Obesity-Related Cardiorenal Disease

download Obesity-Related Cardiorenal Disease

of 13

Embed Size (px)

Transcript of Obesity-Related Cardiorenal Disease

  • 8/13/2019 Obesity-Related Cardiorenal Disease


    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.


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease

    2/13540 | SEPTEMBER 2013 | VOLUME 9 www.nature.com/nrneph

    Overweight women (BMI 25.029.9 kg/m 2) have a five-fold higher risk of T2DM than do those with a BMI

  • 8/13/2019 Obesity-Related Cardiorenal Disease


  • 8/13/2019 Obesity-Related Cardiorenal Disease

    4/13542 | SEPTEMBER 2013 | VOLUME 9 www.nature.com/nrneph

    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


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease


    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.


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease

    6/13544 | SEPTEMBER 2013 | VOLUME 9 www.nature.com/nrneph

    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


    CRS type 4Chronic



    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


    CRS type 1Acute


    Acute diseasesuccessfully


    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.


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease


    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.


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease

    8/13546 | SEPTEMBER 2013 | VOLUME 9 www.nature.com/nrneph

    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

  • 8/13/2019 Obesity-Related Cardiorenal Disease


    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.

    1. WHO. World Health Organisation Fact Sheet No.311: Obesity and Overweight [online], http://www.who.int/mediacentre/factsheets/fs311/en/index.html (2013).

    2. Ford, E. S., Giles, W. H. & Dietz, W. H. Prevalenceof the metabolic syndrome among US adults:findings from the third National Health andNutrition Examination Survey. JAMA 287 ,356359 (2002).

    3. House, A. A. et al. Definition and classification ofCardio-Renal Syndromes: workgroup statementsfrom the 7th ADQI Consensus Conference.Nephrol. Dial. Transplant. 25 , 14161420 (2010).

    4. Nelson, R., Antonetti , I., Bisognano, J. D. &Sloand, J. Obesity-related cardiorenal syndrome.

    J. Clin. Hypertens. (Greenwich) 12 , 5963 (2010).5. McCullough, P. A. Why is chronic kidney disease

    the spoiler for cardiovascular outcomes? J. Am. Coll. Cardiol. 41 , 725728 (2003).

    6. Sarnak, M. J. et al. Kidney disease as a riskfactor for development of cardiovasculardisease: a statement from the American HeartAssociation Councils on Kidney in CardiovascularDisease, High Blood Pressure Research, ClinicalCardiology, and Epidemiology and Prevention.Circulation 108 , 21542169 (2003).

    7. Brinkwor th, G. D., Buckley, J. D., Noakes, M. &Clifton, P. M. Renal function following long-termweight loss in individuals with abdominal obesityon a very-low-carbohydrate diet vs high-carbohydrate diet. J. Am. Diet Assoc. 110 ,633638 (2010).

    8. Puterbaugh, J. S. The emperors tailors: thefailure of the medical weight loss paradigm andits causal role in the obesity of America.Diabetes Obes. Metab. 11 , 557570 (2009).

    9. Sjstrm, L. et al. Effects of bariatric surgery onmortality in Swedish obese subjects. N. Engl. J.Med. 357 , 741752 (2007).


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease

    10/13548 | SEPTEMBER 2013 | VOLUME 9 www.nature.com/nrneph

    10. Eilat-Adar, S., Eldar, M. & Goldbourt, U.Association of intentional changes in bodyweight with coronary heart disease event ratesin overweight subjects who have an additionalcoronary risk factor. Am. J. Epidemiol. 161 ,352358 (2005).

    11. Algahim, M. F. et al. Progressive regression ofleft ventricular hypertrophy two years afterbariatric surgery. Am. J. Med. 123 , 549555(2010).

    12. Hsuan, C. F. et al. The effect of surgical weightreduction on left ventricular structure andfunction in severe obesity. Obesity (Silver Spring) 18 , 11881193 (2010).

    13. Navaneethan, S. D. & Yehnert , H. Bariatricsurgery and progression of chronic kidneydisease. Surg. Obes. Relat. Dis. 5 , 662665(2009).

    14. Zalesin, K. C. & McCullough, P. A. Bariatricsurgery for morbid obesity: risks and benefits inchronic kidney disease patients. Adv. ChronicKidney Dis. 13 , 403417 (2006).

    15. Colditz, G. A., Willett, W. C., Rotnitzky, A. &Manson, J. E. Weight gain as a risk factor forclinical diabetes mellitus in women. Ann. Intern.Med. 122 , 481486 (1995).

    16. Han, T. S., Richmond, P., Avenell, A. & Lean, M. E.

    Waist circumference reduction andcardiovascular benefits during weight loss inwomen. Int. J. Obes. Relat. Metab. Disord. 21 ,127134 (1997).

    17. Wildman, R. P. et al. The obese withoutcardiometabolic risk factor clustering and thenormal weight with cardiometabolic risk factorclustering: prevalence and correlates of 2phenotypes among the US population (NHANES19992004). Arch. Intern. Med. 168 ,16171624 (2008).

    18. Thomas, E. L. et al. The missing risk: MRI andMRS phenotyping of abdominal adiposity andectopic fat. Obesity (Silver Spring) 20 , 7687(2012).

    19. Thomas, E. L. et al. Magnetic resonance imagingof total body fat. J. Appl. Physiol. 85 , 17781785

    (1998).20. Stefan, N. et al. Identification andcharacterization of metabolically benign obesityin humans. Arch. Intern. Med. 168 , 16091616(2008).

    21. Karelis, A. D. Metabolically healthy but obeseindividuals. Lancet 372 , 12811283 (2008).

    22. Primeau, V. et al. Characterizing the profile ofobese patients who are metabolically healthy.Int. J. Obes. (Lond.) 35 , 971981 (2011).

