Obesity-Related Cardiorenal Disease

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    1/13NATURE REVIEWS | NEPHROLOGY VOLUME 9 | SEPTEMBER 2013 | 539

    Department of InternalMedicine, Endocrineand Diabetes Unit(W. Fenske ),Department ofMedicine, Division ofNephrology(C. Drechsler ),University HospitalWrzburg,Oberduerrbacherstr 6,

    97080 Wrzburg,Germany. Departmentof Surgery and Cancer,Imperial CollegeLondon, 10 th Floor,Queen Elizabeth theQueen Mother Building,St Marys Hospital,Praed Street, LondonW2 1NY, UK(T. Athanasiou,L. Harling, A. Darzi,H. Ashrafian ).

    Correspondence to:H. [email protected]

    Obesity-related cardiorenal disease:the benefits of bariatric surgeryWiebke Fenske, Thanos Athanasiou, Leanne Harling, Christiane Drechsler, Ara Darziand Hutan Ashrafian

    Abstract | The inexorable increase in the prevalence of obesity is a global health concern, which will result in aconcomitant 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 physiologicallyinterdependent, 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 orpharmacotherapy. Bariatric surgery offers both sustained weight loss and favourable metabolic changes,

    including dramatic improvements in glycaemic control and symptoms of type 2 diabetes mellitus. Proceduressuch as Roux-en-Y gastric bypass offer immediate multisystemic benefits, including bile flow alteration, reducedgastric size, anatomical gut rearrangement and altered flow of nutrients, vagal manipulation and enterichormone modulation. In patients with cardiorenal syndrome, bariatric surgery also offers renoprotection andcardioprotection, and attenuates both kidney and heart failure by improving organ perfusion and reversingmetabolic dysfunction. However, further research is required to understand how bariatric surgery acts on thecardiorenal axis, and its pioneering role in novel treatments and interventions for cardiorenal disease.

    Fenske, W. et al. Nat. Rev. Nephrol. 9 , 539551 (2013); published online 6 August 2013; doi:10.1038/nrneph.2013.145

    IntroductionOver the past three decades, the prevalence of obesity(defined as a BMI 30 kg/m2) has reached pandemiclevels and poses a major threat to modern public health.In 2008, approximately 500 million people worldwide wereconsidered to be clinically obese, a figure expected to riseto 700 million by 2015.1 Obesity-related metabolic syn-drome now affects approximately 25% of the adult popula-tion, and at least 2.8 million adults die each year owing toobesity and obesity-related cardiovascular disease. 1,2

    The close physiological interdependence of the heartand kidneys is well recognized; these organs shareresponsibility for haemodynamic stability and end-organperfusion via the tight-knit control of cardiac output, volume status and vascular tone. Key medi ators of thecardiorenal system include the sympathetic nervoussystem, 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 kidneyconsequently elicits a cascade of mediators that affectthe other organ, explaining why renal failure frequentlyaccompanies cardiac dysfunction and vice versa. Thiscomplex is referred to as cardiorenal syndrome, an indi-cator of poor prognosis frequently observed in patientswith obesity. Cardiorenal syndrome can be definedas disorders of the heart and kidney whereby acute

    or chronic dysfunction in one organ induces acute orchronic dysfunction of the other (Table 1). 36

    Although weight loss and metabolic modulationproduce beneficial effects on both cardiac and renalfunction, 7 the availability of effective therapeutic strat-egies for sustained weight loss and management of meta-bolic dysfunction remains limited. 8 However, with thesuccess of emerging bariatric surgical interventions, 9 weight loss and metabolic enhancement have become anovel therapeutic option for obesity-associated cardiacand renal disease. 7,10

    Previous articles have focused on the potential ameli-orating effects of bariatric surgery on either cardiac 11,12 orrenal function. 13,14 In this Review, we concentrate on thecardiorenal interface, and analyse the complex pathologi-cal mechanisms by which obesity might affect physio-

    logical cardiorenal interactions. In addition, we discussthe potential roles of surgically induced weight loss andmetabolic enhancement in the prevention and treatmentof obesity-related cardiorenal syndrome.

    Obesity-related cardiorenal dysfunctionThe complex association between obesity and cardio-renal function is made up of a multitude of pathologicalprocesses (Figure 1).

