Aims
To investigate the renal effects of fitness in people with diabetes with mild renal dysfunction.  Methods
The effect of a 12-week exercise programme on estimated GFR in 128 people with diabetes was evaluated.  Results
All cardiometabolic variables improved after 12 weeks of supervised exercise. Although there was a modest 3.9% increase in estimated GFR from baseline in the 128 people who completed the study, those with baseline chronic kidney disease stages 2 and 3 were found to have significant (6 and 12%, respectively; p \u3c 0.01) improvements in post-exercise estimated GFR. Moreover, 42% of the people with chronic kidney disease stage 3 improved to chronic kidney disease stage 2 after the intervention.  Conclusion
Short-term exercise improves renal function in those with more moderate baseline chronic kidney disease. Thus, renal function appears to be responsive to enhanced physical fitness. Being a strong and modifiable risk factor, enhanced fitness should be considered a non-pharmacological adjunct in the management of diabetic kidney disease

Gandhi, S. M.

Kheirbek, Raya E.

Kokkinos, Peter

Nylen, Eric S.

English

George Washington University: Health Sciences Research Commons (HSRC)

Himmelfarb Health Sciences Library, The George Washington UniversityHealth Sciences Research CommonsMedicine Faculty Publications Medicine10-2015Enhanced fitness and renal function in Type 2diabetes.Eric S. NylenGeorge Washington UniversityS. M. GandhiGeorge Washington UniversityRaya E. KheirbekGeorge Washington UniversityPeter KokkinosGeorge Washington UniversityFollow this and additional works at: https://hsrc.himmelfarb.gwu.edu/smhs_medicine_facpubsPart of the Endocrine System Diseases Commons, Endocrinology, Diabetes, and MetabolismCommons, and the Nephrology CommonsThis Journal Article is brought to you for free and open access by the Medicine at Health Sciences Research Commons. It has been accepted forinclusion in Medicine Faculty Publications by an authorized administrator of Health Sciences Research Commons. For more information, pleasecontact hsrc@gwu.edu.Recommended CitationEpub ahead of printShort Report: TreatmentEnhanced fitness and renal function in Type 2 diabetesE. S. Nylen1,2, S. M. Gandhi1,2, R. Kheirbek3 and P. Kokkinos4,5,61Department of Endocrinology, Veterans Affairs Medical Center, 2Department of Endocrinology, George Washington University School of Medicine and HealthSciences, 3Departments of Geriatrics, 4Cardiology, Veterans Affairs Medical Center, 5Department of Cardiology, George Washington University School ofMedicine and Health Sciences, and 6Department of Cardiology, Georgetown University School of Medicine, Washington, DC, USAAccepted 1 May 2015AbstractAims To investigate the renal effects of fitness in people with diabetes with mild renal dysfunction.Methods The effect of a 12-week exercise programme on estimated GFR in 128 people with diabetes was evaluated.Results All cardiometabolic variables improved after 12 weeks of supervised exercise. Although there was a modest3.9% increase in estimated GFR from baseline in the 128 people who completed the study, those with baseline chronickidney disease stages 2 and 3 were found to have significant (6 and 12%, respectively; p < 0.01) improvements in post-exercise estimated GFR. Moreover, 42% of the people with chronic kidney disease stage 3 improved to chronic kidneydisease stage 2 after the intervention.Conclusion Short-term exercise improves renal function in those with more moderate baseline chronic kidney disease.Thus, renal function appears to be responsive to enhanced physical fitness. Being a strong and modifiable risk factor,enhanced fitness should be considered a non-pharmacological adjunct in the management of diabetic kidney disease.Diabet. Med. 32, 1342–1345 (2015)IntroductionDiabetes is the leading cause of chronic kidney disease andprogression to end-stage renal disease, and estimated GFR(eGFR) is an independent predictor of death and cardiovas-cular events [1]. Approximately 40% of people with diabeteswill develop chronic kidney disease. The vast majority of thesepeople will have mild to moderate stages of chronic kidneydisease based on eGFR (i.e. stages 1–3) [2], although they willalso be significantly susceptible to cardiovascular disease [3].Despite multifactorial diabetes treatment methods, the rate