    23. Kloting, N. et al. Insulin-sensitive obesity. Am. J.Physiol. Endocrinol. Metab. 299 , E506E515(2010).

    24. Stefan, N. & Haring, H. U. The metabolicallybenign and malignant fatty liver. Diabetes 60 ,20112017 (2011).

    25. Cohen, J. C., Horton, J. D. & Hobbs, H. H. Human

    fatty liver disease: old questions and newinsights. Science 332 , 15191523 (2011).26. Grujic, D. et al. Beta3-adrenergic receptors on

    white and brown adipocytes mediate beta3-selective agonist-induced effects on energyexpenditure, insulin secretion, and food intake.A study using transgenic and gene knockoutmice. J. Biol. Chem. 272 , 1768617693 (1997).

    27. Abbott, R. D., Donahue, R. P., Kannel, W. B. &Wilson, P. W. The impact of diabetes on survivalfollowing myocardial infarction in men vs women.The Framingham Study. JAMA 260 , 34563460(1988).

    28. Yamagishi, S. & Imaizumi, T. Diabetic vascularcomplications: pathophysiology, biochemicalbasis and potential therapeutic strategy. Curr.Pharm. Des. 11 , 22792299 (2005).

    29. Gerstein, H. C. et al. Effects of intensive glucoselowering in type 2 diabetes. N. Engl. J. Med. 358 ,25452559 (2008).

    30. Griffin, K. A., Kramer, H. & Bidani, A. K. Adverserenal consequences of obesity. Am. J. Physiol.Renal Physiol. 294, F685F696 (2008).

    31. Kambham, N., Markowitz, G. S., Valeri, A. M.,Lin, J. & DAgati, V. D. Obesity-relatedglomerulopathy: an emerging epidemic. KidneyInt. 59 , 14981509 (2001).

    32. Alexander, M. P. et al. Kidney pathologicalchanges in metabolic syndrome: a cross-sectional study. Am. J. Kidney Dis. 53 , 751759(2009).

    33. Tsuboi, N. et al. Low glomerular density withglomerulomegaly in obesity-relatedglomerulopathy. Clin. J. Am. Soc. Nephrol. 7 ,735741 (2012).

    34. Deji, N. et al. Structural and functional changesin the kidneys of high-fat diet-induced obesemice. Am. J. Physiol. Renal Physiol. 296 ,F118F126 (2009).

    35. Nagase, M. et al. Enhanced aldosteronesignaling in the early nephropathy of rats withmetabolic syndrome: possible contribution offat-derived factors. J. Am. Soc. Nephrol. 17 ,34383446 (2006).

    36. Nagase, M. et al. Podocyte injury underlies theglomerulopathy of Dahl salt-hypertensive ratsand is reversed by aldosterone blocker.Hypertension 47 , 10841093 (2006).

    37. Rubler, S. et al. New type of cardiomyopathyassociated with diabetic glomerulosclerosis. Am.

    J. Cardiol. 30 , 595602 (1972).38. Galderisi, M. et al. Left ventricular hypertrophy,

    compliance and ventricular filling. J. Int. Med.Res. 19 , 103111 (1991).

    39. Shehadeh, A. & Regan, T. J. Cardiacconsequences of diabetes mellitus. Clin. Cardiol. 18 , 301305 (1995).

    40. Regan, T. J. et al. Evidence for cardiomyopathy infamilial diabetes mellitus. J. Clin. Invest. 60 ,884899 (1977).

    41. Alpert, M. A. Obesity cardiomyopathy:

    pathophysiology and evolution of the clinicalsyndrome. Am. J. Med. Sci. 321 , 225236(2001).

    42. Poirier, P. et al. Obesity and cardiovasculardisease: pathophysiology, evaluation, and effectof weight loss: an update of the 1997 AmericanHeart Association Scientific Statement onObesity and Heart Disease from the ObesityCommittee of the Council on Nutrition, PhysicalActivity, and Metabolism. Circulation 113 ,898918 (2006).

    43. Pinna, G. A., Curzu, M. M., Sechi, M.,Chelucci, G. & Maciocco, E. Synthesis anddopamine D2-like receptor binding affinity ofsubstituted 5-phenyl-pyrrole-3-carboxamides.Farmaco 54 , 542550 (1999).

    44. Hu, R. M., Levin, E. R., Pedram, A. & Frank, H. J.

    Insulin stimulates production and secretion ofendothelin from bovine endothelial cells.Diabetes 42 , 351358 (1993).

    45. Kim, J. A., Montagnani, M., Koh, K. K. &Quon, M. J. Reciprocal relationships betweeninsulin resistance and endothelial dysfunction:molecular and pathophysiological mechanisms.Circulation 113 , 18881904 (2006).

    46. Vinik, A. I. The metabolic basis of atherogenicdyslipidemia. Clin. Cornerstone 7 , 2735 (2005).

    47. James, W. P. Assessing obesity: are ethnicdifferences in body mass index and waistclassification criteria justified? Obes. Rev. 6 ,179181 (2005).

    48. McFarlane, S. I., Banerji, M. & Sowers, J. R.Insulin resistance and cardiovascular disease.

    J. Clin. Endocrinol. Metab. 86 , 713718 (2001).

    49. Sowers, J. R. Insulin resistance andhypertension. Am. J. Physiol. Heart Circ. Physiol. 286 , H1597H1602 (2004).

    50. Sowers, J. R., Epstein, M. & Frohlich, E. D.Diabetes, hypertension, and cardiovasculardisease: an update. Hypertension 37 ,10531059 (2001).

    51. Edwards, M. S., Craven, T. E., Burke, G. L.,Dean, R. H. & Hansen, K. J. Renovasculardisease and the risk of adverse coronary events

    in the elderly: a prospective, population-basedstudy. Arch. Intern. Med. 165 , 207213 (2005).52. U. S. Renal Data System. USRDS 2003 Annual

    Data Report: Atlas of chronic kidney disease andend-stage renal disease in the United States[online], http://www.usrds.org/atlas03.aspx (2003).