    T2DM and metabolic syndromePatients who are overweight or obese account for~8090% of all cases of type 2 diabetes mellitus (T2DM).

    Competing interestsThe authors declare no competing interests.

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    mailto:h.ashrafian@%20imperial.ac.ukmailto:h.ashrafian@%20imperial.ac.ukhttp://www.nature.com/doifinder/10.1038/nrneph.2013.145http://www.nature.com/doifinder/10.1038/nrneph.2013.145mailto:h.ashrafian@%20imperial.ac.ukmailto:h.ashrafian@%20imperial.ac.uk
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    Overweight women (BMI 25.029.9 kg/m 2) have a five-fold higher risk of T2DM than do those with a BMI

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    atherosclerotic lesions in the renal artery might decreaserenal perfusion and impair renal function, which exa-cerbates hypertension and potentiates the cycle of furtheratherosclerosis, cardiovascular events and progression ofrenal disease.52

    Sympathetic activation and inflammationThe sympathetic nervous system is an important reg-ulator of metabolic and cardiovascular f unction. 53 An obesity-related reduction in baroreceptor sensitiv-ity, and a diminished response to heart rate variationand blood pressure, might produce chronic cardiacsympathetic overstimulation and reduce parasympa-thetic drive, leading to increased catecholamine levelsand obesity-related hypertension. 5457 Elevated circula-ting levels of free fatty acids, insulin, leptin and angio-tensin II potentiate these effects, and a concomitantrise in central sympathetic outflow increases arterialstiffness.56,58 Reduced beat-to-beat heart rate variabilityand decreased parasympathetic activity is a powerfulpredictor of death after myocardial infarction. Thesetwo parameters are also markedly reduced in patientswho are overweight or obese, and when combined withobesity related sympathetic overactivity, lead to a state ofsympathetic dominance. 59

    Obesity is also often associated with low-grade chronicinflammation, which is attributed to local hypoxia withinthe expanding adipose tissue 60 that stimulates the expres-sion and secretion of cytokines (such as leptin, apelin,PAI-1, VEGF) and decreases adiponectin release. 61 Thisinflammation is further characterized by increased levelsof circulating C-reactive protein, 62 tumour necrosisfactor (TNF), 6365 IL-6, IL-8 and IL-10,6668 transform-ing growth factor , haptoglobin and serum amyloid A.These inflammatory cytokines have profound vaso-active effects leading to the release of prostanoids, leuko-trienes, inducible NO synthase, bradykinin, ROS andplatelet-activating factor, all of which negatively affect vascular reactivity, endothelial function, and promoteathero sclerosis.69,70 Furthermore, the presence of thisproinflammatory cytokine profile might be a powerfulpredictor of (and aetiological contributor to) cardio- vascular, renal and cerebrovascular disease, 7173 and hasbeen independently associated with death from coronaryheart disease in apparently healthy men and women. 74,75

    Leptin is secreted by adipocytes at levels that arein direct proportion to adipose tissue mass, and acts

    under physiological conditions on hypothalamic neuro-peptide Y and agouti-related peptide neurons to reducefood intake. 76,77 Elevated circulating leptin levels, whichare found in patients with obesity whose hypothalamusand smooth muscle cells are resistant to the anorecticactions of leptin, promote hypertension by increasingrenal sympathetic activity 7880a mechanism linkingsympathetic hyperactivity to cardiorenal deteriora-tion.8183 Leptin increases oxidative stress by stimulatingproduction of ROS, which react with NO, 84 decreasingits bioavailability and increasing Na +,K+-ATPase activity,which promotes vasoconstriction and renal Na 2+ reten-tion. Elevated leptin levels also predict the develop ment of

    hypertension independently of BMI, insulin resistance, orbaseline blood pressure. 85,86 Furthermore, chronic hyper-leptinaemia potentiates renal fibrosis and produces glo-merulosclerosis and proteinuria in both normal-weightrats and mice with metabolic syndrome as a result ofchronic feeding of a high-fat diet. 34,87 Leptin inducesthe proliferation, differentiation, and functional activa-tion of myelocytic progenitor cells as well as primitivehaemopoietic and progenitor cells in the heart, promo tingmyocyte growth, hypertrophy and sub sequent cardiacdysfunction. 8893 In rats, postinfarction myocardial hyper-trophy is mediated by leptin, and can be reversed by leptinreceptor blockade. 94 Furthermore, by activating fatty acidoxidation, reducing circulating triglyceride levels andsubsequently altering adenylate cyclase function, leptinproduces direct negative inotropic effects (Figure 1). 95,96

