5412Cd01.pdf

REVIEW ARTICLE

Obesity in Kidney TransplanWinnie Chan, MSc,*, Jos A. Bosch, PhD, David Jo

Anna C. Phillips, PhD, and Richard Borrows, MA{,j

Kidney transplantation is the preferred modality of renal replacement t

marginally over the recent decade, mainly because of the developmen

factor for cardiovascular disease and is common before and after trans

pre- and post-transplant obesity on patient and graft survival, discuss

kidney transplant outcomes, and explores the role of nutritional inte

Although the role of pretransplant obesity remains uncertain, post-tra

Nutritional intervention is effective in achieving post-transplant weight

lished. Future research should focus on conducting nutritional interve

transplantation.

2014 by the National Kidney Foundation, Inc. All rights reserved.associated with increased risk of graft failure. Obesity ishttp://dx.doi.org/10.1053/j.jrn.2013.09.002graft.According to the World Health Organization, over-

weight is defined as a body mass index (BMI) of 25.0 to29.9 kg/m2; and obesity is defined as a BMI of 30.0 kg/m2 or greater.14 Before transplantation, the role of obesityon long-term patient and graft survival remains uncertain.However, available evidence suggests that obesity predis-poses to delayed graft function with a subsequent effecton graft failure.7 After transplantation, obesity is stronglyassociated with reduced long-term patient and graft sur-vival,7 but it failed to display an independent relationshipwith CVD risk.15-18 However, obesity leads to a higherprevalence of CVD risk factors including hypertension,dyslipidemia, diabetes mellitus, and insulin resistance, allof which are independently associated with increased riskof graft failure.15-18 These individual conditions alsocluster as part of metabolic syndrome. A recent subanalysisof the Assessment of LEscol in Renal Transplantation(ALERT) study revealed that metabolic syndrome was

19

*Department of Nutrition and Dietetics, Therapy Services South Suite, Queen

Elizabeth Hospital Birmingham, Birmingham, United Kingdom.School of Sport and Exercise Sciences, University of Birmingham, Birming-

ham, United Kingdom.School of Healthcare Science, Manchester Metropolitan University, Manches-

ter, United Kingdom.Division of Metabolic and Vascular Health, Warwick Medical School, Uni-

versity of Warwick, Coventry, United Kingdom.{Centre for Translational Inflammation Research, University of Birmingham,

Birmingham, United Kingdom.jjDepartment of Nephrology and Kidney Transplantation, Queen Elizabeth

Hospital Birmingham, Birmingham, United Kingdom.

Support: W.C. is funded by the British Renal Society and the National Health

Service West Midlands Strategic Health Authority.

Address correspondence to Winnie Chan, MSc, Department of Nutrition and

Dietetics, Therapy Services South Suite, 1st Floor Queen Elizabeth Hospital

Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2WB, United

Kingdom. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. All rights reserved.1051-2276/$36.00Introduction

KIDNEY TRANSPLANTATION IS the preferredmodality of renal replacement therapy for many pa-tients with end-stage renal disease.1 Compared to remain-ing on the transplant waiting list, kidney transplantationimproves long-term survival,2 enhances quality of life,3

demonstrates cost benefit,4 and rectifies uremia and me-tabolic abnormalities contributing to an overall sense ofwell-being.5 Despite several advantages after successfultransplantation, the corollary of the current shortage oforgans is that only a proportion of patients on the transplantwaiting list proceed to transplantation, with up to 40%dying while waiting on dialysis.6 It is crucial that the bestpossible use is made of those transplanted kidneys (grafts);therefore, optimizing patient and graft survival after trans-plantation should be a priority in this patient group.Journal of Renal Nutrition, Vol 24, No 1 (January), 2014: pp 1-12tationnes, PhD, Philip G. McTernan, PhD,

j

herapy. Long-term patient and graft survival have only improved

t of cardiovascular disease after transplantation. Obesity is a risk

plantation. This article reviews the literature assessing the role of

es the underlying obesity-related mechanisms leading to inferior

rvention on improving long-term outcomes of transplantation.

nsplant obesity increases the risk of graft failure and mortality.

loss, but the effect on long-term outcomes has not been estab-

ntion studies aiming to improve long-term outcomes of kidney

Short-term patient and graft survival have substantiallyimproved over the recent decades, with most centers re-porting both survival rates at 1 year of greater than 90%.7

However, long-term success has been difficult to accom-plish as evident by the marginal increase in patient and graftsurvival rates over the past 15 years.8 This phenomenon ismultifactorial. Firstly, modification of alloimmunity usingimmunosuppression has reduced short-term early acute re-jection rates,8 but the nephrotoxicity of immunosup-pressive medication is known to limit long-term graftsurvival.9 Secondly, the use of maintenance immunosup-pressive therapy is associated with increased risk of infec-tion and malignancy.10 Thirdly, cardiovascular disease(CVD) is a well-known long-term complication in kidneytransplant recipients (KTRs)11; it is the leading cause ofdeath after transplantation12 and death with a functioning