ofchronic kidney disease is rising and end-stage renal diseaserates continue to show a poor response to these treatments [4].Cardiorespiratory fitness, as measured by exercise capac-ity, is a modifiable risk factor and a strong predictor ofmortality in chronic illnesses, including Type 2 diabetes[5,6]. Although physical activity is the essential componentfor improving cardiorespiratory fitness [7], people withchronic kidney disease are known to have reduced physicalfunction, low physical activity, increased muscle wasting andconsequently have diminished exercise capacity [8]. Con-flicting results, however, have been reported with regard tothe role of exercise training in chronic kidney disease [9–12],which is perhaps related to the predominance of people withend-stage renal disease in interventional studies [13]. Despitethe paucity of information on the milder stages of chronickidney disease, eGFR correlates with physical activity andexercise capacity and can therefore serve as a guide to renalresponsiveness [14].The aim of the present study was to correlate exercisecapacity to eGFR in response to a short-term interventionalexercise programme in people with Type 2 diabetes.MethodsExercise cohortA total of 128 people with Type 2 diabetes were enrolled in asupervised exercise programme for 12 weeks. The exclusioncriteria included failure to pass an exercise tolerance test, amajor illness in the last 6 months (myocardial infarction,congestive heart failure, stroke, pneumonia or acute kidneydisease) or HbA1c level > 9% ( > 75 mmol/mol).Exercise programmeAfter providing signed consent, the patients were givencomprehensive nutritional and physical activity guidance.The biweekly exercise sessions were supervised by a trainedexercise physiologist and consisted of a 1-h session thatCorrespondence to: Eric Nylen. E-mail: enylen@gmail.com1342Published 2015.This article is a U.S. Government work and is in the public domain in the USADIABETICMedicineDOI: 10.1111/dme.12789included warm-up and cool-down and 30 min of combinedaerobic and resistance training at an exercise intensity of 50–80% of heart rate reserve. The patients were also encouragedto be physically active during the rest of the week. Baselineand post-exercise data included BMI, systolic and diastolicblood pressure (mmHg), HbA1c (mmol/mol and %), creat-inine (lmol/l) and urinary albuminuria (mg/g creatinine).Capillary glucose was obtained before and immediately aftereach exercise session. Diabetes and other medication adjust-ments were unchanged during the 12-week period, unlessclinically indicated.Statistical analysisThe pre- and post-exercise responses were analysed using thepaired t-statistic. All 128 patients participated in a minimumof 15 supervised sessions for 12 consecutive weeks. Allhypotheses were two-sided and P values < 0.05 were takento indicate statistical significance. All statistical analyses wereperformed using SPSS software version 22.0 (SPSS Inc.).ResultsA total of 128 people with Type 2 diabetes were recruitedand completed the exercise programme. The majority wereblack (79%) and male (95%), and their mean  SD age was62  2.1 years. The change in eGFR from baseline using the‘CKD-EPI’ formula [15] in the entire cohort was 3.9%(mean  sd eGFR at baseline: 76.1  21.9 ml/min/1.73 m2;after exercise programme: 79.1  19.7 ml/min/1.73 m2).The patients were then classified into three groups basedon baseline eGFR: group 1 included patients witheGFR > 89 ml/min/1.73 m2 (n = 38), group 2 includedpatients with eGFR 60–89 ml/min/1.73 m2 (n = 53) andgroup 3 included patients with chronic kidney diseasestage 3 with eGFR 30–59 ml/min/1.73 m2 (n = 37). Thosewith chronic kidney disease stage 3 were slightly older(age 63.8  7.2 years compared with 62.0  2.1 and62.5  7.4 years in the groups with chronic kidney diseasestages 1 and 2, respectively) and had a longer duration ofdiabetes (8.9  9.2 years compared with 7.5  2.8 and5.9  6.8 years in the groups with chronic kidney disease1 and 2, respectively). Exercise for 12 weeks resulted inimproved trends in all cardiometabolic variables as shownin Table 1. Notably, there was a significant improvement inmetabolic equivalents in all three groups (P < 0.001); HbA1clevels were significantly lower in those with chronic kidneydisease stages 1 and 3 (P < 0.001); and plasma glucose levelswere significantly