Nephrology 16 (2011) 704–709

Original Article

Effect of exercise on albuminuria in people with diabetes

nep_1508

704..709

KENG-HEE KOH,1,3 BOLONGHOGE DAYANATH,2 JAMES CG DOERY,2,4 KEVAN R POLKINGHORNE,1 HELENA TEEDE5 and PETER G KERR1 Departments of 1Nephrology and 2Pathology, Monash Medical Centre, Melbourne, Victoria, Australia; and 3Department of Medicine, Kuching Hospital, Sarawak, Malaysia; and 4Department of Medicine, Monash University, and 5Jean Hailes Research Group, Monash University, Melbourne, Victoria, Australia

KEY WORDS: diabetes mellitus, exercise, spot urinary albumin-creatinine ratio. Correspondence: Dr Keng-Hee Koh, 19, Jalan Saga SD 8/2E, Bandar Sri Damansara, 52200 Kuala Lumpur, Malaysia. Email: [email protected], [email protected] Accepted for publication 13 June 2011. Accepted manuscript online 19 August 2011. doi:10.1111/j.1440-1797.2011.01508.x Grant support: none. Conflict of interest statement. None declared.

SUMMARY AT A GLANCE It has long been known that exercise can induce proteinuria. This paper shows that exercise increases uACR estimation in normoalbuminuric subjects with diabetes with a larger effect in females. It remains speculative for the underlying pathogenesis and the potential for exercise to unmask albuminuria at an earlier stage of diabetic nephropathy requires further research.

ABSTRACT: Aim:

Spot urine measurement of albumin is now the most commonly accepted approach to screening for proteinuria. Exertion prior to the collection may potentially influence the result of spot urine albumin estimation. We aim to evaluate the effect of exercise on albuminuria in subjects at various stages of diabetic nephropathy in comparison with healthy control volunteers. Methods: Thirty-five people with diabetes (19 with normoalbuminuria (NA), nine with microalbuminuria (MA) and seven with overt proteinuria (OP)) and nine control subjects were assessed. A 1 km treadmill walk was performed. Four spot urine specimens were collected: first morning void, immediately prior to exercise, and 1 h and 2 h after exercise. A random effects linear regression mixed model was used to assess the effect of exercise on albumin/creatinine ratio (uACR). Results are presented separately for male and female subjects with diabetes due to a significant exercise/ gender interaction (P < 0.05). Results: No significant effect of exercise on uACR was seen in control subjects. In NA males with diabetes no effect of exercise was seen, while in females uACR 1 h after exercise was significantly higher than the early morning sample (3.55 mg/mmol (96% confidence interval 0.27–6.83). Both female and male diabetes subjects with MA have increase in uACR 1 h after exercise (87.8, -24.3–199.4 and 6.7, 2.1–11.3). For both males and females with OP, uACR was significantly increased 1 h post exercise (67.5, 22–113 and 21.6, 8.4–34.8, respectively). In all groups uACR at 2 h after exercise was not significantly different to the early morning sample. Conclusions: Exercise increased uACR estimation in normoalbuminuric subjects with diabetes with a larger effect in females. Whether exercise unmasks early diabetic nephropathy in NA subjects requires further study.

Spot urine specimens with estimation of the albumin/ creatinine ratio (uACR) are now the accepted routine approach to estimating albuminuria.1,2 The Guideline Development Group of the National Institute for Clinical Excellence has suggested that the morning urinary ACR is the most reliable test because it is most concentrated.1 The American Diabetes Association has a similar recommendation with the intention of maintaining the uniformity of measurement and avoiding the diurnal variation and exacerbation by exertion.3 Following that, an ACR finding of

704

30–70 g/mol should be repeated with a morning urine specimen to confirm its range of overt albuminuria. While the recommendation for the collection of spot urine specimens is for the first morning void, in the real world of clinical medicine, many samples are performed during the day with some degree of activity, e.g. walking to clinic. The prevailing view has been to avoid exertion prior to urine collection on the premise that it might exacerbate the albuminuria3 although there has been limited formal study of this view.4 One previous study in 25 people with diabetes © 2011 The Authors Nephrology © 2011 Asian Pacific Society of Nephrology

Exercise-induced albuminuria in people with diabetes

compared to healthy controls demonstrated that exercise increased urinary protein in the people with diabetes.5 However, the effect of exercise in people with diabetes with various stages of albuminuria is unknown especially in people with diabetes type II. Therefore, the clinical implication of exercise induced proteinuria remained an appropriate focus for research.6–8 The aims of this study were therefore to examine the effect of exercise on the extent of albuminuria in people with diabetes with various stages of diabetic kidney disease in addition to healthy control volunteers. We hypothesized that spot urinary specimens collected after a mild degree of exertion would demonstrate increased albuminuria and unmask early diabetic nephropathy among people with diabetes with otherwise normoalbuminuria.

METHODS Study population Adult (age >18 years) subjects with diabetes mellitus (DM) attending the DM clinic at Monash Medical Centre were invited to participate in the study. We enrolled almost equal numbers of people with diabetes with normoalbuminuria (24 h urine albumin 160 mmHg), amputation of limbs or symptomatic peripheral vascular disease. This study was approved by the Human Research and Ethics Committee of Southern Health, Victoria. All subjects provided written informed consent.

