much more aggressive disease course than diabetic nephro pathy, resulting in a significantly higher incidence of nephrotic syndrome and ESRD.31 Furthermore, visceral adipose tissue promotes direct renal compression, impairing both vascular (vasa recta) and renal tubular (loop of Henle) function, 3134 as well as promoting RAAS activation.35,36 Aside from atherosclerotic disease, diabetic cardiomyopathy and heart failure are important risk factors for cardiac morbidity and mortality in patients with obesity.37 Diabetic cardiomyopathy is typically characterized by increased preload and afterload values, due to increased metabolic activity of the excess adipocytes. This adipocyte load might also increase left ventricular wall stress and result in left ventricular dilatation, compensatory eccentric left ventricular hypertrophy and decreased diastolic compliance, which in severe cases can be accompanied by systolic dysfunction.3840 A similar remodelling process might also occur in the right ventricle, particularly in the presence of pulmonary arterial hypertension secondary to obesity-related obstructive sleep apnoea. Affected patients are at increased risk of progressive heart failure and sudden cardiac death.41 Furthermore, obesity-related cardiomyopathy is not confined to the ventricles; mechanical atrial stretch and subsequent dilatation contribute to an increased risk of atrial fibrillation and stroke (Table2).42
Overweight women (BMI 25.029.9kg/m2) have a fivefold higher risk of T2DM than do those with aBMI <20kg/m, 2,15 and severe obesity (BMI 35kg/m 2 ) increases this risk 93-fold.16 Despite the strong association between excess body adiposity and T2DM, not all obese individuals will develop T2DM. Whether this relationship is causative or not is, therefore, still under debate. In fact, about 30% of patients with obesity are considered metabolically healthy; that is, they do not have insulin resistance, metabolic dysfunction, inflammation, dyslipidaemia or hypertension.17 Conversely, a subgroup of patients with normal weight and little subcutaneous fat, but a markedly increased visceral fat mass, demonstrates insulin resistance and increased cardiometabolic risk. 18,19 Metabolically healthy patients with obesity have less fatty infiltration of the liver and skeletal muscle than do metabolically abnormal obese individuals matched for BMI,2023 leading to the suggestion that insulin resistance and metabolic syndrome are associated with non alcoholic fatty liver disease (NAFLD), which is discussed below in more detail.24,25 However, ~40% of patients with hepatic steatosis are not insulin resistant,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, myocardial infarction and pulmonary ooedema) secondary to acute renal failure Left ventricular hypertrophy and diastolic heart failure secondary to renal failure Sepsis, diabetes mellitus, vasculitis, amyloidosis
4 5
*Estimated glomerular filtration rate <60ml/min/1.73m2. Abbreviation: CRS, cardiorenal syndrome. Table adapted from Shah, B. N. & Greaves, K. Int. J. Nephrol. 2011, 920195 (2011), which is published under an open-access license by SAGE-Hindawi Access to Research.
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Decreases Direct nephrotoxic effects Proteinuria Kidney function GFR Improves Glomerulosclerosis, hyperfiltration Sympathetic activity Na+ reabsorption, volume overload
Type 2 diabetes mellitus
Endothelial injury, 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. The network of interactions between obesity, cardiac and renal impairment comprises a complex multisystemic dialogue including neurohormonal, endocrine, paracrine and inflammatory signalling. Metabolic surgery can reverse systemic hypertension, improve systolic and diastolic function and precipitate reverse cardiac remodelling leading to improvement of obesityassociated cardiomyopathy. By modulating the entero-cardiac axis, metabolic surgery might also improve cardiac function via the actions of hormones such as GLP1 and ghrelin and the adipokines leptin and adiponectin. Sustained weight loss after surgery may reduce glomerular hyperfiltration, reduce albuminuria and improve renal function. Furthermore, resolution of type2 diabetes mellitus and systemic hypertension might reduce progression or even reverse chronic kidney disease. Abbreviations: , decreased; , increased; GFR, glomerular filtration rate; RAAS, reninangiotensinaldosterone system.
Metabolic effects of T2DM Metabolic changes resulting from both hyperglycaemia and insulin resistance also have deleterious effects on cardiovascular health. Hyperglycaemia increasesthe activation of protein kinase C and stimulates both thesorbitolaldose reductase pathway (wherein glucose is reduced to sorbitol, which is converted to fructose) and the RAAS, and also increases the generation of advanced glycation end products and reactive oxygen species (ROS).28 The hyperinsulinaemia associated with T2DM produces sympathoexcitatory and Na2+-retaining effects, leading to a rise in blood pressure. 43 Insulin resistance affects a number of signalling pathways, ultimately downregulating the PI3K pathway and the vasoprotective effects of NO, while leaving the MAPK pathway un affected. These changes promote the release of endothelin1 and lead to vasoconstriction and athero sclerosis.44,45 Furthermore, defective PI3K signalling impairs glucose uptake, leading to hyperglycaemia and hyperinsulinaemia, which lead to further stimulation of the MAPK pathway and a reduction in NO production.
levels of HDL cholesterol. 46 These changes in lipid profile potentiate the direct and indirect mechanisms of endothelial injury, including subendothelial macrophage uptake of LDL (resulting in the formation of foam cells), vascular smooth muscle cell proliferation, and eventually atherosclerotic plaque formation (Figure1).4850 Renal atherosclerosis, which can lead to renal artery stenosis, is an independent risk factor for the progression of cardiovascular disease and results in renal vascular hypertension and ischaemic nephropathy.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: , decreases; , increases; , no change
Obesity
Bariatricsurgery/ 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.46 Increased cardiovascular risk and atherogenic dyslipidaemia might develop even in patients with a normal BMI (>21kg/m2)46,47 who present with a combination of elevated serum triglyceride levels, increased levels of small dense LDL particles, and decreased

