Assessing Glycemic Control in MaintenanceHemodialysis Patients With Type 2DiabetesSARA KAZEMPOUR-ARDEBILI, MD1

VARUNIKA L. LECAMWASAM, MRCP2

THUSHARA DASSANYAKE, BSC2

ANDREW H. FRANKEL, MD, FRCP2

FREDERICK W.K. TAM, PHD, FRCP2

ANNE DORNHORST, DM, FRCP3

GARY FROST, PHD1

JEREMY J.O. TURNER, DPHIL, MRCP1

OBJECTIVE Optimizing glycemic control in diabetic patients undergoing maintenancehemodialysis requires accurate assessment. We hypothesize that 1) 48-h continuous glucosemonitoring (CGM) provides additional, clinically relevant, information to that provided by theA1C measurement and 2) glycemic profiles differ significantly between day on and day offdialysis.

RESEARCHDESIGNANDMETHODS With the use of GlucoDay S, 48-h CGM wasperformed in 19 type 2 diabetic subjects undergoing hemodialysis to capture consecutive 24-hperiods on and off dialysis. Energy intake was calculated using food diaries. A1C was assayed bya high-performance liquid chromatography method.

RESULTS CGM data were available for 17 subjects (13 male) with a mean (range) age of61.5 years (4279 years) and diabetes duration of 18.8 years (430 years). The 24-h CGM areaunder the glucose curve and 24-h mean glucose values were significantly higher during the dayoff dialysis than on dialysis (5,932.1 2,673.6 vs. 4,694 1,988.0 mmol 3 min1 l1, P0.022, and 12.6 5.6 vs. 9.8 3.8 mmol/l, P 0.013, respectively), independent of energyintake. Asymptomatic hypoglycemia occurred in 4 subjects, 3 within 24 h of dialysis, and theglucose nadir in 14 subjects occurred within 24 h of dialysis.

CONCLUSIONS Glucose values are significantly lower on dialysis days than on nondi-alysis days despite similar energy intake. The risk of asymptomatic hypoglycemia was highestwithin 24 h of dialysis. Physicians caring for patients undergoing hemodialysis need to be awareof this phenomenon and consider enhanced glycemic monitoring after a hemodialysis session.CGM provides glycemic information in addition to A1C, which is potentially relevant to clinicalmanagement.

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D iabetic nephropathy is the leadingcause of end-stage renal failure(ESRF) (1), representing 3045%of the U.K. and U.S. (2) populations un-dergoing long-term maintenance hemo-dialysis. The patients typically are elderlytype 2 diabetic patients with establishedmicro- and macrovascular disease (3).Hypoglycemia is common because of im-paired renal gluconeogenesis, malnutri-tion, and the increased half-life of insulinand hypoglycemic agents (4). The annual

mortality among diabetic patients under-going hemodialysis is high and is pre-dominately due to cardiovascular disease(CVD) (2).

Intensive glycemic management de-lays progression of microvascular disease(5 8) and improves malnutrition (9);however, large randomized controlled tri-als show no mortality benefit in high-riskgroups with CVD (7,10). Hypoglycemicevents increase with intensive treatmentand in the presence of CVD can cause fatal

dysrhythmia (11). U.K. diabetes guide-lines advise against intensive treatmentaimed to lower A1C levels 6.5% (12),whereas American guidelines cautionagainst values 7% (13). No evidence-based guidelines for the glycemic targetsfor diabetic patients with ESRF undergo-ing long-term maintenance hemodialysisare available.

In patients without ESRF, the A1Cvalue is routinely used to assess long-termglycemic control, and assays are standard-ized to those used in the Diabetes Controland Complications Trial (14). There is astrong correlation between A1C valuesand the weighted mean glucose values ofthe preceding 23 months (14).

The validity of the A1C measurementin patients with ESRF undergoing hemo-dialysis depends on the methodology(15). A number of factors may influencethe assay including altered red blood cell(RBC) life span and metabolic and me-chanical factors (16). Potential metabolicfactors are interference from carbamy-lated hemoglobin formed in uremia andacetylated hemoglobin formed from long-term aspirin use (17).