131

with most weight gain within the first 12 months after

CHAN ET AL2modifiable by nutritional intervention, but the effect ofweight loss resulting from these interventions on long-term patient and graft survival has not beenwell established.The purposes of this article are to review the relevant lit-

erature assessing the role of pre- and post-transplant obesityon patient and graft survival, to discuss the potential under-lying mechanisms by which obesity induces its detrimentaleffects leading to inferior kidney transplant outcomes, andto explore the role of nutritional intervention on improvingthe long-term outcomes of kidney transplantation. Finally,this article aims to identify gaps in current literature andrecommends potential areas for future research.

Prevalence and Effect of Obesity BeforeTransplantation

Overweight and obesity are common at the time oftransplantation.20 Currently, 60% of KTRs are overweightat the time of transplantation, representing a 116% increasefrom 1987.20 Indeed, many transplant centers in theUnited Kingdom and United States exclude patientswith a BMI greater than 30 or 35 kg/m2.21 A BMI of35 kg/m2 or greater was the third most common reasonto exclude as many as 10% of patients from transplanta-tion.22 Despite this, the effect of pretransplant obesity onpatient and graft survival remains controversial, with sev-eral conflicting studies in the literature. Table 1 summa-rizes the studies examining the effect of pretransplantobesity on kidney transplant outcomes. In some studies,although pretransplant obesity had no effect on long-term outcomes, it demonstrated a negative effect onshort-term outcomes including graft failure within thefirst year post-transplant,23 post-transplant surgical com-plications, and delayed graft function.24-29 Despite thelack of relationship between pretransplant obesity andlong-term outcomes in these studies, it is important tonote that delayed graft function is associated with reducedlong-term graft survival.7,30 Some studies showed thatobesity exerts a negative effect on long-term patient andgraft survival.7,31-36 In contrast, adverse effects of obesityon short- and long-term outcomes were seen in somestudies.31,33 Also, a study by Yamamoto and colleagues35

otherwise demonstrated that although obesity had noeffect on short-term graft survival, decreased medium-and long-term graft survival were observed in obeseKTRs. Finally, Streja and colleagues36 showed that obesitywas associated with graft loss, but it had no effect on mor-tality. In summary, studies with short-term outcome datahave unanimously demonstrated a negative effect ofpretransplant obesity whereas studies with long-term out-come data have yielded variable conclusions. Such con-flicting results from the latter group of studies may partlystem from large variations in the sample size and follow-up period (2-20 years), with studies of larger sample sizeand 6 years or more of follow-up generally showing aneffect.Effect of Body Composition BeforeTransplantation

Given the conflicting data on the effect of pretransplantobesity on patient and graft survival, a recent study exploredthe effect of body composition on long-term patient andgraft survival rates. It showed that sarcopenic obesity beforetransplantation was associated with increased mortality andgraft failure,36 and sarcopenia in the study was defined asreduced pretransplant muscle mass represented by lowerpretransplant serum creatinine in patients with BMI of30 kg/m2 or greater.

Effect of Weight Loss During TransplantListing

Although the effect of pretransplant obesity on patientand graft survival remains unclear, Schold and colleaguesreported that weight loss during transplant listing had noeffect on long-term outcomes after transplantation, includ-ing mortality risk and graft loss across the entire BMI spec-trum.37 The same study also highlighted that substantialweight loss pretransplant was associated with rapid weightgain after transplantation.37 This finding and the observedobesity paradox in the dialysis population38 suggest thatweight loss before transplantation may not necessarily bebeneficial because mortality risk during transplant listingand after transplantation is not alleviated. However, the au-thors highlighted that this information needs to be inter-preted with caution because data on BMI were takenfrom the registry; therefore, crucial information includingthe nature of weight change and other aspects of nutritionalstatus is unavailable.37 Intentional weight loss that is poten-tially beneficial may be masked by weight loss that is a man-ifestation of malnutrition or progressive disease.37

In addition, a retrospective study of the U.S. Renal DataSystem registry found that substantial weight loss wasachieved with bariatric surgery in a cohort of patients be-fore transplant listing and being wait-listed for transplanta-tion.39 These results were similar to findings from recentstudies which demonstrated that laparoscopic Roux-en-Ygastric bypass and laparoscopic sleeve gastrectomy were ef-fective procedures for weight loss and improved candidacyfor kidney transplantation.40,41 However, perioperativecomplications and mortality within a 30-day period afterbariatric surgery were evident.39,41 Also, the effect ofintentional weight loss induced by bariatric surgery onshort- and long-term patient and graft survival has notyet been examined.