    53. Dulloo, A. G. Biomedicine. A sympathetic defenseagainst obesity. Science 297 , 780781 (2002).

    54. Rossi, M. et al. Cardiac autonomic dysfunction inobese subjects. Clin. Sci. (Lond.) 76 , 567572(1989).

    55. Petretta, M. et al. Assessment of cardiacautonomic control by heart period variability inpatients with early-onset familial obesity. Eur. J.Clin. Invest. 25 , 826832 (1995).

    56. Grassi, G. et al. Sympathetic activation in obese

    normotensive subjects. Hypertension 25 ,560563 (1995).57. Esler, M. et al. Mechanisms of sympathetic

    activation in obesity-related hypertension.Hypertension 48 , 787796 (2006).

    58. Kotsis, V. T., Stabouli, S. V., Papamichael, C. M.& Zakopoulos, N. A. Impact of obesity in intimamedia thickness of carotid arteries. Obesity(Silver Spring) 14 , 17081715 (2006).

    59. Tentolouris, N., Argyrakopoulou, G. &Katsilambros, N. Perturbed autonomic nervoussystem function in metabolic syndrome.Neuromolecular Med. 10 , 169178 (2008).

    60. Trayhurn, P. & Wood, I. S. Adipokines:inflammation and the pleiotropic role of whiteadipose tissue. Br. J. Nutr. 92 , 347355 (2004).

    61. Trayhurn, P., Wang, B. & Wood, I. S. Hypoxia and

    the endocrine and signalling role of whiteadipose tissue. Arch. Physiol. Biochem. 114 ,267276 (2008).

    62. Hak, A. E. et al. Associations of C-reactiveprotein with measures of obesity, insulinresistance, and subclinical atherosclerosis inhealthy, middle-aged women. Arterioscler.Thromb. Vasc. Biol. 19 , 19861991 (1999).

    63. Ito, H. et al. Association of serum tumournecrosis factor-alpha with serum low-densitylipoprotein-cholesterol and blood pressure inapparently healthy Japanese women. Clin. Exp.Pharmacol. Physiol. 28 , 188192 (2001).

    64. Bautista, L. E., Vera, L. M., Arenas, I. A. &Gamarra, G. Independent association betweeninflammatory markers (C-reactive protein,interleukin-6, and TNF-alpha) and essential

    hypertension. J. Hum. Hypertens. 19 , 149154(2005).65. Tilg, H. & Moschen, A. R. Adipocytokines:

    mediators linking adipose tissue, inflammationand immunity. Nat. Rev. Immunol. 6 , 772783(2006).

    66. Ridker, P. M., Rifai, N., Stampfer, M. J. &Hennekens, C. H. Plasma concentration ofinterleukin-6 and the risk of future myocardialinfarction among apparently healthy men.Circulation 101 , 17671772 (2000).

    67. Langenberg, C., Bergstrom, J., Scheidt-Nave, C.,Pfeilschifter, J. & Barrett-Connor, E.Cardiovascular death and the metabolicsyndrome: role of adiposity-signaling hormonesand inflammatory markers. Diabetes Care 29 ,13631369 (2006).


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease


    68. Chae, C. U., Lee, R. T., Rifai, N. & Ridker, P. M.Blood pressure and inflammation in apparentlyhealthy men. Hypertension 38 , 399403(2001).

    69. Vila, E. & Salaices, M. Cytokines and vascularreactivity in resistance arteries. Am. J. Physiol.Heart Circ. Physiol. 288 , H1016H1021 (2005).

    70. Virdis, A. & Schiffrin, E. L. Vascularinflammation: a role in vascular disease inhypertension? Curr. Opin. Nephrol. Hypertens.

    12 , 181187 (2003).71. Lagrand, W. K. et al. C-reactive protein as acardiovascular risk factor: more than anepiphenomenon? Circulation 100 , 96102(1999).

    72. Munkhaugen, J., Lydersen, S., Widere, T. E. &Hallan, S. Prehypertension, obesity, and risk ofkidney disease: 20-year follow-up of the HUNT Istudy in Norway. Am. J. Kidney Dis. 54 , 638646(2009).

    73. Chakrabarti, S. K. et al. Evidence for activationof inflammatory lipoxygenase pathways invisceral adipose tissue of obese zucker rats.

    Am. J. Physiol. Endocrinol. Metab. 300 ,E175E187 (2011).

    74. Kuller, L. H., Tracy, R. P., Shaten, J. &Meilahn, E. N. Relation of C-reactive protein and

    coronary heart disease in the MRFIT nestedcase-control study. Multiple Risk FactorIntervention Trial. Am. J. Epidemiol. 144 ,537547 (1996).

    75. Ridker, P. M., Cushman, M., Stampfer, M. J.,Tracy, R. P. & Hennekens, C. H. Inflammation,aspirin, and the risk of cardiovascular disease inapparently healthy men. N. Engl. J. Med. 336 ,973979 (1997).

    76. Zhang, Y. et al. Positional cloning of the mouseobese gene and its human homologue. Nature 372 , 425432 (1994).

    77. Schwartz, M. W., Seeley, R. J., Campfield, L. A.,Burn, P. & Baskin, D. G. Identification of targetsof leptin action in rat hypothalamus. J. Clin.Invest. 98 , 11011106 (1996).

    78. Marsh, A. J. et al. Cardiovascular responses

    evoked by leptin acting on neurons in theventromedial and dorsomedial hypothalamus.Hypertension 42 , 488493 (2003).

    79. Rahmouni, K., Morgan, D. A., Morgan, G. M.,Mark, A. L. & Haynes, W. G. Role of selectiveleptin resistance in diet-induced obesityhypertension. Diabetes 54 , 20122018 (2005).

    80. Correia, M. L. et al. Role of cor ticotrophin-releasing factor in effects of leptin onsympathetic nerve activity and arterial pressure.Hypertension 38 , 384388 (2001).

    81. Haynes, W. G., Sivitz, W. I., Morgan, D. A.,Walsh, S. A. & Mark, A. L. Sympathetic andcardiorenal actions of leptin. Hypertension 30 ,619623 (1997).