A limitation of the A1C value in pa-tients undergoing hemodialysis is that it isnot informative regarding glycemic con-trol on the days on and off dialysis. In theU.K., maintenance hemodialysis is typi-cally given in a hospital setting three timesa week, with sessions lasting 4512 h. TheCGM devices that measure glucose every3 min using a biosensor and a subcutane-ous microbore cannula are, in contrast,ideally suited to examine the effect of di-alysis on glucose profiles over a 48-h pe-riod. Thus, in the present study we testthe hypotheses 1) that 48-h CGM pro-vides additional, clinically relevant, infor-mation to that provided by the A1Cmeasurement in patients undergoing he-modialysis and 2) that 24-h glucose pro-files are different on the day that includesa dialysis session compared with those ona day that does not.

RESEARCH DESIGN ANDMETHODS The study was ap-proved by the Hammersmith Hospital Re-search Ethics Committee, and written

From the 1Department of Investigative Medicine, Imperial College London, Hammersmith Campus, Lon-don, U.K.; the 2Imperial College Kidney and Transplant Institute, Division of Medicine, HammersmithHospital, London, U.K.; and the 3Department of Medicine, Imperial College London, HammersmithCampus, London, U.K.

Corresponding author: Sara Kazempour-Ardebili, s.kazempour@imperial.ac.uk.Received 15 September 2008 and accepted 16 January 2009. DOI: 10.2337/dc08-1688. 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c hO R I G I N A L A R T I C L E

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informed consent was obtained (Registra-tion No. 2002/6260). Study objectiveswere to compare glucose profiles fromdays on and off dialysis using 48-h CGMin type 2 diabetic patients, to examine theassociation between self-reported food in-take and CGM values, and to evaluate gly-cemic assessment obtained using 48-hCGM in type 2 diabetic patients undergo-ing maintenance hemodialysis.

Nineteen (14 male) type 2 diabeticsubjects were recruited from the mainte-nance hemodialysis program at ImperialCollege Kidney and Transplant Institute(ICKTI). Dialysis was performed against a2 mmol/l glucose-containing dialysatefor 4512 h during the morning, after-noon, or early evening. Inclusion criteriawere a stable hemoglobin level, defined asa10% change in hemoglobin value andno blood transfusion in the preceding 3months, a stable dose of erythropoietin,and no hemoglobinopathy. A history ofCVD was established as documentedischemic heart disease (history of myocar-dial infarction, a revascularization proce-dure, or angiographically provencoronary disease), cerebrovascular dis-ease (history of cerebrovascular accidentor transient ischemic attack), or periph-eral vascular disease (history of amputa-tion due to gangrene, a revascularizationprocedure, or peripheral vascular disease

proven angiographically or by Dopplerultrasonography).

Blood samplesBlood samples were taken at the start ofdialysis for measurement of A1C, hemo-globin, albumin, and urea.

CGMDay 1. Subjects attended ICKTI, andbefore they started dialysis a GlucoDayS CGM device from A.Menarini Diagnos-tics (Florence, Italy) (18) was fitted andplaced in a pouch to be worn around thewaist. The CGM biosensor was calibratedretrospectively using capillary bloodglucose testing as advised by themanufacturer.Day 3 (48 h later). Subjects attendedICKTI, and before their dialysis sessionthe CGM device was removed. The datawere downloaded to a computer usingdedicated software (GlucoDay S Data Pre-sentation Software).

Exclusion criteriaExclusion criteria were prospectively de-fined as type 1 diabetes, intercurrent ill-ness, changes to medication regimenduring the monitoring period, or occur-rence of prolonged hypoglycemia.

Patient diariesOn day 1, subjects were given a 48-h di-ary to record the exact time and amount offood, drink, and medications taken dur-ing the entire CGM monitoring period,together with any episodes of symptom-atic hypoglycemia and all capillary bloodglucose results.