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atherosclerotic lesions in the renal artery might decrease renal perfusion and impair renal function, which exa cerbates hypertension and potentiates the cycle of further atherosclerosis, cardiovascular events and progression of renal disease.52 hypertension independently of BMI, insulin resistance, or baseline blood pressure.85,86 Furthermore, 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.34,87 Leptin induces the proliferation, differentiation, and functional activation of myelocytic progenitor cells as well as primitive haemopoietic and progenitor cells in the heart, promoting myocyte growth, hypertrophy and sub sequent cardiac dysfunction.8893 In rats, postinfarction myocardial hypertrophy is mediated by leptin, and can be reversed by leptin receptor blockade.94 Furthermore, by activating fatty acid oxidation, reducing circulating triglyceride levels and subsequently altering adenylate cyclase function, leptin produces direct negative inotropic effects (Figure1).95,96 Under normal conditions, apelin decreases blood pressure and prevents hypertension by inducing vaso dilatation.97,98 The role of apelin in obesity-related hypertension is not yet fully understood. However, resistance to the hypotensive effects of apelin might develop in the long term, or high circulating apelin levels might enable this protein to cross the bloodbrain barrier and act in the central nervous system to stimulate sympathetic outflow and increase blood pressure in individuals withobesity.99 Adiponectin is a 244 amino acid protein, the levels of which are inversely correlated with fat mass in adults anduniquelyreflect the metabolic activity of adipo cytes. 100 Adiponectin promotes insulin sensitivity, skeletal muscle lipid oxidation and adipocyte differentiation.101 By heightening NO synthase activity and NO production, and reducing ROS generation, this hormone exerts cardioprotective effects.102 However, reduced production of adiponectin in patients with obesity confers an increased risk of cardiovascular disease (Figure1).103
Sympathetic activation and inflammation The sympathetic nervous system is an important regulator of metabolic and cardiovascular function. 53 Anobesity-related reduction in baroreceptor sensitivity, and a diminished response to heart rate variation and blood pressure, might produce chronic cardiac sympathetic overstimulation and reduce parasympathetic drive, leading to increased catecholamine levels and obesity-related hypertension.5457 Elevated circula ting levels of free fatty acids, insulin, leptin and angio tensinII potentiate these effects, and a concomitant rise in central sympathetic outflow increases arterial stiffness.56,58 Reduced beat-to-beat heart rate variability and decreased parasympathetic activity is a powerful predictor of death after myocardial infarction. These two parameters are also markedly reduced in patients who are overweight or obese, and when combined with obesity related sympathetic overactivity, lead to a state of sympatheticdominance.59 Obesity is also often associated with low-grade chronic inflammation, which is attributed to local hypoxia within the expanding adipose tissue60 that stimulates the expression and secretion of cytokines (such as leptin, apelin, PAI1, VEGF) and decreases adiponectin release.61 This inflammation is further characterized by increased levels of circulating Creactive protein, 62 tumour necrosis factor (TNF),6365 IL6, IL8 and IL10,6668 transforming growth factor , haptoglobin and serum amyloidA. These inflammatory cytokines have profound vaso active effects leading to the release of prostanoids, leuko trienes, inducible NO synthase, bradykinin, ROS and platelet-activating factor, all of which negatively affect vascular reactivity, endothelial function, and promote atherosclerosis.69,70 Furthermore, the presence of this proinflammatory cytokine profile might be a powerful predictor of (and aetiological contributor to) cardiovascular, renal and cerebrovascular disease,7173 and has been independently associated with death from coronary heart disease in apparently healthy men and women.74,75 Leptin is secreted by adipocytes at levels that are in direct proportion to adipose tissue mass, and acts under physiological conditions on hypothalamic neuro peptideY and agouti-related peptide neurons to reduce food intake.76,77 Elevated circulating leptin levels, which are found in patients with obesity whose hypothalamus and smooth muscle cells are resistant to the anorectic actions of leptin, promote hypertension by increasing renal sympathetic activity 7880a mechanism linking sympathetic hyperactivity to cardiorenal deterioration.8183 Leptin increases oxidative stress by stimulating production of ROS, which react with NO,84 decreasing its bioavailability and increasing Na+,K+-ATPase activity, which promotes vasoconstriction and renal Na2+ retention. Elevated leptin levels also predict the development of
RAAS activation in adipose tissue White adipose tissue abundantly expresses renin, angiotensin II and angiotensinogen receptors, which suggests that local production of angiotensin in this tissue might be controlled at the adipocyte level.104106 Subsequent increases in circulating angiotensinogen levels serve both as a cause and mediator of adipocyte hyper trophy, activating angiotensin II, inducing systemic vaso constriction, promoting renal Na2+ and water retention and increasing aldosterone production. High aldosterone levels also promote inflammation and oxidative stress in the renal and cardiac vessel wall, and contribute to cardiovascular fibrotic changes and hypertrophy, as well as tubulointerstitial inflammation, renal fibrosis, glomerulosclerosis, mesangial proliferation and podocyte dysfunction.107 Furthermore, these effects of aldo sterone might occur both directly and independently of angiotensin II, as the antiproteinuric influence of angiotensinII inhibition can be reversed by aldosterone infusion.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.109