    82. Haynes, W. G., Morgan, D. A., Walsh, S. A.,Sivitz, W. I. & Mark, A. L. Cardiovascular

    consequences of obesity: role of leptin. Clin. Exp.Pharmacol. Physiol. 25 , 6569 (1998).83. de Courten, M. et al. Hyperleptinaemia: the

    missing link in the, metabolic syndrome? Diabet.Med. 14 , 200208 (1997).

    84. Beltowski, J., Borkowska, E., Wojcicka, G. &Marciniak, A. Regulation of renal ouabain-resistant Na +-ATPase by leptin, nitric oxide,reactive oxygen species, and cyclic nucleotides:implications for obesity-associated hypertension.Clin. Exp. Hypertens. 29 , 189207 (2007).

    85. Galletti, F. et al. High-circulating leptin levels areassociated with greater risk of hypertension inmen independently of body mass and insulinresistance: results of an eight-year follow-upstudy. J. Clin. Endocrinol. Metab. 93 , 39223926(2008).

    86. Kramer, C. K., von Muhlen, D. & Barrett-Connor, E. Does leptin predict incidenthypertension in older adults? Clin. Endocrinol.(Oxf.) 73 , 201205 (2010).

    87. Wolf, G. & Ziyadeh, F. N. Leptin and renalfibrosis. Contrib. Nephrol. 151 , 175183 (2006).

    88. Karmazyn, M., Purdham, D. M., Rajapurohitam, V.& Zeidan, A. Leptin as a cardiac hypertrophicfactor: a potential target for therapeutics. TrendsCardiovasc. Med. 17 , 206211 (2007).

    89. Rajapurohitam, V., Gan, X. T., Kirshenbaum, L. A.& Karmazyn, M. The obesity-associated peptideleptin induces hypertrophy in neonatal ratventricular myocytes. Circ. Res. 93 , 277279(2003).

    90. Selthofer-Relatic, K. et al. Hyperleptinemia non-haemodynamic risk factor for the leftventricular hypertrophy development inhypertensive overweight females. Coll. Antropol. 32 , 681685 (2008).

    91. Umemoto, Y. et al. Leptin stimulates theproliferation of murine myelocytic and primitivehematopoietic progenitor cells. Blood 90 ,34383443 (1997).

    92. Paolisso, G. et al. Plasma leptin level isassociated with myocardial wall thickness inhypertensive insulin-resistant men. Hypertension

    34 , 10471052 (1999).93. Leyva, F. et al. Hyperleptinaemia in chronic heartfailure. Relationships with insulin. Eur. Heart J. 19 , 15471551 (1998).

    94. Purdham, D. M. et al. A neutralizing leptinreceptor antibody mitigates hypertrophy andhemodynamic dysfunction in the postinfarctedrat heart. Am. J. Physiol. Heart Circ. Physiol. 295 ,H441H446 (2008).

    95. Barouch, L. A., Berkowitz, D. E., Harrison, R. W.,ODonnell, C. P. & Hare, J. M. Disruption of leptinsignaling contributes to cardiac hypertrophyindependently of body weight in mice. Circulation 108 , 754759 (2003).

    96. Luo, J. D., Zhang, G. S. & Chen, M. S. Leptin andcardiovascular diseases. Drug News Perspect. 18 , 427431 (2005).

    97. Reaux, A. et al. Physiological role of a novelneuropeptide, apelin, and its receptor in the ratbrain. J. Neurochem. 77 , 10851096 (2001).

    98. Ishida, J. et al. Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo . J. Biol.Chem. 279 , 2627426279 (2004).

    99. Higuchi, K. et al. Apelin, an APJ receptor ligand,regulates body adiposity and favors themessenger ribonucleic acid expression ofuncoupling proteins in mice. Endocrinology 148 ,26902697 (2007).

    100. Bacha, F., Saad, R., Gungor, N. & Arslanian, S. A.Adiponectin in youth: relationship to visceraladiposity, insulin sensitivity, and beta-cellfunction. Diabetes Care 27 , 547552 (2004).

    101. Kadowaki, T. & Yamauchi, T. Adiponectin and

    adiponectin receptors. Endocr. Rev. 26 ,439451 (2005).102. Shibata, R. et al. Adiponectin protects against

    myocardial ischemia-reperfusion injury throughAMPK- and COX-2-dependent mechanisms. Nat.Med. 11 , 10961103 (2005).

    103. Hashimoto, N. et al. Association ofhypoadiponectinemia in men with early onset ofcoronary heart disease and multiple coronaryartery stenoses. Metabolism 55 , 16531657(2006).

    104. Ruano, M. et al. HOMA, QUICKI and MFfm tomeasure insulin resistance in morbid obesity.Obes. Surg. 16 , 549553 (2006).

    105. Kidambi, S. et al. Association of adrenal steroidswith hypertension and the metabolic syndromein blacks. Hypertension 49 , 704711 (2007).

    106. Campbell, D. J. Circulating and tissueangiotensin systems. J. Clin. Invest. 79 , 16(1987).

    107. Briet, M. & Schiffrin, E. L. Aldosterone: effectson the kidney and cardiovascular system. Nat.Rev. Nephrol. 6 , 261273 (2010).

    108. Greene, E. L., Kren, S. & Hostetter, T. H. Role ofaldosterone in the remnant kidney model in therat. J. Clin. Invest. 98 , 10631068 (1996).

    109. Ronco, C., Haapio, M., House, A. A., Anavekar, N.

    & Bellomo, R. Cardiorenal syndrome. J. Am. Coll.Cardiol. 52 , 15271539 (2008).110. Kanbay, M. et al. Uric acid and pentraxin-3 levels

    are independently associated with coronaryartery disease risk in patients with stage 2 and3 kidney disease. Am. J. Nephrol. 33 , 325331(2011).

    111. Kanbay, M. et al. Serum uric acid level andendothelial dysfunction in patients withnondiabetic chronic kidney disease. Am. J.Nephrol. 33 , 298304 (2011).

    112. Anker, S. D. et al. Uric acid and survival inchronic heart failure: validation and applicationin metabolic, functional, and hemodynamicstaging. Circulation 107 , 19911997 (2003).