Prevalence and Causes of Obesity AfterTransplantation

Weight gain after transplantation is very commonand occurs in up to 50% of KTRs,42,43 affecting obeseand nonobese patients.44 The average weight gain aftertransplantation is between 10% and 35% of body weight,

Table 1. Summary of Studies Showing the Effect of Pretransplant Obesity on Kidney Transplant Outcomes

Study

Sample

Size Study Type

Exposure

Variable Outcome Measures Key Findings

Effect on Kidney Transplant

Outcomes

Lynch et al (2009)24 869 Retrospective BMI - Surgical site infection

post-transplantation- 3-y graft survival

- 3-y patient survival

- Prevalence of surgical site

infection is higher among obeseKTRs.

- Obesity had no independent

effect on 3-y graft and patientsurvival outcomes.

- Effect on short-term outcome

- No effect on long-term outcomes

Johnson et al (2002)25 493 Retrospective BMI - Superficial wound breakdown

- Complete wound dehiscence

- Wound infections- Other postoperative

complications

- Hospitalization rates

- Delayed graft function- Acute rejection episodes

- 5-y graft survival


- Raised BMI predicts wound

breakdown.

- BMI does not predict other post-operative complications, hospi-

talization rates, or 5-y graft and

patient survival.



Bennett et al (2004)26 173 Retrospective BMI - Wound infections- Other surgical complications

- 3-y graft survival


- Patients with BMI . 30 kg/m2

have increased wound infections.

- No difference in other surgical

complications or 3-y graft andpatient survival between different

BMI categories.

- Effect on short-term outcome- No effect on long-term outcomes

Massarweh et al

(2005)27193 Retrospective BMI - Graft loss (total loss of graft

function or patient death witha functioning graft) with mean

follow-up time of 24 mo

- Acute rejection rates

- Post-transplant surgicalcomplications

- Patients with BMI$ 30 kg/m2 had

increased incidence ofpost-transplant surgical

complications.

- No difference in acute rejection

rates, long-term mortality, andrisk of graft failure between

patients with BMI, 30 kg/m2 and$30 kg/m2.



Hoogeveen et al

(2011)71,810 Prospective BMI - Patient survival in a 20-y

follow-up study with median

follow-up time of 8.3 y

- Graft survival in a 20-y follow-upstudy with median follow-up time

of 8.3 y

- Obesity (BMI. 30 kg/m2) is a riskfactor for patient mortality and

graft failure independent of other

cardiovascular risk factors.- Obesity (BMI . 30 kg/m2)

increased the risk of death and

graft failure by 20-40%

compared with normal BMI.- A high BMI (.30 kg/m2)

post-transplantation was more

strongly related to death and graft

failure compared withpretransplant obesity.

- Effect on long-term outcomes

(Continued )

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Table 1. Summary of Studies Showing the Effect of Pretransplant Obesity on Kidney Transplant Outcomes (Continued )

Study

Sample

Size Study Type

Exposure

Variable Outcome Measures Key Findings

Effect on Kidney Transplant

Outcomes

Meier-Kriesche et al

(2002)3151,927 Retrospective BMI - Primary study endpoints were

graft and patient survival for up to10 y post-transplant.

- Secondary study endpoints were

death-censored graft survival,

chronic allograft failure, delayedgraft function, and acute

rejection.

- Very high and very low BMI were

associated with worse patientand graft survival.

- Very high and very low BMI were

associated with death-censored

graft failure and chronic allograftfailure.

- Elevated BMI was associated

with increased risk of delayed

graft function.- No association between BMI and

acute rejection.



Sancho et al (2007)32 337 Retrospective BMI - Graft survival with a meanfollow-up of 54 mo

- Patient survival with a mean

follow-up of 54 mo

- Acute rejection episodes- Post-transplant comorbidity

- Compared with normal weightpatients (BMI , 25 kg/m2), over-weight patients (BMI . 30 kg/m2)displayed higher

incidence of hypertension, leftventricular hypertrophy,

dyslipidemia, acute tubular

necrosis, acute rejection

episodes, and post-transplantdiabetes.

- No difference in graft survival be-

tween BMI categories.- Compared with normal weight

patients (BMI , 25 kg/m2),patient survival was lower

in overweight patients(BMI . 30 kg/m2).

- Effect on graft survival- Patient survival was lower in

overweight patients

Gore et al (2006)33 27,377 Retrospective BMI - Intermediate measures of graft

outcome

- Overall graft survival for up to 6 ypost-transplantation

- Morbid obesity (BMI $ 35 kg/m2)

was independently associated

with increased risk of delayedgraft function, prolonged

hospitalization, and acute

rejection in the postoperative

period.- Morbid obesity (BMI $ 35 kg/m2)

decreased overall graft survival.

- Effect on short-term outcomes


Schwarznau et al(2008)23

81 Retrospective BMI - Graft loss within the first year afterkidney transplant

- Increased BMI was anindependent risk factor for

graft loss within the first year

post-transplant

- Effect on short-term outcome.