improved in the chronic kidney diseasestage 1 group (P = 0.001). After the exercise programme,there was no significant change in eGFR in those withchronic kidney disease stage 1. By contrast, for patients in thechronic kidney disease stages 2 and 3 groups, there was asignificant and gradual improvement in eGFR (improvementsof 6 and 12%, respectively; P = 0.003 and P = 0.0007).Interestingly, 42% of the people with chronic kidney diseasestage 3 improved to chronic kidney disease 1 or 2 (n = 16)after the intervention.DiscussionThe present study shows that renal function is responsive tothe level of fitness as measured by exercise capacity. Askidney function plays a central role in diabetes morbidity andmortality, these results may be of clinical significance.The present study showed that supervised physical activityfor 12 weeks had a positive impact on all cardiometabolicvariables including renal function. More specifically, asignificant improvement in eGFR was seen in those patientswith a compromised baseline renal function, i.e. those withchronic kidney disease stages 2 and 3; 42% of the lattergroup reverted to chronic kidney disease stage 1 or 2.Exercise had less of an impact, therefore, in those with anormal baseline eGFR, which could reflect the inaccuracy ofTable 1 Cardiometabolic response to exerciseChronic kidney disease stage 1(n = 38)Chronic kidney disease stage 2(n = 53)Chronic kidney disease stage 3(n = 37)Before exercise After exercise Before exercise After exercise Before exercise After exerciseMETs 8.7  2 10.2  2.4* 8.4  0.3 10.0  2.4* 6.9  1.6 8.4  2.3*Weight, kg 101.3  16.7 99.6  14.0 101.7  16.5 99.4  14.5 102.7  17.2 101.7  17.0Systolic blood pressure 121.4  14.6 116.1  13.8 124.4  15.4 121.2  14.4 128  15 124  14Diastolic blood pressure 71.4  9.6 68.1  9.7 72.9  9.8 70.8  11.4 71  8 69  8HbA1c, mmol/mol 61  16 52  10* 62  19 57  14 66  21 56  13*HbA1c, % 7.7  1.5 6.9  0.9* 7.8  1.7 7.4  1.3 8.2  1.9 7.3  1.2*Glucose, mmol/l 7.65  2.7 6.43  1.7* 8.05  2.9 7.10  2.1 8.05  3.1 7.49  3.8Creatinine, lmol/l 70.9  15.3 67.9  9.2 86.2  16.0 86.9  19.1 114.4  25.9 106.8  28.2UAE†, mg/g 40.5  87 32.9  81 22.6  36 16.7  21 46.8  35 31.8  22eGFR, ml/min/1.73 m2 103.6  11.2 100.6  13.1 73.5  6.9 78.3  13.1 51.6  8.7 58  13.2METs, metabolic equivalents; UAE, urinary albumin excretion.*P < 0.05.†Median and interquartile range (quartile 1 to 3).Published 2015.This article is a U.S. Government work and is in the public domain in the USA 1343Research article DIABETICMedicinethe formula for eGFR in those with closer to normal renalfunction, and/or the fact that these patients need a higherexercise dose to show a change.We believe these results to be clinically relevant becauseexercise is a non-invasive and non-pharmaceutical treatmentmethod that can be performed and adapted at an individuallevel. Indeed, the cumulative exercise dose in the presentinterventional study was less than the recommended150 min/week [16]. Potentially, a similar amount of exercisecould help those patients with progressive kidney disease notonly to improve their kidney function but also to possiblyprevent or delay the need for dialysis in the long term. Asfitness is a modifiable risk factor in most patients, anappropriate exercise programme could be implemented forpeople at high risk of developing chronic kidney disease toprevent or at least attenuate the rate of progression. Indeed,a recent meta-analysis supports a multitude of benefits fromphysical activity of > 30 min/session for 3 days per week inpatients with chronic kidney disease [11] although themajority of studies have been in those with more advancedstages of chronic kidney disease, including those receivingdialysis or who have undergone transplants [11–13]. Todate, little research has been conducted in the majority ofpatients who have the pre-dialysis range of chronic kidneydisease stages and who have significant cardiovasculardisease risk [3] and the highest potential for comorbiditymodulation. Moreover, there is a lack of exercise promotionin these patients [17]. Aerobic exercise in patients at the pre-dialysis stage has been shown to increase exercise capacitysignificantly, as measured by peak oxygen consumption(VO2 max) [9], exercise tolerance [9] and anaerobic threshold[9]. Moreover, in one study, there was a significantimprovement in eGFR after 12 