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Hyperuricaemia Hyperuricaemia is an important obesity-related risk factor for a number of cardiovascular conditions, including coronary artery disease,110 endothelial dysfunction, stroke111 and heart failure,112 and is an independent predictor of 1year mortality in patients with acute myocardial infarction.113 Serum uric acid levels are a strong independent predictor of hypertension,114117 dyslipidaemia, T2DM,118 obesity 119 and NAFLD,120 as well as kidney dysfunction 121123 and metabolic syndrome as a whole. 124126 In humans, uric acid in serum is the metabolic end product of purine degradation. Uric acid production occurs in the liver and small intestine as a result of the activity of xanthine oxidase. Hyperinsulinaemia leads to increased uric acid synthesis as well as reduced renal excretion of both uric acid and Na2+.127 Previous studies report that the relationship between serum uric acid levels and cardiometabolic disease is observed not only in individuals with hyperuricaemia, but also in those with uric acid levels in the normal to high-normal range.128130 Hence, 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, but also as an independent risk factor for metabolicsyndrome.131,132 The rise in consumption of fructose over the past three decades correlates temporally with the rise in the prevalence of metabolic syndrome, and might be considered a hallmark of todays obesity epidemic.133 One unique aspect of fructose ingestion, 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.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, as the hyper tension, insulin resistance, and renal dynamic and histo logical changes associated with metabolic syndrome can be ameliorated by treatment with xanthine oxidase inhibitors.131,135 The detrimental effects of hyper uricaemia include generation of mitochondrial oxidative stress,120 inhibition of endothelial NO synthase (which reduces NO bioavailability),132 stimulation of vascular smooth muscle cell proliferation, expression of vaso active and inflammatory mediators,136 and activation of theRAAS.137 Furthermore, several studies have demonstrated a strong relationship between serum uric acid levels and NAFLD, the most common form of chronic liver disease, which is regarded as the hepatic manifestation of metabolic syndrome.120,138140 In patients with metabolic syndrome, the increased oxidative stress and proinflammatory environment produced by high uric acid levels stimulates synthesis of CC motif chemokine 2 (also known as monocyte chemoattractant protein 1) and increases levels of IL6 and TNF,141 leading to a possible mechanism though which uric acid contributes to the pathogenesis of NAFLD.
Cardiorenal syndrome
The inherent crosstalk between the kidneys and heart can result in cardiorenal syndrome, which often presents as worsening renal function in patients with heart failure. The direct mechanisms underlying this inter action are unclear but are probably mediated by a reduction in glomerular filtration rate (GFR). 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, humoral factors (such as natriuretic peptides) released from the heart, inflammatory cytokines and modulators of renal function, such as anti-diuretic hormone. Similarly, reciprocal renal effects are produced on the myocardium secondary to anaemia, activation of the RAAS, accumulation of uraemic toxins, prohypertrophic agents (such as angiotensin II and endothelin 1) and biochemical inducers of apoptosis such as inter leukins and other inflammatory cytokines. These changes can lead to acute, chronic, abrupt, primary and secondary cardiorenal decompensation, which correspond to types15 cardiorenal syndrome, respectively (Table1).109,142 The added pathological effects of obesity on the cardio vascular and renal systems, and their interaction, are also likely to accentuate the severity of cardio renal syndrome. Furthermore, heart failure and renal dysfunction can be worsened by obesity-related systemic inflammation, insulin resistance, metabolic syndrome, cardiomyo p athy and primary renal disease, through cardiac and renal fatty infiltration and dis ordered biological signals.143 However, determining the relative contribution of obesity to cardiac and renal disease via the cardiorenal axis will require increased scrutiny and further research using invitro and invivo models to reveal important mechanistic information. Bariatric procedures might offer a unique opportunity to disrupt crosstalk between the cardiovascular and renal systems, thereby breaking the vicious cycle of pathology and its sequelae that leads to both renal failure and heart failure. Emerging evidence indicates that cardiorenal syndrome is derived from the accumulation of uraemic toxins, including the highly protein-bound molecule indoxyl sulphate, which has prohypertrophic, fibrogenic and oxidative stress inducing effects.144 Roux-enY gastric bypass (RYGB) powerfully modulates postoperative levels of this toxin, and this change is associated with profound shifts in the patients gut flora, in addition to a multitude of beneficial metabolic effects.145
Treatment of cardiorenal disease