CHAN

ETAL

4

Meier-Kriesche et al

(1999)34405 Retrospective BMI - 7-y graft survival


- BMI . 25 kg/m2 conferred a2-fold relative risk of long-termgraft loss and patient death.

- The 7-y actuarial graft survival

was higher among the nonobeseKTRs (BMI # 25 kg/m2)

compared with the obese KTRs

(BMI . 25 kg/m2): 88% vs. 72%.- The 7-y actuarial patient survival

was higher among the nonobese

KTRs (BMI # 25 kg/m2)

compared with the obese KTRs

(BMI . 25 kg/m2): 92% vs. 81%.


Howard et al (2001)28 833 Retrospective BMI - 1- and 5-y graft survival

- 1- and 5-y patient survival

- Higher incidence of delayed graft

function was found in overweight

KTRs (BMI between 25.0 and29.9 kg/m2) and obese KTRs (BMI

$ 30.0 kg/m2).

- Higher incidence of post-

transplant diabetes mellitus wasfound in obese KTRs (BMI $

30.0 kg/m2).

- Death with a functioning graft was

less common among obese KTRs(BMI $ 30.0 kg/m2) compared

with normal weight KTRs (BMI

,25 kg/m2) and overweight KTRs(BMI $ 25 and ,30 kg/m2).

- No difference in 1- and 5-y graft

and patient survival between

different BMI categories(,25.0 kg/m2, 25.0-29.9 kg/m2,and $30.0 kg/m2).

- Effect on short-term outcome.


Marks et al (2004)29 247 Retrospective BMI - 3-y graft survival

- 3-y patient survival- Postoperative complications

- Rejection episodes

- Length of hospital stay

- Readmission rate within the first6 mo post-transplant

- No difference in actuarial patient

and graft survival rate for the first3 y after transplant between non-

obese and morbidly obese KTRs.

- Length of hospital stay, number of

readmissions within the first 6 mopost-transplant, and the number

of major wound complications

were greater for morbidly obeseKTRs compared with nonobese

KTRs.



(Continued )

OBESITYIN

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Table

1.Summary

ofStudiesShowingtheEffectofPretransplantObesityonKidneyTransplantOutcomes(Continued)

Study

Sample

Size

StudyType

Exposure

Variable

OutcomeMeasures

KeyFindings

EffectonKidneyTransplant

Outcomes

Yamamoto

etal

(2002)35

56

Retrospective

BMI

-1-,3-and5-ygraftsurvival

-1-,3-and5-ypatientsurvival

-Delayedgraftfunction

-Acute

rejection

-Obesity(BMI.

30kg/m

2)isnot

ariskfactorfordelayedgraft

function,acute

rejection,and1-y

graftsurvival.

-Decreased3-and5-y

graft

survivaltrendwasobservedin

obeseKTRs(BMI.

30kg/m

2).

-Nodifferenceinpatientsurvival

betweenobeseandnonobese

KTRsat1-,2-,and5-y

post-

transplant.

-Noeffectonshort-term

outcomes

-Effectonmedium-and

long-term

graftsurvival

-Noeffectonpatientsurvivalin

short,medium,andlongterm

Strejaetal(2011)36

10,090

Retrospective

BMI

-Graftsurvivalupto

6y

post-transplant

-Patientsurvivalupto

6y

post-transplant

-Upto

6ypost-transplantation,

obesity(BMI.

30kg/m

2)w

asnot

associatedwithmortality,

althoughitshowedatrendtoward

highergraftloss.

-Effectonlong-term

graftloss

-Noeffectonlong-term

patient

survival

BMI,bodymassindex;KTRs,kidneytransplantrecipients.

CHAN ET AL6transplantation.42,45-47 Much of the weight gain post-transplant is attributed to an increase in body fat mass, espe-cially in the abdominal area.48,49

Excessive weight gain and increased fat mass in KTRs istraditionally attributed to the immunosuppression treat-ment protocol post-transplantation. This is due to thewell-known hyperphagic effect of steroids and their adverseinfluence on adipocytes, resting energy expenditure, andlipid oxidation, resulting in centripetal obesity (i.e., in-creased fat deposition in the peritoneum, mediastinum,and subcutaneous sites such as the face and neck).49 How-ever, recent evidence suggests that the effect of steroids onweight gain is controversial. Table 2 summarizes the studiesshowing the effect of steroids onweight gain and body com-position. First, an early study by Ratcliffe and colleagues50