    113. Basar, N. et al. Elevated serum uric acid predictsangiographic impaired reperfusion and 1-year

    mortality in ST-segment elevation myocardialinfarction patients undergoing percutaneouscoronary intervention. J. Investig. Med. 59 ,931937 (2011).

    114. Masuo, K., Kawaguchi, H., Mikami, H.,Ogihara, T. & Tuck, M. L. Serum uric acid andplasma norepinephrine concentrations predictsubsequent weight gain and blood pressureelevation. Hypertension 42 , 474480 (2003).

    115. Johnson, R. J., Herrera-Acosta, J., Schreiner, G. F.& Rodriguez-Iturbe, B. Subtle acquired renalinjury as a mechanism of salt-sensitivehypertension. N. Engl. J. Med. 346 , 913923(2002).

    116. Johnson, R. J., Feig, D. I., Herrera-Acosta, J. &Kang, D. H. Resurrection of uric acid as a causalrisk factor in essential hypertension.

    Hypertension 45 , 1820 (2005).117. Johnson, R. J., Rodriguez-Iturbe, B., Kang, D. H.,Feig, D. I. & Herrera-Acosta, J. A unifying pathwayfor essential hypertension. Am. J. Hypertens. 18 ,431440 (2005).

    118. Lv, Q. et al. High serum uric Acid and increasedrisk of type 2 diabetes: a systemic review andmeta-analysis of prospective cohort studies.PLoS ONE 8 , e56864 (2013).

    119. Jin, Y. L. et al. Uric acid levels, even in the normalrange, are associated with increasedcardiovascular risk: The Guangzhou BiobankCohort Study. Int. J. Cardiol. http://dx.doi.org/10.1016/j.ijcard.2013.01.214 .

    120. Lanaspa, M. A. et al. Uric acid induces hepaticsteatosis by generation of mitochondrialoxidative stress: potential role in fructose-

    dependent and -independent fatty liver. J. Biol.Chem. 287 , 4073240744 (2012).121. Lee, J. E. et al. Serum uric acid is associated

    with microalbuminuria in prehypertension.Hypertension 47 , 962967 (2006).

    122. Rosolowsky, E. T. et al. High-normal serum uricacid is associated with impaired glomerularfiltration rate in nonproteinuric patients withtype 1 diabetes. Clin. J. Am. Soc. Nephrol. 3 ,706713 (2008).

    123. Iseki, K. et al. Significance of hyperuricemia as arisk factor for developing ESRD in a screenedcohort. Am. J. Kidney Dis. 44 , 642650 (2004).

    124. Ford, E. S., Li, C., Cook, S. & Choi, H. K. Serumconcentrations of uric acid and the metabolicsyndrome among US children and adolescents.Circulation 115 , 25262532 (2007).


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease

    12/13550 | SEPTEMBER 2013 | VOLUME 9 www.nature.com/nrneph

    125. Choi, H. K. & Ford, E. S. Prevalence of themetabolic syndrome in individuals withhyperuricemia. Am. J. Med. 120 , 442447(2007).

    126. Pacifico, L. et al. Serum uric acid and itsassociation with metabolic syndrome andcarotid atherosclerosis in obese children. Eur. J.Endocrinol. 160 , 4552 (2009).

    127. Quinones-Galvan, A. & Ferrannini, E. Renaleffects of insulin in man. J. Nephrol. 10 ,

    188191 (1997).128. Feig, D. I. & Johnson, R. J. Hyperuricemia inchildhood primary hypertension. Hypertension 42 , 247252 (2003).

    129. Niskanen, L. K. et al. Uric acid level as a riskfactor for cardiovascular and all-cause mortalityin middle-aged men: a prospective cohort study.

    Arch. Intern. Med. 164 , 15461551 (2004).130. Hongo, M. et al. Association between serum uric

    acid levels and cardiometabolic risk factorsamong Japanese junior high school students.Circ. J. 74 , 15701577 (2010).

    131. Nakagawa, T. et al. A causal role for uric acid infructose-induced metabolic syndrome. Am. J.Physiol. Renal Physiol. 290 , F625F631 (2006).

    132. Khosla, U. M. et al. Hyperuricemia inducesendothelial dysfunction. Kidney Int. 67 ,

    17391742 (2005).133. Sui, X., Church, T. S., Meriwether, R. A., Lobelo, F.& Blair, S. N. Uric acid and the development ofmetabolic syndrome in women and men.Metabolism 57 , 845852 (2008).

    134. Hallfrisch, J. Metabolic effects of dietaryfructose. FASEB J. 4 , 26522660 (1990).

    135. Sanchez-Lozada, L. G. et al. Effects of febuxostaton metabolic and renal alterations in rats withfructose-induced metabolic syndrome. Am. J.Physiol. Renal Physiol. 294 , F710F718 (2008).

    136. Johnson, R. J. et al. Is there a pathogenetic rolefor uric acid in hypertension and cardiovascularand renal disease? Hypertension 41 ,11831190 (2003).

    137. Mazzali, M. et al. Elevated uric acid increasesblood pressure in the rat by a novel crystal-

    independent mechanism. Hypertension 38 ,11011106 (2001).138. Xu, C., Yu, C., Xu, L., Miao, M. & Li, Y. High serum

    uric acid increases the risk for nonalcoholic fattyliver disease: a prospective observational study.PLoS ONE 5 , e11578 (2010).

    139. Lee, J. W. et al. Serum uric acid as a predictor forthe development of nonalcoholic fatty liverdisease in apparently healthy subjects: a 5-yearretrospective cohort study. Gut Liver 4 , 378383(2010).

    140. Hwang, I. C., Suh, S. Y., Suh, A. R. & Ahn, H. Y.The relationship between normal serum uric acidand nonalcoholic fatty liver disease. J. KoreanMed. Sci. 26 , 386391 (2011).