We propose an algorithm for the management of obesityrelated cardiorenal disease (Figure2). This algorithm clarifies the role of bariatric surgery in the treatment of chronic cardiorenal syndrome in patients with a BMI of3540kg/m2 and obesity-related comorbidities (such as T2DM), or in patients with a BMI of 40kg/m2 (morbid obesity). Surgery might also be considered for patients with a BMI of 3035kg/m2 who have obesity-specific renal or cardiac disease. In the acute setting, primary cardiac or renal disease should be managed supportively, before consideration of surgical intervention.
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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.g. obesity-related e.g. 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. Acute obesity associated CRS (type1 or type3) should be managed primarily with supportive renal and cardiac therapy in order to successfully treat the acute pathology. Once stabilized, these patients can be considered for metabolic surgical intervention in order to reduce the risk of disease progression. However, where CRS has reached a chronic (type2 or type4) stable state, patients may be considered for early surgical intervention. In secondary, type 5CRS, the underlying cause should be sought and treated before consideration for surgical intervention. Patients should be considered for surgery if BMI >40kg/m2 or if BMI >35kg/m2 with obesity-associated co-morbidities such as type2 diabetes mellitus. Patients with lower BMIs (>30kg/m2) may also be considered for surgical intervention where specific obesity-related cardiomyopathy or nephropathy is present, in order to reduce the risk of disease progression. Abbreviation: CRS, cardiorenal syndrome.
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. However, the hybrid RYGB is considered by some units as the gold standard bariatric procedure in appropriately selected patients, given its low morbidity and profound metabolic effects.155 By bypassing the duodenum, 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; reduction of gastric size; anatomical gut rearrangement and altered flow of nutrients; vagal manipulation; and enteric gut hormone modulation)156 that modulate the enteroinsular, enterocardiac and entero renal axes independently of the weight-reducing effects of this surgery.143,157159 The BRAVE effects occur almost instantaneously after gastric bypass surgery.156,160162
Reduced cardiovascular disease Bariatric surgery has beneficial effects on both structural and functional cardiac status. Surgical intervention can improve diastolic function and precipitate reverse remodelling of the heart, particularly in patients with pre-existing systolic dysfunction and long- standing morbid obesity. These beneficial effects are partly ascribed to a reduction in systemic hypertension (Table2).163,164 Furthermore, bariatric surgery might lead to symptomatic improvement in all stages of obesity-related cardiomyopathy, and can improve left ventricular systolic function even in patients with severe heart failure who are awaiting a heart transplant.165,166 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.167 However, the SOS study results demonstrated a decrease in cardiovascular morbidity and mortality in patients 20years after gastric bypass, independently of baseline BMI.151 Furthermore, these data are now supported by cardiac imaging studies demonstrating that bariatric surgery results in improved postoperative cardiac geometry, 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.143,168 Changes in postprandial gut hormone release might also improve cardiac function after bariatric surgery.169 Hormones such as secretin (produced in the duodenum), glucagon (produced in the pancreas), and vasoactive intestinal peptide (produced in the gut, pancreas, and brain) act as inotropes by activating cardiac membrane adenylate cyclase.170 Moreover, two pivotal hormones that are modulated by gastric bypass surgery, glucagon- like peptide1 (GLP1) and ghrelin, also modulate cardiac function, and have key roles in the enterocardiac axis (Figure1). GLP1 is a satiety hormone produced by duodenal cells, and levels of this hormone are upregulated after bariatric surgery. By enhancing myocardial glucose uptake, GLP1 is cardio protective, particularly in patients with dilated cardiomyo pathy or left ventricular systolic dysfunction. 171173 By contrast, production of the appetite-stimulating hormone
Positive effects of bariatric surgery