    Under normal conditions, apelin decreases bloodpressure and prevents hypertension by inducing vaso-dilatation. 97,98 The role of apelin in obesity-related hyper-tension is not yet fully understood. However, resistanceto the hypotensive effects of apelin might develop inthe long term, or high circulating apelin levels mightenable this protein to cross the bloodbrain barrier andact in the central nervous system to stimulate sympa-thetic outflow and increase blood pressure in individualswith obesity.99

    Adiponectin is a 244 amino acid protein, the levelsof which are inversely correlated with fat mass in adultsanduniquelyreflect the metabolic activity of adipo-cytes.100 Adiponectin promotes insulin sensitivity,skeletal muscle lipid oxidation and adipocyte differen-tiation. 101 By heightening NO synthase activity and NOproduction, and reducing ROS generation, this hormoneexerts cardioprotective effects. 102 However, reduced pro-duction of adiponectin in patients with obesity confersan increased risk of cardiovascular disease (Figure 1). 103

    RAAS activation in adipose tissueWhite adipose tissue abundantly expresses renin, angio-tensin II and angiotensinogen receptors, which suggeststhat local production of angiotensin in this tissue mightbe controlled at the adipocyte level. 104106 Subsequentincreases in circulating angiotensinogen levels serveboth as a cause and mediator of adipocyte hyper trophy,activating angiotensin II, inducing systemic vaso-constriction, promoting renal Na 2+ and water retentionand increasing aldosterone production. High aldosterone

    levels also promote inflammation and oxidative stressin the renal and cardiac vessel wall, and contribute tocardiovascular fibrotic changes and hypertrophy, aswell as tubulointerstitial inflammation, renal fibrosis,glomerulosclerosis, mesangial proliferation and podo-cyte dysfunction. 107 Furthermore, these effects of aldo-sterone might occur both directly and independently ofangiotensin II, as the antiproteinuric influence of angio-tensin II inhibition can be reversed by aldosterone infu-sion.108 Results from animal models demonstrating theprotective effect of antioxidant administration have alsohighlighted the role increased oxidative stress in bothcardiovascular and renal injury. 109

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    HyperuricaemiaHyperuricaemia is an important obesity-related riskfactor for a number of cardiovascular conditions,including coronary artery disease, 110 endothelial dys-function, stroke 111 and heart failure, 112 and is an inde-pendent predictor of 1-year mortality in patients withacute myocardial infarction. 113

    Serum uric acid levels are a strong independent pre-dictor of hypertension, 114117 dyslipidaemia, T2DM, 118 obesity 119 and NAFLD,120 as well as kidney dysfunc-tion 121123 and metabolic syndrome as a whole. 124126 In humans, uric acid in serum is the metabolic endproduct of purine degradation. Uric acid produc-tion occurs in the liver and small intestine as a resultof the activity of xanthine oxidase. Hyperinsulinaemialeads to increased uric acid synthesis as well as reducedrenal excretion of both uric acid and Na 2+.127 Previousstudies report that the relationship between serum uricacid levels and cardiometabolic disease is observed notonly in individuals with hyperuricaemia, but also inthose with uric acid levels in the normal to high-normalrange.128130 Hence, the conventional view of this associa-tion as a simple epiphenomenon has evolved into a morecomplex understanding of the dual role of serum uricacid levels as a consequence of hypertension and meta-bolic syndrome, but also as an independent risk factorfor metabolic syndrome. 131,132