showed that KTRs on steroid withdrawal therapy achieveda significant reduction in body weight compared withsteroid-maintenance therapy. Another study by van denHam and colleagues49 indicated that weight gain after thefirst year post-transplant was significantly and positively re-lated to cumulative steroid dose. Further studies by Rogersand colleagues51 and Woodle and colleagues52 showed thatearly steroid withdrawal minimizes weight gain in KTRs.However, contrasting studies proposed that the role of ste-roid use on post-transplant weight gain is only partial be-cause an increase in body weight was seen in all KTRsregardless of the immunosuppression protocol.42,49,53 Inparticular, Elster and colleagues53 reported no significantdifference in weight gain between patients treated withsteroids and patients on steroid-avoidance therapy, andJohnson and colleagues42 found no correlation betweenweight gain and cumulative steroid dose, which in part issimilar to findings from van den Ham and colleagues,49 inwhich weight gain in the first year post-transplant wasrelated neither to maintenance nor to cumulative steroiddose. Furthermore, a single-center study showed no differ-ence in fat mass between steroid-avoidance and steroid-maintenance protocols, and no relationship was observedbetween cumulative steroid dose and body composition.54

Although the effect of immunosuppressive protocol onweight gain and changes in body composition is controver-sial, other contributing factors for post-transplant weightgain should be considered. Age, gender, ethnicity, pretrans-plant BMI, dialysis modality, the occurrence and treatmentof rejection, and graft function have all been suggested assignificant contributors toweight changes after transplanta-tion.42,45,49 It is important to note that weight gain post-transplantation may be largely due to lifting of previousdietary restrictions, improved appetite after the correctionof uremia, and the enhanced sense of well-being that occurswith transplantation.

Effect of Obesity After TransplantationIrrespective of the contributing factors to post-transplant

weight gain, obesity after transplantation is known to

Table 2. Summary of Studies Showing the Effect of Steroids on Weight Gain and Body Composition

Study

Sample

Size Study Type Exposure Variable Study Protocol

Key Findings in Relation to Weight Gain

and Body Composition

Ratcliffe et al (1996)50 100 Randomized controlled trial of steroid

withdrawal

Body weight KTRs were randomized either to reduce

prednisolone treatment to 0 over 4 mo

or to maintain their tripleimmunosuppression unchanged.

- Steroid withdrawal was associated

with a significant reduction in body

weight, whereas slight weight in-crease was observed in the control

group.

van den Ham et al(2003)49

123 Longitudinal study with a follow-upperiod of 5 y

Body weight KTRs on either steroid- or steroid-freeimmunosuppression therapy.

- Weight gain occurred in all KTRs. Nodifference in weight gain was found

between KTRs on steroid- or steroid-

free immunosuppression therapy.

- Within the first year post-transplant,increase in body weight was related

neither to maintenance nor

cumulative steroid dose.

- After the first year post-transplant,cumulative steroid dose was

positively related to weight gain.

Rogers et al (2005)51 301 Prospective study with a follow-upperiod of 12 mo

Body weight KTRs on either CCST or CSWD within7 d post-transplant.

- Weight gain was significantly higherin KTRs on CCST at 3, 6, and 12 mo

post-transplant.

- Early CSWDminimized weight gain in

KTRs.Woodle et al (2008)52 386 5-y randomized, double-blind,

placebo-controlled trial

Body weight KTRs on either early CSWD or CCS. - CSWD led to significantly lower

weight gain compared with CCS.

Johnson et al (1993)42 115 Retrospective study with an endpoint

of 5 y post-transplantation

Body weight Potential factors (including cumulative

steroid dose) influencing post-transplantation weight gain were

assessed.

- Weight gain did not correlate with

cumulative steroid dose.

Elster et al (2008)53 95 Retrospective study with 3-y

follow-up data

Body weight

BMI

KTRs who received either lymphocyte

depletion-based steroid sparing ortraditional immunosuppressive

therapy that included steroids for

maintenance immunosuppression.

- Regardless of immunosuppression

therapy, BMI and body weight in-creased post-transplant in all KTRs.

van den Ham (2000)48 77 Cross-sectional study Body composition KTRs on 0-, 5-, or 10-mg maintenance

steroid therapy.

- No significant differences in fat mass,

lean body mass, and body fat distri-

bution among KTRs on 0-, 5-, and 10-

mg maintenance steroid therapy.- No significant relationships between

cumulative steroid dosage and body

composition and body fat distribution

parameters in KTRs.

BMI, body mass index; CCS, chronic low-dose corticosteroid therapy; CCST, chronic corticosteroid therapy; CSWD, corticosteroid withdrawal therapy; KTRs, kidney transplant

recipients.