weeks of aerobic exercisein overweight patients with chronic kidney disease stages 3and 4 [18].The response of increased exercise capacity supports thelikelihood that causal mechanism(s) may exist. The salutaryresponse to exercise may be related to several factors.People with diabetes are known to exercise significantly lessthan the general population, and this is most likelycompounded in those with diabetes and chronic kidneydisease. Patients with chronic kidney disease have a 50–80% reduction in exercise capacity [19], a high degree ofinactivity, muscle wasting, reduced muscle function andmuscle weakness [10,11]. Other causal factors could berelated to the kidney disease itself, such as endothelialdysfunction, oxidative stress, inflammation and dyslipida-emia [20]; for example, regular exercise affects structuraland functional adaptations of the endothelial response tovasoconstrictors and vasodilators and exercise also has anti-inflammatory effects.Strengths of the present study include its supervisedexercise approach, which enhances individual guidance andcompliance. Its limitations include not knowing the precisecause of chronic kidney disease and limitations inherent tothe eGFR calculation; we used the CKD-EPI formula,considered by many to be the optimum method [15].In summary, we show that a short-term interventionalexercise programme improved eGFR in those with mild tomoderate chronic kidney disease (stages 2 and 3). Because amoderate intensity exercise programme was effective inimproving fitness, we suggest that exercise interventions forindividuals at risk of chronic kidney disease and those withpre-clinical chronic kidney disease merit scrutiny in arandomized trial.AcknowledgementsWe thank the LIVe team: Monica Aiken, Katie Himmerick,Lauren Korshak, Irue Namata-Elangwe, Joseph Powell andHelen Sheriff of the Veterans Affairs Medical Center,Washington, DC, for their essential role in performing theexercise stress tests, nutritional and exercise counselling andassistance with data collection.Competing interestsNone declared.References1 Go AS, Glenn M, Fan D, McCulloch CE, Hsu CY. Chronic KidneyDisease and the Risks of Death, Cardiovascular Events, andHospitalization. N Engl J Med 2004; 351: 1296–1305.2 De Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, HimmelfarbJ. Temporal trends in the prevalence of diabetic kidney disease inthe United States. JAMA 2011; 305: 2532–2539.3 Papademetriou V, Lovato L, Doumas M, Nylen E, Mottl A, CohenRM et al. Chronic kidney disease and intensive glycemic controlincrease cardiovascular risk in patients with type 2 diabetes. KidneyInt 2015; 87: 649–659.4 Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D et al.Changes in Diabetes-Related Complications in the United States,1990–2010. N Engl J Med 2014; 370: 1514–1523.5 Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE.Exercise capacity and mortality among men referred for exercisetesting. N Engl J Med 2002; 346: 793–801.6 Kokkinos P, Myers J, Nylen E, Panagiotakos DB, Manolis A,Pittaras A et al. Exercise capacity and all-cause mortality in AfricanAmerican and Caucasian men with type 2 diabetes. Diabetes Care2009; 32: 623–628.7 Bouchard C, An P, Rice T, Skinner JS, Wilmore JH, Gagnon J et al.Familial aggregation of VO2 max response to exercise training:Results from the HERITAGE family study. 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Nephron Clin Pract 2010; 116:c330–c336.18 Baria F, Kamimura MA, Aoike DT, Ammirati A, Rocha ML, deMello MT et al. Randomized controlled trial to evaluate the impactof aerobic exercise on visceral fat in overweight chronic kidneydisease patients. Nephrol Dial Transplant 2014; 29: 857–864.19 Johansen KL, Painter P. Exercise in individuals with CKD. Am JKid Dis 2012; 59: 126–134.20 Van Craenenbroeck AH, Van Craenenbroeck EM, Kouidi E,Vrints CJ, Couttenye MM, Conraads VM. Vascular Effects ofExercise Training in CKD: Current Evidence and Pathophysio-logical Mechanisms. Clin J Am Soc Nephrol 2014; 9: 1305–1318.Published 2015.This article is a U.S. Government work and is in the public domain in the USA 1345Research article DIABETICMedicine

Enhanced fitness and renal function in Type 2 diabetes.

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Enhanced fitness and renal function in Type 2 diabetes.

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