Laboratory analysisA1C measurements were performed inthe hospitals clinical biochemistry lab-oratory using a Diabetes Control andComplications Trialaligned HA-8160A1C autoanalyzer (A.Menarini Diag-nostics). This analyzer is not subject tointerference by urea, as this reverse-phase cation exchange high-perfor-mance liquid chromatography (HPLC)method provides good separation ofA1C from carbamylated hemoglobinA1. Hemoglobin measurements wereperformed in the hospitals routine he-matology laboratory using a XE2100autoanalyzer (Sysmex, Kobe, Japan)running a variation of the CyMet hemo-globin absorptiometric method. Serumurea and serum albumin tests were per-formed on an Architect ci8200 mul-tichannel analyzer (Abbott Diagnostics,North Chicago, IL).

Table 1Clinical details of 17 subjects whose CGM data were included in the final analysis

nAge

(years) Sex

Duration ofdiabetes(years)

Urea(mmol/l)

CVD(yes/no)* Medication

Hb(g/dl)

A1C(%)

Time undergoingdialysis (years)

Erythropoietindose

(g/week)

1 53 M 20 5.1 Yes Gliclazide, 40 mg b.i.d. 13.4 5.1 1.2 302 59 M 18 19.3 Yes Gliclazide, 80 mg q.d. 11.3 5.3 3.7 803 65 M 6 15.1 Yes Diet 12.9 6 1.3 154 72 M 16 22.3 Yes Gliclazide, 80 mg q.d. 9.9 6 3 1005 63 M 20 23.0 Yes Humulin M3 (8 units b.i.d.) 14.6 6.4 3.6 306 52 M 18 28.2 Yes Gliclazide, 40 mg b.i.d. 15.1 6.5 3.7 307 65 M 24 14.0 Yes NovoRapid (10 units A.M.),

Glargine (35 units P.M.)12.1 6.6 2.8 60

8 68 M 26 14.0 Yes NovoMix 30 (10 units b.i.d.) 10.9 5.6 7.7 309 65 M 30 17.9 Yes Mixtard 30 (10 units, 8 units) 12 6.7 5.4 1010 67 M 18 24.0 Yes Gliclazide, 40 mg b.i.d. 13.1 6.7 10.2 6011 58 F 9 17.0 No Mixtard 50 (23 units, 24 units) 9.3 7.4 0.5 8012 53 M 13 26.7 Yes Gliclazide, 160 mg b.i.d. 11.7 7.9 2.7 4013 79 M 22 21.9 Yes Mixtard 30 (18 units, 12 units) 14 8 6.8 2014 42 M 26 16.0 Yes Mixtard 30 (18 units, 12 units) 13.4 8.5 3.9 1515 65 F 30 13.2 Yes Mixtard 30 (6 units b.i.d.) 13.8 7.3 6.2 5016 65 F 4 14.5 Yes Gliclazide, 160 mg b.i.d. 12.4 8.9 3.3 3017 54 F 19 17.8 No NovoMix 30 (16 units, 10 units) 11.7 9.2 1.7 60

*Documented history of vascular disease defined as ischemic heart disease (history of myocardial infarction, revascularization procedure or angiographically provencoronary disease), cerebrovascular disease (history of cerebrovascular accident or transient ischemia attack) or peripheral vascular disease (history of amputation dueto gangrene, revascularization procedure, or peripheral vascular disease proven angiographically or by Doppler ultrasonography). F, female; M, male.

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Assessment of glycemic controlThe 48-h glucose profiles were quanti-fied, using dedicated software (GlucoDayS Data Presentation Software), as the areaunder the 3-min glucose curve (AUC) andthe mean glucose value. The time periodsstudied were the first 24-h period startingthe first hour of dialysis (day on dialysis)and the 24-h period ending 1 h before thenext dialysis session (day off dialysis). The6-h nocturnal periods from midnight to6:00 A.M. for each of these 24-h periodswere also examined to determine the ef-fect of dialysis. Hypoglycemia, defined asa continuous glucose reading 2.5mmol/l for30 min, was identified fromthe CGM profiles. Subjects were ques-tioned regarding symptoms of hypoglyce-mia at the end of the CGM period.