    141. Dawson, J. & Walters, M. Uric acid and xanthineoxidase: future therapeutic targets in the

    prevention of cardiovascular disease? Br. J. Clin.Pharmacol. 62 , 633644 (2006).142. Ronco, C. et al. Cardio-renal syndromes: report

    from the consensus conference of the acutedialysis quality initiative. Eur. Heart J. 31 ,703711 (2010).

    143. Ashrafian, H., le Roux ., C. W., Darzi, A. &Athanasiou, T. Effects of bariatric surgery oncardiovascular function. Circulation 118 ,20912102 (2008).

    144. Lekawanvijit, S., Kompa, A. R., Wang, B. H.,Kelly, D. J. & Krum, H. Cardiorenal syndrome: theemerging role of protein-bound uremic toxins.Circ. Res. 111 , 14701483 (2012).

    145. Li, J. V. et al. Metabolic surgery profoundlyinfluences gut microbial-host metabolic cross-talk. Gut 60 , 12141223 (2011).

    146. Fenske, W., Parker, J. & Bloom, S. R.Pharmacotherapy for obesity: a field in crisis?Expert Rev. Endocrinol. Metab. 6 , 563577(2011).

    147. Flum, D. R. et al. Perioperative safety in thelongitudinal assessment of bariatric surgery.N. Engl. J. Med. 361 , 445454 (2009).

    148. Ashrafian, H., Darzi, A. & Athanasiou, T. Bariatr icsurgery - can we afford to do it or deny doing it?Frontline Gastroenterol. 2 , 8289 (2011).

    149. Buchwald, H. & Oien, D. M. Metabolic/bariatricsurgery worldwide 2008. Obes. Surg. 19 ,16051611 (2009).

    150. Carlsson, L. M. et al. Bariatric surgery andprevention of type 2 diabetes in Swedish obesesubjects. N. Engl. J. Med. 367 , 695704 (2012).

    151. Sjostrom, L. et al. Bariatric surgery and long-termcardiovascular events. JAMA 307 , 5665(2012).

    152. Salem, L., Jensen, C. C. & Flum, D. R. Arebariatric surgical outcomes worth their cost?A systematic review. J. Am. Coll. Surg. 200 ,270278 (2005).

    153. Nguyen, N. T. et al. Laparoscopic versus opengastric bypass: a randomized study of outcomes,quality of life, and costs. Ann. Surg. 234 ,279289; discussion 289291 (2001).

    154. Buchwald, H. et al. Weight and type 2 diabetesafter bariatric surgery: systematic review andmeta-analysis. Am. J. Med. 122 , 248256.e5(2009).

    155. Tice, J. A., Karliner, L., Walsh, J., Petersen, A. J. &Feldman, M. D. Gastric banding or bypass?A systematic review comparing the two mostpopular bariatric procedures. Am. J. Med. 121 ,885893 (2008).

    156. Ashrafian, H. et al. Metabolic surgery: anevolution through bariatric animal models. Obes.Rev. 11 , 907920 (2010).

    157. Michell, A. R., Debnam, E. S. & Unwin, R. J.Regulation of renal function by thegastrointestinal tract: potential role of gut-derived peptides and hormones. Annu. Rev.Physiol. 70 , 379403 (2008).

    158. Lennane, R. J., Carey, R. M., Goodwin, T. J. &Peart, W. S. A comparison of natriuresis afteroral and intravenous sodium loading in sodium-depleted man: evidence for a gastrointestinal orportal monitor of sodium intake. Clin. Sci. Mol.Med. 49 , 437440 (1975).

    159. Patriti, A., Facchiano, E., Sanna, A., Gulla, N. &Donini, A. The enteroinsular axis and therecovery from type 2 diabetes after bariatricsurgery. Obes. Surg. 14 , 840848 (2004).

    160. Ashrafian, H. et al. Diabetes resolution andhyperinsulinaemia after metabolic Roux-en-Ygastric bypass. Obes. Rev. 12 , e257e272(2011).

    161. Ashrafian, H., Darzi, A. & Athanasiou, T.Autobionics: a new paradigm in regenerativemedicine and surgery. Regen. Med. 5 , 279288

    (2010).162. Ashrafian, H. et al. Metabolic surgery andobstructive sleep apnoea: the protective effectsof bariatric procedures. Thorax 67 , 442449(2012).

    163. Kardassis, D. et al. Impact of body composition,fat distribution and sustained weight loss oncardiac function in obesity. Int. J. Cardiol. 159 ,128133 (2012).

    164. MacMahon, S. W., Wilcken, D. E. &Macdonald, G. J. The effect of weight reductionon left ventricular mass. A randomizedcontrolled trial in young, overweighthypertensive patients. N. Engl. J. Med. 314 ,334339 (1986).

    165. McCloskey, C. A. et al. Bariatric surgery improvescardiac function in morbidly obese patients with

    severe cardiomyopathy. Surg. Obes. Relat. Dis. 3 ,503507 (2007).

    166. Huffman, C., Wagman, G., Fudim, M., Zolty, R. &Vittorio, T. Reversible cardiomyopathiesareview. Transplant. Proc. 42 , 36733678 (2010).

    167. Pontiroli, A. E., Frige, F., Paganelli, M. & Folli, F.In morbid obesity, metabolic abnormalities andadhesion molecules correlate with visceral fat,not with subcutaneous fat: effect of weight lossthrough surgery. Obes. Surg. 19 , 745750

    (2009).168. Ashrafian, H., Athanasiou, T. & le Roux ., C. W.Heart remodelling and obesity: the complexitiesand variation of cardiac geometry. Heart 97 ,171172 (2011).

    169. Barraclough, M. A. & Bloom, S. R. Vipoma of thepancreas: observations on the diarhrhea andcirculatory disturbances. Arch. Intern. Med. 139 ,467471 (1979).

    170. Chatelain, P., Robberecht, P., de Neef, P.,Claeys, M. & Christophe, J. Low responsivenessof cardiac adenylate cyclase activity to peptidehormones in spontaneously hypertensive rats.FEBS Lett. 107 , 8690 (1979).