Decreased cardiovascular risk Weight loss seems to be a simple answer to most obesityrelated health problems. However, lifestyle, behavioural and pharmacological weight-loss strategies provide limited efficacy, particularly in the long term.8,146 Various types of surgical procedures have, therefore, been developed to achieve efficient and sustained weight loss in patients with excess weight. These procedures are termed bariatric surgeries. 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 >40kg/m2) or those who have a BMI 35kg/m2 and life-changing or life-threatening obesity-related comorbid ities. Bariatric procedures can be divided into three broad categories based on their mechanism of action: restrictive, bypass and hybrid surgeries (Box1). These procedures are now primarily performed using minimally invasive laparoscopic techniques, which, when performed in a centre of excellence, are safe and have an operative mortality not dissimilar to that of laparoscopic cholecystectomy.147149 The prospective, 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 20years in patients with obesity),9,150,151 but also improve quality of life,152 decrease obesity-related disease,153 and increase life expectancy.154

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ghrelin (by P/D1cells in the stomach) is upregulated after nonrestrictive bariatric procedures. Ghrelin promotes vasodilatation and reduces susceptibility to (as well as improving tolerance of) coronary artery disease.174 Infusion of ghrelin in patients with heart failure significantly improves the cardiac index, stroke volume and left ventricular ejection fraction, and reduces left ventricular wall stress.175 Moreover, ghrelin resistance in the setting of hyperghrelinaemia has been implicated as a precipitating factor in cardiac failure(Figure1).176 Gastric bypass surgery also modulates adipokine release, decreases plasma leptin levels and promotes adiponectin production.135,136 In turn, these changes might lead to reductions in inflammatory mediator release, intimal hyperplasia, myocardial hypertrophy and blood pressure.143,177,178 However, the reader should note that similar changes in adipokine profiles and inflammation can be observed following chronic starvation, 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, future studies must aim to standardize changes in biochemical markers according to a measure of preoperative and postoperative BMI.
Improved glycaemic control Despite substantial advances in the management of T2DM, the cost of treatment and regular follow-up is high and pharmacological treatment is poorly adhered to in this setting. The role of gastric bypass surgery in reversing or ameliorating T2DM was first identified in the 1980s, in studies showing that 7483% of patients with a preoperative diagnosis of T2DM remained free from the disease 14years after bariatric surgery.180 By contrast, only half of medically treated patients with T2DM attained adequate glycaemic control.181,182 A meta-analysis of 221 studies found that resolution of T2DM occurred in 80.3% of patients who underwent gastric bypass. This figure reached 95.1% in patients undergoing bilio pancreatic diversion with or without duodenal switch; however, the increased surgical morbidity and mortality associated with this procedure has limited its uptake.183 Initially, the antidiabetic effect of RYGB was attributed to absolute weight reduction. However, a dramatic improvement in glycaemic control is observed within days of the surgery, long before any pronounced weight loss occurs,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.143,149,180,183,185 Furthermore, RYGB and biliopancreatic diversion improve blood sugar levels more effectively than do other bariatric procedures, such as sleeve gastrectomy, gastric banding and vertical banded gastroplasty, despite resulting in similar weight reductions.186 In fact, after RYGB, 30% of patients had normal blood sugar levels and no longer required anti diabetic pharmacotherapy by the time of hospital discharge (an average 2.8 of days after the surgery).187 The mechanisms whereby RYGB induces resolution of T2DM can be categorized according to the organ systems
Box 1 | Types of bariatric procedure