Dietetic analysisCompleted food diaries were checkedduring a dietary consultation with a reg-istered dietitian. Food portions were ver-ified using a pictorial food atlas (19).Comparisons of dietary intake during the24-h periods on and off dialysis were per-formed by a data analyst blinded to thestudy using the Dietplan6 software pack-age (Forestfield Software). The daily en-ergy requirement was calculated to be3035 kcal/kg ideal body weight (20).

Statistical analysisThe CGM data were exported into SPSSsoftware (version 14; SPSS for Windows;LEAD Technologies) and tested for nor-mality using the Shapiro-Wilk test.

All normally distributed data are ex-pressed as means SD and nonnormallydistributed data are expressed as median(range). All comparisons of the glycemicprofiles and dietary intake between dayson and off dialysis were analyzed usingpaired Students t tests. Linear regressionanalysis was used to assess the relation-ship between laboratory A1C and weeklyerythropoietin dose, serum urea, and se-rum albumin. The level of significancewas defined as P 0.05.

RESULTS Nineteen (14 male) sub-jects were recruited, and 2 were subse-quently excluded, one because ofrepeated hypoglycemia during both mon-itoring periods and one because of CGMtechnical failure. The age, duration of di-abetes, and years of dialysis [mean SD(range)] of the 17 (13 male) subjects in-cluded were 61.5 8.8 years (4279years), 18.8 7.6 years (430 years), and4 2.6 years (0.510.2 years), respec-

tively. Previous CVD history, diabetesmedications, erythropoietin dose, A1C,hemoglobin, and urea values are given inTable 1.

A1C valuesThe A1C (mean SD) was 6.9 1.2%(range 5.19.2%), with seven subjectshaving A1C 6.5% (Table 1). Results oflinear regression analysis among A1C anderythropoietin dose, serum albumin, andurea were not significant (r2 0.17, P0.0995; r2 0.161, P 0.536; and r20.163, P 0.533, respectively).

Hemoglobin valuesMean SD hemoglobin was 12.4 1.6g/l (range 9.315.1 g/l).

Analysis of glycemic profilesThe 24-h AUC glucose values and mean24-h CGM data were significantly higherthe day off dialysis than the day on dialy-

sis (5,932.1 2,673.6 vs. 4,694 1,988mmol 3 min1 l1, P 0.022, and12.6 5.6 vs. 9.8 3.8 mmol/l, P 0.013, respectively) (Fig. 1). The differ-ence in the 24-h mean glucose levels forthe day off dialysis to the day on dialysisranged from 2.1 to 10.4 mmol/l.

The AUC glucose profiles and themean glucose values for the 6-h nocturnalperiod from midnight to 6:00 A.M. weresignificantly higher for the second thanfor the first night (1,541 834 vs.1,137 529 mmol 3 min1 l1, P 0.05, and 12.9 7.0 vs. 9.5 4.4mmol/l, P 0.05, respectively), with amedian 6-h mean nocturnal glucose dif-ference of 4.2 mmol/l (range 8.5 to17.1 mmol/l) (Fig. 2).

Analysis of hypoglycemiaFour of the 17 subjects had CGM record-ings of 2.5 mmol/l for 30 min; in 3subjects, this recording occurred in the

Figure 1CGM data for day on (day 1) and day off (day 2) dialysis, expressed as AUC glucose(A) andmean glucose (B) for each 24-h period., data for individual subjects;f, mean SDfor each 24-h period.A: Mean SD area under the 3-min glucose curve for the whole study groupwas 5,932.1 2,673.6 mmol 3 min1 l1 on the day off dialysis vs. 4,694 1,988 mmol 3min1 l1 on the day on dialysis (P 0.022). B: Mean SD CGM glucose values for the wholegroup were 12.6 5.6 mmol/l on the day off dialysis vs. 9.8 3.8 mmol/l on the day on dialysis(P 0.013).

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first 24-h monitoring period. Examina-tion of individual CGM profiles showedthat 14 of 17 subjects reached their glu-cose nadir (range 1.38 9.81 mmol/l)within the first 24 h, with 10 of 17 havingtheir lowest reading within 12 h of start-ing dialysis. No subject reported any epi-sode of symptomatic hypoglycemia.