    The rise in consumption of fructose over the pastthree decades correlates temporally with the rise in theprevalence of metabolic syndrome, and might be con-sidered a hallmark of todays obesity epidemic. 133 Oneunique aspect of fructose ingestion, in comparison withthe intake of glucose and other dietary sugars, is that itrapidly contributes to depletion of ATP and increasesthe generation and release of uric acid by hepatocytes. 134 The resulting rise in serum uric acid levels after fruc-tose ingestion is likely to have a key role in promotingthe development of metabolic syndrome, as the hyper-tension, insulin resistance, and renal dynamic andhistological changes associated with metabolic syn-drome can be ameliorated by treatment with xanthineoxidase inhibitors. 131,135 The detrimental effects of hyper-uricaemia include generation of mitochondrial oxidativestress,120 inhibition of endothelial NO synthase (whichreduces NO bioavailability), 132 stimulation of vascularsmooth muscle cell proliferation, expression of vaso-active and inflammatory mediators, 136 and activation of

    the RAAS.137Furthermore, several studies have demonstrated

    a strong relationship between serum uric acid levelsand NAFLD, the most common form of chronic liverdisease, which is regarded as the hepatic manifestation ofmetabolic syndrome. 120,138140 In patients with metabolicsyndrome, the increased oxidative stress and proinflam-matory environment produced by high uric acid levelsstimulates synthesis of C-C motif chemokine 2 (alsoknown as monocyte chemoattractant protein 1) andincreases levels of IL-6 and TNF,141 leading to a possiblemechanism though which uric acid contributes to thepathogenesis of NAFLD.

    Cardiorenal syndromeThe inherent crosstalk between the kidneys and heartcan result in cardiorenal syndrome, which often pre-sents as worsening renal function in patients with heartfailure. The direct mechanisms underlying this inter-action are unclear but are probably mediated by a reduc-tion in glomerular filtration rate (GFR). The declinein GFR is partly due to a reduction in renal blood flowand other cardiac failure signals to the kidneys includ-ing sympathetic activation, humoral factors (such asnatriuretic peptides) released from the heart, inflamma-tory cytokines and modulators of renal function, such asanti-diuretic hormone. Similarly, reciprocal renal effectsare produced on the myocardium secondary to anaemia,activation of the RAAS, accumulation of uraemic toxins,prohypertrophic agents (such as angiotensin II andendothelin- 1) and biochemical inducers of apoptosissuch as inter leukins and other inflammatory cytokines.These changes can lead to acute, chronic, abrupt, primaryand secondary cardiorenal decompensation, which cor-respond to types 15 cardiorenal syndrome, respectively(Table 1). 109,142 The added pathological effects of obesityon the cardio vascular and renal systems, and their inter-action, are also likely to accentuate the severity of cardio-renal syndrome. Furthermore, heart failure and renaldysfunction can be worsened by obesity-related systemicinflammation, insulin resistance, metabolic syndrome,cardiomyo pathy and primary renal disease, throughcardiac and renal fatty infiltration and dis ordered bio-logical signals.143 However, determining the relativecontribution of obesity to cardiac and renal disease viathe cardiorenal axis will require increased scrutiny andfurther research using in vitro and in vivo models to revealimportant mechanistic information.

    Bariatric procedures might offer a unique opportunityto disrupt crosstalk between the cardiovascular and renalsystems, thereby breaking the vicious cycle of pathologyand its sequelae that leads to both renal failure and heartfailure. Emerging evidence indicates that cardiorenalsyndrome is derived from the accumulation of uraemictoxins, including the highly protein-bound moleculeindoxyl sulphate, which has prohypertrophic, fibro-genic and oxidative stress inducing effects. 144 Roux-en-Ygastric bypass (RYGB) powerfully modulates postopera-tive levels of this toxin, and this change is associated withprofound shifts in the patients gut flora, in addition to amultitude of beneficial metabolic effects. 145

    Treatment of cardiorenal diseaseWe propose an algorithm for the management of obesity-related cardiorenal disease (Figure 2). This algorithmclarifies the role of bariatric surgery in the treatment ofchronic cardiorenal syndrome in patients with a BMIof 3540 kg/m2 and obesity-related comorbidities (such asT2DM), or in patients with a BMI of 40 kg/m 2 (morbidobesity). Surgery might also be considered for patientswith a BMI of 3035 kg/m2 who have obesity-specificrenal or cardiac disease. In the acute setting, primarycardiac or renal disease should be managed supportively,before consideration of surgical intervention.

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    Positive effects of bariatric surgeryDecreased cardiovascular risk Weight loss seems to be a simple answer to most obesity-related health problems. However, lifestyle, behaviouraland pharmacological weight-loss strategies providelimited efficacy, particularly in the long term. 8,146 Varioustypes of surgical procedures have, therefore, been devel-oped to achieve efficient and sustained weight loss inpatients with excess weight. These procedures are termedbariatric surgeries.