Careful postoperative nutritional follow-up of all patients after bariatric surgery is vital (and should be standard practice).
Restrictive procedures Restrictive procedures, which limit the amount of food that can be consumed by surgically reducing the size of the stomach. Examples: laparoscopic adjustable gastric banding, sleeve gastrectomy Advantages: Procedures can be performed in a short time while offering durable metabolic benefits. Disadvantages: Beneficial effects may occur in association with weight loss and therefore are not always immediate. Some procedures have management profiles that may require regular review, re-intervention and modification (for example, adjustable gastric band). Bypass procedures These procedures bypass a segment of the small intestine, which leads to metabolic changes. This class of operations has been traditionally termed malabsorptive procedures, although the evidence for malabsorption remains generally unquantified (with the some specific exceptions). Partial ileal bypass aims to reduce cholesterol absorption from the distal ileum. Biliopancreatic diversion aims to reduce the absorption of fats and other nutrients. Examples: jejunoileal bypass, biliopancreatic diversion with or without duodenal switch, partial ileal bypass, ileal interposition Advantages: Immediate and long-lasting metabolic enhancement and resolution of disease. Disadvantages: Typically longer procedures with higher degree of complexity requiring multiple gastrointestinal anastomoses. Some procedures such as the biliopancreatic diversion have malabsorbtive effects that require intense nutritional monitoring and follow-up. Hybrid procedures Hybrid procedures offer a combination of restriction and bypass to restrict food intake by creating a small gastric pouch; they also demonstrate the powerful metabolic benefits of bypass procedures. In Roux-enY gastric bypass, the foregut is bypassed but 95% of the small bowel is left intact, which avoids many of the adverse effects of other bypass procedures. Example: Roux-enY 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. Disadvantages: As with bypass procedures, they have a typically longer operative time with a higher degree of complexity requiring multiple gastrointestinal anastomoses. Some cases have led to conditions such as nesidioblastosis.
in which they exert their principal actions (Figure3).160 Early postsurgical resolution of T2DM is thought to occur via manipulation of vagal nerve signalling and changesin gustatory neurohormonal signalling,188,189 alterations inbile metabolism, 190 gut microbiota modulation, 145 ashift in metabolite profiles191 and a reduction in inflammation.192 Persistent early changes include the powerful gut hormone effects that occur almost immediately after RYGB surgery and persist for many months thereafter.193 Two randomized controlled trials194,195 have demonstrated the pronounced efficacy of this form of bariatric surgery compared with medical treatment of T2DM up to 2years after the procedure. One study in particular revealed the results were statistically independent of patients baseline BMI,194 adding support for weight-independent amelioration of insulin resistance and improvement of T2DM control after RYGBsurgery.160 The long-term effects of this type of bariatric surgery are mediated by alterations in fat metabolism and adipo kine secretion,196,197 caloric restriction and weight loss,197
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the progression of NAFLD to fibrosis,202 cirrhosis,203 hepatocellular carcinoma,204 and terminal liver failure.205 However, the benefits of bariatric surgery in patients with NAFLD who are at high risk of liver cirrhosis, and the role of surgery in modulating other complications of NAFLD (such as T2DM and cardiovascular disease), are still poorly understood. Bariatric surgery might be associated with a histological improvement in steatosis, inflammation and fibrosis in patients with nonalcoholic steato hepatitis, the most severe form of NAFLD;206 however, the majority of the available evidence of this benefit comes from retrospective or nonrandomized studies. Further research is, therefore, required to elucidate the role of bariatric surgery in these patients. The potential role of bariatric surgery in the treatment of NAFLD is complex and the underlying mechanisms are not fully understood. However, 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. In addition to weight loss, bariatric surgery might mitigate NAFLD by normalizing insulin resistance and serum uric acid levels,207 decreasing dyslipidaemia208,209 and inflammation,210,211 and improving hepatic metabolism, perhaps through bile-acid-mediated enhancement of hepatocyte function.156,161 The SOS trial results revealed a significant and persistent decrease in uric acid levels at both 2yearsand 10years of follow-up in patients who underwent bariatric surgery, when compared with the levels in obese patients who did not undergo such procedures.207