Analysis of the food diariesTwo subjects failed to complete their 48-hfood diaries (subjects 6 and 15). Analysisof the 15 completed diaries showed nosignificant difference between recordeddietary intakes for the day on dialysis andthe day off dialysis (1,636 603 vs.1,702 559 kcal, respectively, P 0.596). There was no trend towardgreater food intake on either day, with 7subjects recording a greater calorie intakeduring the day on dialysis versus 8 duringthe day off dialysis. The timing of the di-

alysis shift did not appear to influence theenergy intake (data not shown). The totalenergy intake for each subject was signif-icantly lower, both on dialysis days (mean1,636 kcal/day) and off dialysis days(mean 1,702 kcal/day), than the esti-mated mean energy requirement (2,000kcal/day) (P 0.01; data not shown).

MedicationsNo subject recorded a change in fre-quency or dosing of medications, includ-ing insulin, on the 2 days.

CONCLUSIONS The need to bal-ance glycemic targets to avoid hypoglyce-mia with the risks of microvasculardisease from hyperglycemia requires ac-curate glycemic assessment. This is espe-cially so for diabetic patients undergoingmaintenance hemodialysis, who have ahigh prevalence of microvascular and ma-

crovascular disease and an increased riskof asymptomatic hypoglycemia duringhemodialysis (21). The use of continuoussubcutaneous glucose monitors is ideallysuited for diabetic patients undergoinghemodialysis because, unlike A1C mea-surements, they can examine short-termglycemic changes around the time of di-alysis and are unaffected by urea, RBC lifespan, and RBC production.

The need to set the appropriate glyce-mic targets for type 2 diabetic patientswith a high CVD risk was highlighted bythe Action to Control Cardiovascular Riskin Diabetes (ACCORD) (7) and the Actionin Diabetes and Vascular Disease: Pre-terax and Diamicron Modified ReleaseControlled Evaluation (ADVANCE) (8)randomized controlled trials. These stud-ies recruited subjects at high risk of CVD,and neither showed any CVD benefitfrom targeting A1C levels 6.5 and 7%,respectively. The ACCORD study actuallyshowed a small increase in overall mortal-ity when A1C 6.5% was targeted. Thatlow A1C levels may not confer survivalbenefit in ESRF was also suggested by a1-year follow-up study of 23,000 Ameri-can diabetic subjects (22). In contrast,good glycemic control before dialysisdoes appear to have some CVD benefit(23). Thus, it may be necessary for A1Ctargets originally based on low CVD riskpopulations without chronic kidney dis-ease to be reevaluated for diabetic patientsundergoing hemodialysis.

The A1C is a measure of the irrevers-ible nonenzymatic glycation product ofone or both NH2-terminal valines of the-hemoglobin chain. In ESRF, the A1Cassay can be affected by interference fromcarbamylated hemoglobin formed fromurea-derived isocyanate that accumulatesin uremia (24). However, advances in re-verse-phase cation exchange HPLC ana-lyzers, as used in this study, allow forgreater hemoglobin peak separation (25).

Shortened RBC life span or increasedRBC production (16) can occur in ESRF,and both can falsely lower A1C values byreducing the RBC glycemic exposuretime. However, a study of 23 patients un-dergoing hemodialysis who were receiv-ing regular erythropoietin therapy andhad stable hemoglobin values concludedthat the ambient glucose concentrationrather than RBC life span was the majordeterminant, as no correlation betweenRBC life span and A1C measured by ei-ther immunoassay or HPLC was shown(26). Starting or increasing erythropoietintreatment could, by increasing RBC pro-

Figure 2Nocturnal CGM data for the 6-h period from midnight to 6:00 A.M. for day on (night1) and day off (night 2) dialysis, expressed as AUC glucose (A) andmean glucose (B)., datafor individual subjects; f, mean SD for each 24-h period. A: Mean SD area under the 3-minglucose curve for the whole study group was 1,541 834 mmol 3 min1 l1 for the night of theday off dialysis (night 2) vs. 1,137 529 mmol 3 min1 l1 for the night of the day on dialysis(night 1) (P 0.05). B: Mean SD CGM glucose values for the whole group were 12.9 7.0mmol/l on night 2 vs. 9.5 4.4 mmol/l on night 1.