    The individuals who are most widely accepted to havean indication for bariatric surgery are patients seen in amultidisciplinary obesity unit who are morbidly obese(BMI >40 kg/m2) or those who have a BMI 35 kg/m 2 and life-changing or life-threatening obesity-relatedcomorbid ities. Bariatric procedures can be divided into

    three broad categories based on their mechanism ofaction: restrictive, bypass and hybrid surgeries (Box 1).These procedures are now primarily performed usingminimally invasive laparoscopic techniques, which,when performed in a centre of excellence, are safe andhave an operative mortality not dissimilar to that oflaparoscopic cholecystectomy.147149 The prospective, con-trolled Swedish Obese Subjects (SOS) trial demonstratedthat bariatric operations are not only effective comparedwith medical treatment (in terms of the reduction inweight over 20 years in patients with obesity), 9,150,151 butalso improve quality of life, 152 decrease obesity-relateddisease,153 and increase life expectancy. 154

    Each type of bariatric surgery is associated with aunique benefit and risk profile that should guide thechoice of procedure for each individual patient. However,the hybrid RYGB is considered by some units as the goldstandard bariatric procedure in appropriately selectedpatients, given its low morbidity and profound meta-bolic effects.155 By bypassing the duodenum, the anatomi-cal rearrangement of the upper gastrointestinal tract inpatients after RYGB provokes several pleiotropic physio-logical effects (summarized by the acronym BRAVE: bileflow alteration; reduction of gastric size; anatomical gutrearrangement and altered flow of nutrients; vagal manip-ulation; and enteric gut hormone modulation) 156 thatmodulate the enteroinsular, enterocardiac and entero-renal axes independently of the weight-reducing effectsof this surgery. 143,157159 The BRAVE effects occur almostinstantaneously after gastric bypass surgery. 156,160162

    Reduced cardiovascular diseaseBariatric surgery has beneficial effects on both structuraland functional cardiac status. Surgical intervention canimprove diastolic function and precipitate reverse remod-elling of the heart, particularly in patients with pre- existingsystolic dysfunction and long- standing morbid obesity.These beneficial effects are partly ascribed to a reductionin systemic hypertension (Table 2). 163,164 Furthermore,bariatric surgery might lead to symptomatic improve-ment in all stages of obesity-related cardiomyopathy, andcan improve left ventricular systolic function even inpatients with severe heart failure who are awaiting a hearttransplant. 165,166 Whether these postsurgical changes inthe heart are a direct consequence of the weight reductionor an in direct response to the metabolic and endocrinechanges and reduction in adipose tissue mass is the subjectof ongoing debate. 167 However, the SOS study results dem-onstrated a decrease in cardiovascular morbidity andmortality in patients 20 years after gastric bypass, indepen-dently of baseline BMI.151 Furthermore, these data are nowsupported by cardiac imaging studies demonstrating thatbariatric surgery results in improved postoperative cardiacgeometry, and early molecular data suggesting the presenceof an enterocardiac hormonal axis through which suchprocedures can alter the metabolic milieu independentlyof their effects on body weight. 143,168

    Changes in postprandial gut hormone release mightalso improve cardiac function after bariatric surgery. 169 Hormones such as secretin (produced in the duodenum),

    glucagon (produced in the pancreas), and vasoactive intes-tinal peptide (produced in the gut, pancreas, and brain)act as inotropes by activating cardiac membrane adenylatecyclase.170 Moreover, two pivotal hormones that are mod-ulated by gastric bypass surgery, glucagon- like peptide-1(GLP-1) and ghrelin, also modulate cardiac function, andhave key roles in the enterocardiac axis (Figure 1). GLP-1is a satiety hormone produced by duodenal cells, and levelsof this hormone are upregulated after bariatric surgery. Byenhancing myocardial glucose uptake, GLP-1 is cardio-protective, particularly in patients with dilated cardiomyo-pathy or left ventricular systolic dysfunction. 171173 Bycontrast, production of the appetite-stimulating hormone