    171. le Roux ., C. W. et al. Gut hormone profilesfollowing bariatric surgery favor an anorecticstate, facilitate weight loss, and improve

    metabolic parameters. Ann. Surg. 243 , 108114(2006).172. Nikolaidis, L. A. et al. Effects of glucagon-like

    peptide-1 in patients with acute myocardialinfarction and left ventricular dysfunction aftersuccessful reperfusion. Circulation 109 ,962965 (2004).

    173. Nikolaidis, L. A. et al. Recombinant glucagon-likepeptide-1 increases myocardial glucose uptakeand improves left ventricular performance inconscious dogs with pacing-induced dilatedcardiomyopathy. Circulation 110 , 955961(2004).

    174. Baessler, A. et al. Epistatic interaction betweenhaplotypes of the ghrelin ligand and receptorgenes influence susceptibility to myocardialinfarction and coronary artery disease. Hum.

    Mol. Genet. 16 , 887899 (2007).175. Nagaya, N. et al. Effects of ghrelin administrationon left ventricular function, exercise capacity, andmuscle wasting in patients with chronic heartfailure. Circulation 110 , 36743679 (2004).

    176. Tauber, M. et al. Hyperghrelinemia is a commonfeature of Prader-Willi syndrome and pituitarystalk interruption: a pathophysiologicalhypothesis. Horm. Res. 62 , 4954 (2004).

    177. Lfgren, P. et al. Long-term prospective andcontrolled studies demonstrate adipose tissuehypercellularity and relative leptin deficiency inthe postobese state. J. Clin. Endocrinol. Metab. 90 , 62076213 (2005).

    178. Linscheid, P. et al. Increase in high molecularweight adiponectin by bariatric surgery-inducedweight loss. Diabetes Obes. Metab. 10 ,

    12661270 (2008).179. Meyer, T. E. et al. Long-term caloric restrictionameliorates the decline in diastolic function inhumans. J. Am. Coll. Cardiol. 47 , 398402(2006).

    180. Pories, W. J. et al. Who would have thought it?An operation proves to be the most effectivetherapy for adult-onset diabetes mellitus. Ann.Surg. 222 , 339350; discussion 350352(1995).

    181. Hoerger, T. J., Segel, J. E. , Gregg, E. W. &Saaddine, J. B. Is glycemic control improving inUS adults? Diabetes Care 31 , 8186 (2008).

    182. Knowler, W. C. et al. 10-year follow-up of diabetesincidence and weight loss in the DiabetesPrevention Program Outcomes Study. Lancet 374 , 16771686 (2009).


    2013 Macmillan Publishers Limited. All rights reserved

  • 8/13/2019 Obesity-Related Cardiorenal Disease


    183. Buchwald, H. et al. Bariatric surgery:a systematic review and meta-analysis. JAMA 292 , 17241737 (2004).

    184. Fenske, W. K. et al. Can. a protocol forglycaemic control improve type 2 diabetesoutcomes after gastric bypass? Obes. Surg. 22 ,9096 (2012).

    185. Laferrere, B. et al. Effect of weight loss by gastricbypass surgery versus hypocaloric diet onglucose and incretin levels in patients with

    type 2 diabetes. J. Clin. Endocrinol. Metab. 93 ,24792485 (2008).186. Korner, J., Bessler, M., Inabnet, W., Taveras, C. &

    Holst, J. J. Exaggerated glucagon-like peptide-1and blunted glucose-dependent insulinotropicpeptide secretion are associated with Roux-en-Ygastric bypass but not adjustable gastricbanding. Surg. Obes. Relat. Dis. 3 , 597601(2007).

    187. Schauer, P. R. et al. Effect of laparoscopicRoux - en Y gastric bypass on type 2 diabetesmellitus. Ann. Surg. 238 , 467484; discussion8485 (2003).

    188. Wang, Y. & Liu, J. Combination of bypassingstomach and vagus dissection in high-fat diet-induced obese rats-a long-term investigation.Obes. Surg. 20 , 375379 (2010).

    189. Tonosaki, K., Hori, Y. & Shimizu, Y. Relationshipsbetween insulin release and taste. Biomed. Res. 28 , 7983 (2007).

    190. Jialal, I., Abby, S. L., Misir, S. & Nagendran, S.Concomitant reduction in low-density lipoproteincholesterol and glycated hemoglobin withcolesevelam hydrochloride in patients withtype 2 diabetes: a pooled analysis. Metab.Syndr. Relat. Disord. 7 , 255258 (2009).

    191. Mutch, D. M. et al. Metabolite profiling identifiescandidate markers reflecting the clinicaladaptations associated with Roux-en-Y gastricbypass surgery. PLoS ONE 4 , e7905 (2009).

    192. Kopp, H. P. et al. Impact of weight loss oninflammatory proteins and their association withthe insulin resistance syndrome in morbidlyobese patients. Arterioscler. Thromb. Vasc. Biol.

    23 , 10421047 (2003).193. Ashrafian, H. & le Roux ., C. W. Metabolic surgeryand gut hormones - a review of bariatric entero-humoral modulation. Physiol. Behav. 97 ,620631 (2009).

    194. Mingrone, G. et al. Bariatric surgery versusconventional medical therapy for type 2diabetes. N. Engl. J. Med. 366 , 15771585(2012).

    195. Schauer, P. R. et al. Bariatric surgery versusintensive medical therapy in obese patients withdiabetes. N. Engl. J. Med. 366 , 15671576(2012).

    196. Ballantyne, G. H., Gumbs, A. & Modlin, I. M.Changes in insulin resistance following bariatricsurgery and the adipoinsular axis: role of theadipocytokines, leptin, adiponectin and resistin.

    Obes. Surg. 15 , 692699 (2005).197. Gumbs, A. A., Modlin, I. M. & Ballantyne, G. H.Changes in insulin resistance following bariatric

    surgery: role of caloric restriction and weightloss. Obes. Surg. 15 , 462473 (2005).

    198. Wickremesekera, K., Miller, G., Naotunne, T. D.,Knowles, G. & Stubbs, R. S. Loss of insulinresistance after Roux-en-Y gastric bypasssurgery: a time course study. Obes. Surg. 15 ,474481 (2005).