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duction, falsely lower A1C values by in-creasing the proportion of younger RBCsand thereby reducing glucose exposuretime. In the present study, all subjects hadstable hemoglobin values and their eryth-ropoietin doses had remained constantover the preceding 3 months.

Furthermore, the A1C value may beless informative in the type 2 diabeticpopulation undergoing maintenance he-modialysis and may be less easily trans-lated into mean glycemic values than inother populations. The A1C Derived Av-erage Glucose Study Group (ADAG) in-vestigators recently reported (27) thatA1C levels can be converted to averageglucose levels in type 2 diabetic patients.However, patients with chronic kidneydisease were excluded from this study,and it is possible that the metabolic fluc-tuations seen with hemodialysis mayweaken the relationship between A1Cand average glucose. CGM is one alterna-tive to A1C for assessing glycemia.

The present study showed that over a2-day period the GlucoDay S CGM devicerecorded significantly higher glucose pro-files on the day off dialysis than the day ondialysis. The CGM glucose values duringthe first 24-h monitoring period (day ondialysis), including the 6-h nocturnal pe-riod, were significantly less than those forthe second 24-h monitoring period. Dur-ing the hours of midnight to 6.00 A.M., theonly common time all subjects were rest-ing and not eating, the magnitude of thisdifference ranged from 8.5 to 17.1mmol/l, with a median difference of 4.2mmol/l. These differences in glucose pro-files were not explained by the differencein 24-h energy intake, changes in medi-cation, or dialysis shift. However, thereare potential limitations regarding the ac-curacy of the food diaries, as data werecollected over 48 h only and were self-reported. The food data did highlight thefact that all subjects were likely to be mal-nourished because they consumed lessthan their recommended intake.

The CGM data also showed that 4subjects had hypoglycemia (2.5 mmol/lover 30 min) and that this occurredwithin 24 h of dialysis in three subjects.The lowest glucose recording for 14 sub-jects was within the first 24-h period, withthe majority being within 12 h of dialysis.Thus, the results of our study suggest thattype 2 diabetic patients undergoing main-tenance hemodialysis, who already have avery high risk of cardiovascular morbidityand mortality, may have an increased riskof hypoglycemia in the 24-h period after a

dialysis session. Current renal practice in-cludes assessment of glycemic control byblood glucose measurements while thepatient is undergoing hemodialysis. How-ever, physicians caring for these patientsneed to be aware of this phenomenon andconsider enhanced monitoring for thesepatients who may develop hypoglycemiaseveral hours after they have left the dial-ysis unit.

The subjects in this study were typicalof the U.K. type 2 diabetic populationwith a long duration of diabetes (18.8 7.6 years) and high prevalence rates ofestablished vascular disease (15 of 17subjects) who are undergoing hemodial-ysis. Our preliminary study suggests thatCGM offers clinically useful data for sucha high-risk group. Larger studies on pop-ulations undergoing hemodialysis will berequired to determine whether data fromCGM should be used for medication ad-justments around dialysis days to opti-mize glycemic control and avoidhypoglycemia.

In summary, as glycemic targets be-come redefined to avoid overaggressivemanagement in individuals with highCVD risk, it is important that the mea-surements of glycemic control in patientsundergoing hemodialysis are as informa-tive as possible.

Acknowledgments We are grateful forsupport from the National Institute for HealthResearch Biomedical Research Centre fundingscheme. S.K.-A. is funded by the King FaisalFoundation. J.J.O.T. is a British Heart Foun-dation intermediate fellow. The study wassupported by the Biomedical Research Centreat Imperial Colleges Academic Health ScienceCentre.

No potential conflicts of interest relevant tothis article were reported.

We thank A.Menarini Diagnostics for pro-viding us with the CGM monitors.

Part of the work was presented in abstractform at the annual meeting of The Renal Asso-ciation, Glasgow, Scotland, 2316 May 2008;at the autumn meeting of the Association ofBritish Clinical Diabetologists, London, En-gland, 2728 November 2008; and at the 69thScientific Sessions of the American DiabetesAssociation, New Orleans, Louisiana, 59June 2009.

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