    CRS type 5Secondary cardiorenalsyndrome

    CRS type 2Chronic

    cardiorenalsyndrome

    CRS type 4Chronic

    renocardiacsyndrome

    Treatunderlyingpathology

    Consideration for bariatric surgery

    BMI >40 kg/m 2

    BMI >35 kg/m 2with obesity-related

    comorbiditiese.g. type 2

    diabetes mellitus

    BMI >30 kg/m 2

    with obesity-specic pathology e.g. obesity-related

    nephropathy orcardiomyopathy

    CRS type 3Acute

    renocardiacsyndrome

    CRS type 1Acute

    cardiorenalsyndrome

    Acute diseasesuccessfully

    managed

    Primary renalsupport and therapy

    Primary cardiacsupport and therapy

    Figure 2 | Proposed algorithm for the management of patients with obesity-relatedcardiorenal syndrome. Acute obesity associated CRS (type 1 or type 3) should bemanaged primarily with supportive renal and cardiac therapy in order to successfullytreat 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 (type 2 or type 4) stable state, patientsmay be considered for early surgical intervention. In secondary, type 5 CRS, theunderlying cause should be sought and treated before consideration for surgicalintervention. Patients should be considered for surgery if BMI >40 kg/m 2 or if BMI>35 kg/m 2 with obesity-associated co-morbidities such as type 2 diabetes mellitus.Patients with lower BMIs (>30 kg/m 2) may also be considered for surgicalintervention where specific obesity-related cardiomyopathy or nephropathy ispresent, in order to reduce the risk of disease progression. Abbreviation: CRS,cardiorenal syndrome.

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    ghrelin (by P/D1 cells in the stomach) is upregulatedafter nonrestrictive bariatric procedures. Ghrelin pro-motes vasodilatation and reduces susceptibility to (aswell as improving tolerance of) coronary artery disease. 174 Infusion of ghrelin in patients with heart failure signifi-cantly improves the cardiac index, stroke volume and left ventricular ejection fraction, and reduces left ventricularwall stress.175 Moreover, ghrelin resistance in the setting ofhyperghrelinaemia has been implicated as a precipitatingfactor in cardiac failure (Figure 1). 176

    Gastric bypass surgery also modulates adipokinerelease, decreases plasma leptin levels and promotesadiponectin production. 135,136 In turn, these changesmight lead to reductions in inflammatory mediatorrelease, intimal hyperplasia, myocardial hypertrophy andblood pressure. 143,177,178 However, the reader should notethat similar changes in adipokine profiles and inflamma-tion can be observed following chronic starvation, whichsuggests that at least some of these metabolic effectsoccur as a result of the absolute weight reduction. 179 Todetermine whether adipokine levels modulate the cardio-protective effects of bariatric surgery above and beyondabsolute weight reduction, future studies must aim tostandardize changes in biochemical markers accordingto a measure of preoperative and postoperative BMI.

    Improved glycaemic controlDespite substantial advances in the management ofT2DM, the cost of treatment and regular follow-up ishigh and pharmacological treatment is poorly adheredto in this setting. The role of gastric bypass surgery inreversing or ameliorating T2DM was first identified in the1980s, in studies showing that 7483% of patients with apreoperative diagnosis of T2DM remained free from thedisease 14 years after bariatric surgery. 180 By contrast, onlyhalf of medically treated patients with T2DM attainedadequate glycaemic control. 181,182 A meta-analysis of 221studies found that resolution of T2DM occurred in 80.3%of patients who underwent gastric bypass. This figurereached 95.1% in patients undergoing bilio pancreaticdiversion with or without duodenal switch; however, theincreased surgical morbidity and mortality associatedwith this procedure has limited its uptake. 183

    Initially, the antidiabetic effect of RYGB was attributed toabsolute weight reduction. However, a dramatic improve-ment in glycaemic control is observed within days of thesurgery, long before any pronounced weight loss occurs, 184

    and has a far more potent effect on T2DM than is observedin patients who achieve similar amounts of weight reduc-tion by nonsurgical means. 143,149,180,183,185 Furthermore,RYGB and biliopancreatic diversion improve blood sugarlevels more effectively than do other bariatric procedures,such as sleeve gastrectomy, gastric banding and verticalbanded gastroplasty, despite resulting in similar weightreductions. 186 In fact, after RYGB, 30% of patients hadnormal 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 ofT2DM can be categorized according to the organ systems