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CHAN ET AL8adversely affect cardiovascular risk profile and graft func-tion.55 A recent study by Hoogeveen and colleagues7

showed that 1 year after transplant, BMI and BMI incre-ments were both significant risk factors for mortality andgraft failure in the long term. In contrast, Kovesdy and col-leagues56 reported that higher BMI was associated withlower mortality after adjustment for waist circumferencewhereas higher waist circumference was associated withhigher mortality after adjustment for BMI. The oppositeassociation displayed by BMI and waist circumferencehighlighted the uncertainty of relying on BMI as a markerof obesity in view of its incapability to distinguish amongvisceral adiposity, subcutaneous adiposity, and musclemass. In addition, clinically obese patients with exclusivesubcutaneous fat excess were found in a normal metabolicstate and demonstrated a limited deposition of fat at visceralsites,57 conferring to reduced metabolic risk. These find-ings suggest that not only does waist circumference appearto be a better prognostic marker for obesity than BMI, butvisceral adiposity also adversely affects kidney transplantoutcomes, and increased subcutaneous fat and/or musclemass may be protective against mortality risk. In addition,recent data from a renal transplant population showedthat lower urinary creatinine excretion, a proxy for reducedmuscle mass, was associated with increased mortality andgraft failure.58

Obesity-Related Mechanisms of InferiorKidney Transplant Outcomes

Several mechanisms associating obesity with inferiortransplant outcomes have been proposed; these are summa-rized in Figure 1. Overall, sarcopenic obesity, characterizedby reduced muscle mass coupled with increased fat mass,appears to be the driving force behind these mechanisms.A link between muscle mass and survival has been sug-

gested. Increased muscle mass has been proposed to im-prove skeletal, respiratory, and cardiac muscle functionand consequently improve the muscle-based oxidativemechanism, leading to increased antioxidant defense.56

Therefore, reduced muscle mass may exert a negative effecton the proposed mechanism, leading to increased risk ofCVD, cancer, neurodegenerative disorders, and otherchronic conditions.59 Also, gelsolin produced by the skele-tal muscle has been shown to be associated with improvedsurvival in dialysis patients.56 Although the effect of gelsolinhas not been studied in kidney transplantation, the deple-tion of gelsolin may explain the higher mortality risk inKTRs.The negative metabolic effects of raised BMI and adi-

posity, particularly visceral adiposity, may explain the in-creased CVD risk and graft failure observed in KTRs.First of all, the ALERT trial showed that raised BMI wasassociated with inflammation60; inflammatory markersincluding interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were independently and posi-tively associated with major cardiovascular events and all-cause mortality in KTRs.60 Specifically, visceral adiposetissue is the most metabolically active system that secretesadipokines (cytokines secreted by adipose tissue), and ex-amples include chemerin, IL-6, visfatin, adiponectin, lep-tin, tumor necrosis factor-a, and resistin.61 The role ofadipokine has received preliminary attention in kidneytransplantation. Kaisar and colleagues62 found that adipo-nectin (an adipokine) upregulates high-density lipoproteinand downregulates triglycerides in KTRs, a typical profileof dyslipidemia associated with obesity,62,57 and confersincreased CVD risk in KTRs. However, Chitalia andcolleagues found no association between adiponectin andCVD risk in a kidney transplant population.63 Neverthe-less, adiponectin was shown to correlate inversely with in-flammation in KTRs, characterized by elevated C-reactiveprotein.62 In addition, elevated levels of visfatin werefound to correlate with inflammation and markers ofendothelial damage in KTRs, including raised levels ofhsCRP, prothrombin fragments 1 1 2, and vascular celladhesion molecule.64 Furthermore, raised resistin levelscorrelated with markers of inflammation and endothelialdysfunction in KTRs, including elevated levels of hsCRP,IL-6, thrombomodulin, and vascular cell adhesionmolecule.65

The link between inflammation and mortality in KTRshas been established by Winkelmayer and colleagues.66 In-flammation has been proposed to exert its downstream ad-verse sequelae via the mediation of vascular damage causingvascular inflammation, which in turn leads to the patho-genesis of atherosclerosis in KTRs.60 Another suggestedmechanism associated with adiposity is that adipose tissuessecrete proinflammatory cytokines, including tumor ne-crosis factor-a and IL-6, which sequentially activate therenin-angiotensin-aldosterone pathway, contributing tothe onset and progression of graft damage by sustainingcell growth, inflammation, and fibrosis.7

In addition, the metabolic load of the graft increases asa result of obesity; the graft consequently adapts by in-creasing in size and glomerular filtration.7 The combiningeffects of fibrosis and glomerulomegaly are the most com-mon histologic lesions in patients with obesity-related glo-merulopathy, suggesting that these are important pathwaysleading to graft failure.7