    199. Muscelli, E. et al. Differential effect of weightloss on insulin resistance in surgically treatedobese patients. Am. J. Med. 118 , 5157 (2005).

    200. Service, G. J. et al. Hyperinsulinemichypoglycemia with nesidioblastosis after gastric-bypass surgery. N. Engl. J. Med. 353 , 249254(2005).

    201. ZGraggen, K. et al. Severe recurrenthypoglycemia after gastric bypass surgery. Obes.Surg. 18 , 981988 (2008).

    202. Anstee, Q. M., McPherson, S. & Day, C. P. Howbig a problem is non-alcoholic fatty liverdisease? BMJ 343 , d3897 (2011).

    203. Edmison, J. & McCullough, A. J. Pathogenesis ofnon-alcoholic steatohepatitis: human data. Clin.Liver Dis. 11 , 75104 (2007).

    204. Bugianesi, E. et al. Expanding the natural historyof nonalcoholic steatohepatitis: fromcryptogenic cirrhosis to hepatocellularcarcinoma. Gastroenterology 123 , 134140

    (2002).205. Day, C. P. Non-alcoholic fatty liver disease:current concepts and management strategies.Clin. Med. 6 , 1925 (2006).

    206. Dixon, J. B., Bhathal, P. S., Hughes, N. R. &OBrien, P. E. Nonalcoholic fatty liver disease:Improvement in liver histological analysis withweight loss. Hepatology 39 , 16471654 (2004).

    207. Sjostrom, L. et al. Lifestyle, diabetes, andcardiovascular risk factors 10 years afterbariatric surgery. N. Engl. J. Med. 351 ,26832693 (2004).

    208. Benaiges, D. et al. Impact of restrictive (sleevegastrectomy) vs hybrid bariatric surgery(Roux-en-Y gastric bypass) on lipid profile. Obes.Surg. 22 , 12681275 (2012).

    209. Nguyen, N. T. et al. Resolution of hyperlipidemia

    after laparoscopic Roux-en-Y gastric bypass. J. Am. Coll. Surg. 203 , 2429 (2006).210. Holdstock, C. et al. CRP reduction following

    gastric bypass surgery is most pronounced ininsulin-sensitive subjects. Int. J. Obes. (Lond.) 29 ,12751280 (2005).

    211. Vilarrasa, N. et al. Effect of weight loss inducedby gastric bypass on proinflammatoryinterleukin-18, soluble tumour necrosis factor-alpha receptors, C-reactive protein andadiponectin in morbidly obese patients. Clin.Endocrinol. (Oxf.) 67 , 679686 (2007).

    212. Morales, E., Valero, M. A., Leon, M.,Hernandez, E. & Praga, M. Beneficial effects ofweight loss in overweight patients with chronicproteinuric nephropathies. Am. J. Kidney Dis. 41 ,319327 (2003).

    213. Chagnac, A. et al. The effects of weight loss onrenal function in patients with severe obesity. J. Am. Soc. Nephrol. 14 , 14801486 (2003).

    214. Agnani, S., Vachharajani, V. T., Gupta, R.,Atray, N. K. & Vachharajani, T. J. Does treatingobesity stabilize chronic kidney disease? BMCNephrol. 6 , 7 (2005).

    215. Solerte, S. B., Fioravanti, M., Schifino, N. &Ferrari, E. Effects of diet-therapy on urinaryprotein excretion albuminuria and renalhaemodynamic function in obese diabeticpatients with overt nephropathy. Int. J. Obes. 13 ,203211 (1989).

    216. Praga, M. & Morales, E. Obesity, proteinuria andprogression of renal failure. Curr. Opin. Nephrol.Hypertens. 15 , 481486 (2006).

    217. Navarro-Diaz, M. et al. Effect of drastic weightloss after bariatric surgery on renal parametersin extremely obese patients: long-termfollow-up. J. Am. Soc. Nephrol. 17 , S213S217(2006).

    218. Agrawal, V. et al. The effect of weight loss afterbariatric surgery on albuminuria. Clin. Nephrol. 70 , 194202 (2008).

    219. Saliba, J. et al. Roux-en-Y gastric bypassreverses renal glomerular but not tubularabnormalities in excessively obese diabetics.Surgery 147 , 282287 (2010).

    220. Ruggenenti, P., Perna, A., Ganeva, M., Ene-Iordache, B. & Remuzzi, G. Impact of blood

    pressure control and angiotensin-convertingenzyme inhibitor therapy on new-onsetmicroalbuminuria in type 2 diabetes: a post hocanalysis of the BENEDICT trial. J. Am. Soc.Nephrol. 17 , 34723481 (2006).

    221. Navaneethan, S. D. et al. HMG CoA reductaseinhibitors (statins) for people with chronic kidneydisease not requiring dialysis. CochraneDatabase Systematic Reviews , Issue 2. Art. No.:CD007784 http://dx.doi.org/10.1002/14651858.CD007784 .

    222. Alexander, J. W., Goodman, H. R., Hawver, L. R. &Cardi, M. A. Improvement and stabilization ofchronic kidney disease after gastric bypass.Surg. Obes. Relat. Dis. 5 , 237241 (2009).

    223. Gore, J. L. Obesity and renal transplantation: isbariatric surgery the answer? Transplantation

    87 , 1115 (2009).224. Takata, M. C. et al. Laparoscopic bariatricsurgery improves candidacy in morbidly obesepatients awaiting transplantation. Surg. Obes.Relat. Dis. 4 , 159164; discussion 164165.(2008).

    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.

    Online correspondence

    Nature Reviews Nephrology publishes items of correspondence onl ine only. Suchcontributions are published at the discretion of the Editors and can be subject to peerreview. Correspondence should be no longer than 500 words with up to 15 references andup to two display items, and should represent a scholar ly attempt to comment on a specificarticle that has been published in this journal. To view the correspondence published withthis issue, please go to our homepage at http://www.nature.com/nrneph and follow thelink from the current table of contents.