    in which they exert their principal actions (Figure 3). 160 Early postsurgical resolution of T2DM is thought to occur via manipulation of vagal nerve signalling and changes ingustatory neurohormonal signalling, 188,189 alterationsin bile metabolism, 190 gut microbiota modulation, 145 a shift in metabolite profiles 191 and a reduction in inflam-mation. 192 Persistent early changes include the powerful

    gut hormone effects that occur almost immediately afterRYGB surgery and persist for many months thereafter. 193 Two randomized controlled trials 194,195 have demonstratedthe pronounced efficacy of this form of bariatric surgerycompared with medical treatment of T2DM up to 2 yearsafter the procedure. One study in particular revealed theresults were statistically independent of patients baselineBMI,194 adding support for weight-independent amelio-ration of insulin resistance and improvement of T2DMcontrol after RYGB surgery. 160

    The long-term effects of this type of bariatric surgeryare mediated by alterations in fat metabolism and adipo-kine secretion, 196,197 caloric restriction and weight loss, 197

    Box 1 | Types of bariatric procedure

    Careful postoperative nutritional follow-up of all patients after bariatric surgery isvital (and should be standard practice).Restrictive proceduresRestrictive procedures, which limit the amount of food that can be consumed bysurgically 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 managementprofiles that may require regular review, re-intervention and modification (forexample, adjustable gastric band).

    Bypass proceduresThese procedures bypass a segment of the small intestine, which leads tometabolic changes. This class of operations has been traditionally termedmalabsorptive procedures, although the evidence for malabsorption remainsgenerally unquantified (with the some specific exceptions). Partial ileal bypassaims to reduce cholesterol absorption from the distal ileum. Biliopancreaticdiversion 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 resolutionof disease. Disadvantages: Typically longer procedures with higher degree of complexity

    requiring multiple gastrointestinal anastomoses. Some procedures such asthe biliopancreatic diversion have malabsorbtive effects that require intensenutritional monitoring and follow-up.

    Hybrid proceduresHybrid procedures offer a combination of restriction and bypass to restrict foodintake by creating a small gastric pouch; they also demonstrate the powerfulmetabolic benefits of bypass procedures. In Roux-en-Y gastric bypass, the foregutis bypassed but 95% of the small bowel is left intact, which avoids many of theadverse effects of other bypass procedures. 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 metabolicbenefits and longer term weight-dependent disease resolution effects.

    Disadvantages: As with bypass procedures, they have a typically longer operativetime with a higher degree of complexity requiring multiple gastrointestinalanastomoses. Some cases have led to conditions such as nesidioblastosis.

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    or by a combination thereof. Of particular interest arethe incretin (insulin-stimulating) effects of RYGB andbiliopancreatic diversion. Incretin hormones decreaseinsulin resistance via increasing insulin sensitivityin the liver and muscle, and stimulate insulin releasebefore the post prandial rise in blood glucose. 198,199 In fact,this capacity of RYGB to promote both insulin produc-tion and insulin sensitivity has led to a number of casesof hyperinsulin aemic hypoglycaemia (nesidioblasto-sis), which is characterized by pancreatic -cell hyper-trophy, islet hyperplasia and increased -cell mass. 160 Themechanisms underlying this effect of RYGB surgery arenot yet fully elucidated, but might represent autobionic(that is, the replacement or boosting of physiologicalfunctions by the rearrangement and manipulation of

    existing tissue or organs) 161 augmentation of pancre-atic -cell function. Furthermore, the failure of RYGBsurgery to reverse obesity-induced -cell hypertrophy,or the persistence of changes in gut hormone signallingeven after substantial weight reduction, might contributeto this process. 161,200,201

    Reversal of nonalcoholic fatty liver diseaseT2DM and NAFLD per se are not an indication for bari-atric surgery in patients with a BMI

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    is, therefore, partly mediated by improved glycaemiccontrol and blood pressure reduction, a lthough otherfactors (such as reductions in levels of circulating inflam-matory cytokines, renal lipotoxicity and oxidative stress)are also implicated. 220,221