Improved renal function Weight loss has been associated with a decrease in protein uria in patients both with and without renal impairment.212 Surgically induced weight reduction has an even more pronounced effect in this setting, and improves renal function in patients with pre-existing glomerular hyperfiltration,213,214 a phenomenon that is not observed following nonsurgical weight loss strategies.212,215 Despite these findings, the independent effects of weight loss perse (and, in particular, that of surgery-related weight loss) on renal dysfunction, progression of CKD, and development of ESRD is yet to be fully determined.216 Crucially, restrictive bariatric procedures, such as vertical band gastroplasty, do not confer the same renoprotective effects as RYGB, and can even worsen GFR and renal plasma flow.213 Furthermore, although RYGB surgery is associated with significant reductions in obesity-related albuminuria at 12months and 24months of follow-up, 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, or the creatinine clearance rate.217 Emerging evidence suggests that the largest postRYGB reductions in albuminuria and GFR occur in patients with obesity and concomitant metabolic syndrome or T2DM.218,219 Early post-RYGB improvement in glomerular hyperfiltration also occurs in obese patients without T2DM, but these changes return to baseline by 12months. 219 Surgically induced renoprotection
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. Bariatric surgery might resolve both cardiac disease and renal disease through multifaceted actions with effects on cardiorenal crosstalk, via both direct effects on the heart and kidneys, and indirectly through improved glycaemic control, autonomic nervous system modulation, management of hypertension and appetite control. Through these mechanisms, bariatric surgery modulates obesity-related metabolic dysfunction to induce direct cardiac and renal benefits. Abbreviations: , decreased; , increased.
or by a combination thereof. Of particular interest are the incretin (insulin-stimulating) effects of RYGB and biliopancreatic diversion. Incretin hormones decrease insulin resistance via increasing insulin sensitivity in theliver and muscle, and stimulate insulin release beforethe postprandial rise in blood glucose.198,199 Infact, this capacity of RYGB to promote both insulin production and insulin sensitivity has led to a number of cases of hyperinsulin aemic hypoglycaemia (nesidioblastosis), which is characterized by pancreatic cell hyper trophy, islet hyperplasia and increased cell mass.160 The mechanisms underlying this effect of RYGB surgery are not yet fully elucidated, but might represent autobionic (that is, the replacement or boosting of physiological functions by the rearrangement and manipulation of existing tissue or organs)161 augmentation of pancreatic cell function. Furthermore, the failure of RYGB surgery to reverse obesity-induced cell hypertrophy, or the persistence of changes in gut hormone signalling even after substantial weight reduction, might contribute to thisprocess.161,200,201
Reversal of nonalcoholic fatty liver disease T2DM and NAFLD perse are not an indication for bariatric surgery in patients with a BMI <35kg/m2, despite its beneficial effects on glycaemic control. Weight reduction and amelioration of metabolic disturbances are the mainstays of therapy for NAFLD, as well as for preventing
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is, therefore, partly mediated by improved glycaemic control and blood pressure reduction, although other factors (such as reductions in levels of circulating inflammatory cytokines, renal lipotoxicity and oxidative stress) are also implicated.220,221 Interestingly, RYGB also improves renal function in patients with obesity who already have CKD.222 One study in 45 patients with CKD and various renal pathol ogies demonstrated improvement or stabilization of CKD in nine patients, with complete resolution of glomerulonephritis in one individual; the study was small, but the renoprotective effects of RYGB seemed to be very convincing.222 As such, gastric bypass surgery might delay the need for dialysis and/or kidney transplantation in patients with CKD, and could even have a role in improving comorbidities before transplantation in patients who are morbidly obese and undergoing dialysis.223,224 However, 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. In addition, the reduction in muscle mass associated with weight loss makes serum creatinine levels an unreliable marker of GFR, because creatinine production is proportional to muscle mass. As such, changes in body composition should be examined, together with the amount of weight loss, to fully assess the relationships between obesity, weight reduction andthe effects of surgical intervention. Future studies should determine whether weight loss improves renal function independently of its effects on T2DM, hypertension and hyperlipidaemia and, if so, what effect this improvement has on the progression of renal disease and its associatedmortality. However, despite early research into this field, a number of compelling clinical questions remain un answered. Firstly, we do not yet fully appreciate the extent to which the deleterious