Obesity Intervention StrategiesLifestyle Modification and BehavioralInterventionNo interventional studies currently exist to evaluate the

effect of pretransplant obesity management on the long-term clinical outcomes of kidney transplantation. This isunsurprising because the effect of pretransplant obesityon kidney transplant outcomes remains uncertain. In con-trast, 4 studies have evaluated the effect of lifestyle interven-tions on weight management post-transplantation, with all

plantive

OBESITY IN KIDNEY TRANSPLANTATION 9studies consistently demonstrating that nutritional inter-ventions were effective in achieving weight loss, as summa-rized in Table 3. It is worth noting that lifestyleintervention incorporating dietary advice led to improve-ments in CVD risk factors in KTRs,67-71 but the effect ofweight reduction through lifestyle intervention per se onkidney transplant outcomes, including surrogates suchas acute rejection, remains undetermined.Firstly, Patel and colleagues72 reported that 4 months of

intensive individualized dietary intervention immediatelyafter transplant resulted in significant reduction in bodyweight and BMI. However, 8 months after cessation of di-etary intervention, significant weight gain and increasedBMI were observed. These findings suggested that early in-tensive dietary advice and regular follow-up are effective in

Figure 1. Obesity-related mechanisms of inferior kidney transCVD, cardiovascular disease; hsCRP, high-sensitivity C-reacVCAM, vascular cell adhesion molecule.controlling weight gain in the first year after transplant, anddietary advice should be an important component of post-transplant management. Also, continued dietetic input be-

Table 3. Comparison Between Nutritional Intervention and Steroid

Study Intervention

Patel et al

(1998)724-mo individualized dietary advice immediately post

transplant with regular follow-up compared with n

dietary advice and follow-upLopes et al

(1999)676-mo American Heart Association Step One Diet wit

individualized diet plan and monthly dietetic review

Orazio et al

(2011)73Transtheoretical Model of Health Behaviour Change

incorporating simple exercise advice and nutritiontherapy (Mediterranean-style low glycemic index d

Jezior et al

(2007)74Weight reduction program comprising 2 sessions 6 m

apart

Woodle et al(2008)52

Steroid cessation by day 7 post-transplantationcompared with 5 mg steroid maintenance

Vincenti et al

(2008)76Steroid avoidance immunosuppression protocol

compared with 5-10 mg steroid-maintenance ther

BMI, body mass index.yond the early stage may be beneficial for the durability ofweight control.Moreover, Lopes and colleagues67 showed that the

6 months of the American Heart Association (AHA) StepOne Diet with an individualized diet plan and monthly di-etetic review significantly reduced body weight and bodyfat. This was accompanied by a significant improvementin nutritional intake profile including reductions in calo-ries, dietary cholesterol, total lipids, saturated fats, andmonounsaturated fats. Alongwith this, lipid profile also im-proved, including decreased total and low-density lipopro-tein cholesterol, resulting in reduced CVD risk.Furthermore, Orazio and colleagues,73 by using the

Transtheoretical Model of Health Behaviour Change to in-corporate simple exercise advice and nutrition therapy

t outcomes. BMI, body mass index; CRP, C-reactive protein;protein; IL-6, interleukin-6; TNF-a, tumor necrosis factor-a;(Mediterranean-style low glycemic index diet), producedresults that mirror those of Lopes and colleagues, in whichsignificant weight loss was observed among KTRs with

Minimization Protocols on Weight Changes

Magnitude of Weight Changes

-

o

Dietetic intervention resulted in 5 kg less weight gain

compared with no dietetic intervention

h Significant reduction of 3 kg

iet)

Mean weight reduction not reported, but patients

underwent lifestyle intervention resulted in 3.8%weight loss

o Mean weight unchanged, but 27% of patients enrolled in

weight reduction program experienced weight loss

Steroid cessation resulted in 2.6 kg less weight gaincompared with 5 mg steroid-maintenance therapy

apy

Mean weight reduction not reported, but mean BMI

reduction of 1.0 kg/m2 demonstrated

CHAN ET AL10abnormal glucose tolerance. The progress was also comple-mented with significant improvement in dietary risk factorsfor CVD, including reductions in intakes of energy, totalfat, and percentage saturated fat. Improvement in otherCVD risk factors was also evident, including reductionsin triglycerides, total cholesterol, and low-densitylipoprotein cholesterol. It is important to note that patientswith more than 5% weight loss were associated with in-creased high-density lipoprotein cholesterol.Conversely, a study by Jezior and colleagues74 demon-

strated that a weight reduction program comprising 2 ses-sions 6 months apart failed to achieve an overall weightreduction. Nevertheless, 27% of patients experiencedweight loss after the program. The lack of success couldbe explained by the nature of this study in which no dietaryadvice was given during the program. At the first visit,patients were only given an evaluation of dietary intake fol-lowed by anthropometry assessment and a short descriptionof the negative effects of obesity on post-transplant morbid-ity. Six months later at the second visit, patients then re-ceived dietary advice based on the analysis of the first visit.In addition to dietetic intervention, increased physical

activity level is an important lifestyle modification strategyfor weight reduction. Zelle and colleagues75 reported anassociation between increased physical activity level andreduced mortality in KTRs independent of waist circum-ference, muscle mass, and triglyceride and insulin levels.