    Interestingly, RYGB also improves renal function inpatients with obesity who already have CKD. 222 One studyin 45 patients with CKD and various renal pathol ogiesdemonstrated improvement or stabilization of CKD innine patients, with complete resolution of glomerulo-nephritis in one individual; the study was small, but therenoprotective effects of RYGB seemed to be very con- vincing. 222 As such, gastric bypass surgery might delaythe need for dialysis and/or kidney transplantation inpatients with CKD, and could even have a role in improv-ing comorbidities before transplantation in patients whoare morbidly obese and undergoing dialysis. 223,224

    However, the assessment of renal end points is ham-pered in a number of studies by their use of differingGFR assessment modalities and failure to control forpreoperative BMI. In addition, the reduction in musclemass associated with weight loss makes serum creati-nine levels an unreliable marker of GFR, because cre-atinine production is proportional to muscle mass. Assuch, changes in body composition should be examined,together with the amount of weight loss, to fully assessthe relationships between obesity, weight reductionand the effects of surgical intervention. Future studiesshould determine whether weight loss improves renalfunction independently of its effects on T2DM, hyper-tension and hyperlipidaemia and, if so, what effect thisimprovement has on the progression of renal disease andits associated mortality.

    ConclusionsObesity-related cardiorenal disease results from thecomplex interplay of several shared elements, includ-ing hypertension, autonomic disturbance, dyslipid-aemia and T2DM. These pathophysiological elementscan now be successfully treated with bariatric surgery,which improves both cardiovascular and renal out-comes and offers a unique method to concomitantlymanage both systemic diseases via effects on cardio-renal crosstalk. Increased study of bariatric surgery andits effects on the cardiorenal axis might, therefore, iden-tify important mechanisms that underpin the effects ofweight changes on cardiorenal syndrome and spearhead

    the next generation of interventions for multisystemmetabolic disorders.

    However, despite early research into this field, a numberof compelling clinical questions remain un answered.Firstly, we do not yet fully appreciate the extent to whichthe deleterious effects of obesity are modulated by differ-ing genetic and physiological mechanisms, particularlyin complex organ systems such as the kidney and heart.We also do not completely understand the multifacetedpheno type of obesity, particularly with regard to theinfluence of body composition, total fat mass, adiposetissue distribution and the extent, location and compo-sition of individual fat deposits. Moreover, the contribu-tions of altered crosstalk between muscle and fat, and ofincreased metabolic activity (rather than obesity itself),and the elevated risk of cardiovascular and renal dysfunc-tion in patients with obesity remains unclear. Secondly,the influence of preoperative obesity duration, or thechoice of bariatric procedure, on postsurgical renal andcardio vascular end points requires fur ther clinicaland mechanistic investigation. Thirdly, although encour-aging evidence supports the existence of improved renaland cardiac outcomes after bariatric surgery, the extentto which surgery modulates the need for dialysis, renaltransplantation or cardio vascular interventions and affectsoverall survival and quality of life is yet to be fully delin-eated. Finally, the role of bariatric surgery in managingcardiorenal disease in patients who are only moderatelyobese or of normal weight is, as yet, unknown.

    Future research must focus on improving our knowl-edge of the intermediary physiological factors and geno-typic, proteomic and post-transcriptional variations thatpredispose patients to obesity and metabolic syndrome,to fill the gaps in our understanding of the pathophysi-ology of obesity-associated comorbidities. Both systemsbiology and mechanistic studies, in the context of trans-lational clinical trials, are needed to manage and developthe next generation of interventions and procedures totreat obesity-related, multisystem, cardiorenal disease.

    Review criteria

    A search for original articles published between 1953 and2013 and focusing on obesity-associated comorbidities,renal and cardiac dysfunction and the effects of bariatricsurgery was performed in MEDLINE and PubMed. Thesearch terms used were obesity, renal disease,nephropathy, cardiac disease, cardiomyopathy,cardiorenal, AND bariatric surgery, alone and incombination. All articles identified were English-language,

    full-text papers. We also searched the reference lists ofidentified articles for further relevant papers.

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    AcknowledgementsThe authors research work is supported by individualWellcome Trust fellowships to H. Ashrafian andL. Harling.

    Author contributionsW. Fenske, L. Harling, C. Drechsler andH. Ashrafian researched data for and wrote thearticle. T. Athanasiou, L. Harling, A. Darzi andH. Ashrafian reviewed and edited the manuscript

    before submission. A. Darzi and H. Ashrafianmade substantial contributions to discussions ofthe content.

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