effects of obesity are modulated by differing genetic and physiological mechanisms, particularly in complex organ systems such as the kidney and heart. We also do not completely understand the multifaceted pheno type of obesity, particularly with regard to the influence of body composition, total fat mass, adipose tissue distribution and the extent, location and composition ofindividual fat deposits. Moreover, the contributions of altered crosstalk between muscle and fat, and of increased metabolic activity (rather than obesity itself), and the elevated risk of cardiovascular and renal dysfunction in patients with obesity remains unclear. Secondly, the influence of preoperative obesity duration, or the choice of bari atric procedure, on postsurgical renaland cardio v ascular end points requires further clinical andmechanistic investigation. Thirdly, although encouraging evidence supports the existence of improved renal and cardiac outcomes after bariatric surgery, the extent to which surgery modulates the need for dialysis, renal transplantation or cardiovascular interventions and affects overall survival and quality of life is yet to be fully delineated. Finally, the role of bariatric surgery in managing cardiorenal disease in patients who are only moderately obese or of normal weight is, as yet,unknown. Future research must focus on improving our knowledge of the intermediary physiological factors and genotypic, proteomic and post-transcriptional variations that predispose patients to obesity and metabolic syndrome, to fill the gaps in our understanding of the pathophysiology of obesity-associated comorbidities. Both systems biology and mechanistic studies, in the context of translational clinical trials, are needed to manage and develop the next generation of interventions and procedures to treat obesity-related, multisystem, cardiorenal disease.
Review criteria
A search for original articles published between 1953 and 2013 and focusing on obesity-associated comorbidities, renal and cardiac dysfunction and the effects of bariatric surgery was performed in MEDLINE and PubMed. The search terms used were obesity, renal disease, nephropathy, cardiac disease, cardiomyopathy, cardiorenal, AND bariatric surgery, alone and in combination. All articles identified were English-language, full-text papers. We also searched the reference lists of identified articles for further relevant papers.
7. Brinkworth, G.D., Buckley, J.D., Noakes, M. & Clifton, P .M. Renal function following long-term weight loss in individuals with abdominal obesity on a verylowcarbohydrate diet vs highcarbohydrate diet. J. Am. Diet Assoc. 110, 633638 (2010). Puterbaugh, J.S. The emperors tailors: the failure of the medical weight loss paradigm and its causal role in the obesity of America. Diabetes Obes. Metab. 11, 557570 (2009). Sjstrm, L. etal. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741752 (2007).
Conclusions
Obesity-related cardiorenal disease results from the complex interplay of several shared elements, including hypertension, autonomic disturbance, dyslipid aemia and T2DM. These pathophysiological elements can now be successfully treated with bariatric surgery, which improves both cardiovascular and renal outcomes and offers a unique method to concomitantly manage both systemic diseases via effects on cardio renal crosstalk. Increased study of bariatric surgery and its effects on the cardiorenal axis might, therefore, identify important mechanisms that underpin the effects of weight changes on cardiorenal syndrome and spearhead the next generation of interventions for multisystem metabolic disorders.
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Darzi and H.Ashrafian reviewed and edited the manuscript beforesubmission. A. Darzi and H. Ashrafian madesubstantial contributions to discussions of thecontent.
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Obesity-related cardiorenal disease: thebenefits of bariatric surgery

Obesity-related cardiorenal dysfunction

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high interindividual and intraindividual variability in the body compositionmetabolism relationship.

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Type 2 diabetes mellitus

Endothelial injury, hypoxia

Adipokines/ leptin Sympathetic activity

Dyslipidaemia and atherosclerosis

Endothelial dysfunction Atherosclerosis

RAAS Renal blood flow

Na+ reabsorption Volume overload Preload

Sympathetic activity Vasoconstriction Afterload

Cardiac function Improves

Bariatricsurgery/ weight loss

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Treatment of cardiorenal disease

Acute disease successfully managed

CRS type 1 Acute cardiorenal syndrome

CRS type 2 Chronic cardiorenal syndrome

Treat underlying pathology

Consideration for bariatric surgery

Positive effects of bariatric surgery

Box 1 | Types of bariatric procedure

Autonomic nervous input Hypertension control

Autonomic nervous input Hypertension control

Improved glycaemic control

Chronic renal failure Renoprotection Albuminuria

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