Nutritional Intervention VersusPharmacological Approach

Dietary interventions have shown promising results inweight management when compared with findings fromrecent prospective controlled trials investigating steroidminimization as an immunosuppressive strategy. Woodleand colleagues52 demonstrated that patients on steroidavoidance protocol gained 2.6 kg less weight comparedwith patients on 5-mg maintenance steroid therapy. In ad-dition, Vincenti and colleagues76 reported that patients ona steroid-avoidance protocol gained 1.0 kg/m2 less BMI in-crement compared with patients on 5 to 10 mg of mainte-nance steroid therapy. These results are rather unremarkablecompared with the results from nutritional interventionsshown in Table 3. It is important to note that both stud-ies52,76 using steroid minimization have shown an increasein acute transplant rejection, which raises concerns overthe use of steroid minimization as a strategy for weightmanagement.

Alternative Strategies to WeightManagement

Weightmanagement has generally proven to be a difficultchallenge, involving calorie reduction, increased physicalactivity, and behavioral modification. Pharmacologicaland surgical options are increasingly pursued to tackle theproblem. The use of antiobesity medications has notbeen exclusively studied in KTRs. Sibutramine was associ-ated with hypertension,77 Orlistat interfered with cyclo-sporine absorption decreasing its bioavailability,78 andRimonabant treatment led to increased systemic exposureof cyclosporin A as well as psychiatric complications insome patients.79 Bariatric surgery yielded substantialweight loss in KTRs,39 and gastric bypass procedure hasshown promise in selected KTRs, leading to reduction incardiovascular comorbidity.80

Future Research on Obesity in KidneyTransplantation

The effect of pretransplant obesity on patient and graftsurvival currently remains unclear. Also, clinical trials dem-onstrating the effects of intentional pretransplant weightloss on subsequent patient and graft survival are lacking.Given the well-established contributions of obesity toincreased morbidity and mortality after transplantation, fu-ture research in this area should be channeled toward pro-spective interventional studies aiming to evaluate theeffect of pretransplant intentional weight loss through bari-atric surgery, lifestyle modification, and behavioral inter-vention on short- and long-term outcomes of kidneytransplantation.On the contrary, the adverse effect of obesity after trans-

plantation is well established. Nutritional interventionstudies have shown promising results in achieving weightloss and improving risk factors for CVD, but they lackedhard clinical endpoints (e.g., risk of graft failure andmortal-ity). Future studies should concentrate on evaluating theeffect of weight loss on long-term transplant outcomes.Also, the role of visceral adiposity and its related adipose tis-sue cytokines have only received preliminary attention inkidney transplantation research. At present, there is a lackof preclinical data on this topic, thereby highlighting theneed to develop experimental animal models of renal trans-plant with obesity in parallel to ongoing clinical studies.This will not only aid in dissecting the pathophysiologyof obesity in renal transplant recipients, but also in pavingthe way for possible interventional studies in the future.In addition, further clinical research should assess the effectof varying adipokines on inflammation and the associatedeffects on graft failure and mortality. Likewise, the role ofmuscle mass in KTRs on long-term transplant outcomeshas not been well investigated.

ConclusionIn summary, obesity is common at the time of transplan-

tation and after transplantation. Although the implicationof pretransplant obesity on kidney transplant outcomes re-mains unclear, post-transplant obesity is a significant riskfactor for graft failure and mortality. Obesity interventionpost-transplantation focusing on nutritional therapy hasshown encouraging results in weight management, butthe effect on long-term outcomes has not been

tion based retrospective cohort study. BMJ. 2011;11. 340:c570.

OBESITY IN KIDNEY TRANSPLANTATION 1111. Rigatto C. Management of cardiovascular disease in the renal trans-

plant recipient. Cardiol Clin. 2005;23:331-342.

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2006;113:898-918.demonstrated. There are now emerging data signifying therelevance and benefit of nutritional intervention in KTRs.Therefore, it is important that future research should focuson conducting nutritional intervention studies aiming toimprove kidney transplant outcomes in this populationgroup.

Practical ApplicationThis review article is the first to not only highlight the

role of nutritional intervention and the effect of sarcopeniaon kidney transplant outcomes, but also to illustrate thecomplex pathophysiology of obesity in this patient popula-tion. Future research should focus on conducting prospec-tive studies of nutritional intervention aiming to evaluatethe effect on outcomes of kidney transplantation.

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Obesity in Kidney TransplantationIntroductionPrevalence and Effect of Obesity Before TransplantationEffect of Body Composition Before TransplantationEffect of Weight Loss During Transplant ListingPrevalence and Causes of Obesity After TransplantationEffect of Obesity After TransplantationObesity-Related Mechanisms of Inferior Kidney Transplant OutcomesObesity Intervention StrategiesLifestyle Modification and Behavioral Intervention

Nutritional Intervention Versus Pharmacological ApproachAlternative Strategies to Weight ManagementFuture Research on Obesity in Kidney TransplantationConclusionPractical ApplicationReferences

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