Study outcomes Subjects collected an early morning voided urine specimen, followed by a 24 h timed urine collection at home. These specimens were stored in the refrigerator before being submitted to the laboratory. On the following day, subjects underwent a structured exercise regimen on a treadmill. Spot urine collections were obtained immediately prior to exercise, and 1 h and 2 h after initiation of exercise. Comparisons were made to the early morning urine specimen.

Laboratory methods Fasting glucose, glycosylated hemoglobin (HbA1c), blood hemoglobin, urea and creatinine were assessed in all subjects prior to exercise. The urinary albumin concentration was measured with immunonephelometry (with the lowest detectable level 2 mg/L). Urinary protein concentration was determined using the dye (Pyrogallol Red) binding method (Instrument Beckman Coulter DXC 800, © 2011 The Authors Nephrology © 2011 Asian Pacific Society of Nephrology

Nyon, Switzerland) with the lowest detectable limit 60 mg/L. All tests were performed on fresh urine specimens. In this paper, we only showed the albuminuria result because it is opined as a more specific marker for staging of diabetes nephropathy.

Exercise regimen The exercise involved a 1 km walk with increment of speed gradually from a baseline of 3 km/h up to 7 km/h and gradient from 0 to 2%. The degree of acceleration of speed was generally 0.5 km/h every minute. The investigator adjusted the speed of the treadmill according to the exercise capability of the subject and stopped the exercise earlier if the patient could not walk further because of lethargy or any adverse symptoms. Blood pressure and heart rate were measured in sitting position prior to exercise, immediately after exercise, 5 min after exercise and 1 h after exercise. The height and weight of the patient were recorded. Calculation of energy consumption during the exercise was based on the formulae:9 Estimated gross oxygen consumption (O2)

Resting O2 = 3.5 mL kg min Energy consumption = resting + horizontal + vertical components Walking O2 = (3.5 + 0.1 × S + 1.8 × G × S) mL kg min whereby S represents speed in m/min; G, gradient. 1 MET is defined as resting energy consumption rate, consuming 3.5 mL/kg per min. As each 1 mL/kg/min O2 contributed 0.00505 kCal/kg per min

1 MET = 0.00505 × 3.5 = 0.0177 kCal kg per min Energy consumption rate ( MET ) = O2 3.5 MET Energy consumption rate = O2 × weight ( kg) × 5.05 kCal L Energy consumption rate ( kCal min ) = O2 × Body mass ( kg) × 0.00505 kCal min Total energy consumption ( kCal) = Energy consumption rate ( kCal min ) × time ( min )

Statistical methods The data is presented as mean 1 standard deviation (SD), or median (inter-quartile range) where appropriate. Univariate associations for the clinical variables between the groups were explored using analysis of variance (ANOVA) or the Kruskal–Wallis test for continuous variables, and the c2 test or Fisher’s exact test for categorical variables where appropriate. A random effects linear regression mixed (panel) model was used to assess the effect of exercise on uACR according to the baseline group. Separate models were assessed for each of the four clinical groups. Statistical analyses were performed with SPSS (SPSS Inc. Chicago, IL, USA) and Intercooled Stata 10.1

705

K-H Koh et al.

Table 1 Clinical profile of all subjects in different ranges of albuminuria Healthy volunteers

Age (year) Duration of DM (year) Gender F : M BMI (kg/m2) ACE/ARB use n (%) Hb (g/L) Fasting glucose (mmol/L) HbA1c (%) Urea (mmol/L) Creatinine (mmol/L) eGFR (mL/min) Creatinine clearance (mL/min/1.73 m2)

People with diabetes

Normo-albuminuria (n = 9)

Normo-albuminuria (n = 19)

Micro-albuminuria (n = 9)

Overt Albuminuria (n = 7)

37.7 1 5.0

51.6 1 9.8 13 1 10 8:11 27.3 1 6.3 11 (58) 138 1 20 8.0 1 1.4 9.0 1 3.2 4.9 1 1.9 68 1 14 105 1 24 108 1 41

56.0 1 10.0 12 1 12 3:6 32.0 1 4.5 8 (89) 128 1 14 8.5 1 4.5 8.6 1 2.3 5.7 1 3.0 91 1 13 87 1 43 89 1 45

58.2 1 8.9 14 1 5 2:5 31.6 1 10.0 6 (85) 127 1 19 8.2 1 1.2 9.3 1 1.6 7.9 1 5.9 118 1 104 77 1 39 91 1 47

4:5 22.7 1 3.4 0 4.6 1 0.6 4.4 1 0.8 68 1 17 116 1 37 109 1 30

ACEI/ARB, angiotensin converting enzyme inhibitor / angiotensin II receptor blocker; BMI, body mass index; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate with Modification of Diet in Renal Disease Study (MDRD) formula.10

Table 2 Energy consumption and blood pressure changes with exercise Healthy volunteer

Average energy consumption rate (MET) Maximum energy consumption rate (MET) Net energy consumption per weight (kCal/kg)† Heart Rate (/min) Pre-exercise Immediately after exercise 5 min after exercise Systolic blood pressure (mmHg) Pre-exercise Immediately after exercise 5 min after exercise 1 h after exercise Diastolic blood pressure (mmHg) Pre-exercise Immediately after exercise 5 min after exercise 1 h after exercise

Diabetes mellitus

P-value*

No Albuminuria

No Albuminuria

Micro-Albuminuria

Overt-Albuminuria

4.3 1 0.4 5.1 1 0.6 0.513 (0.505–573)

3.4 1 0.5 3.9 1 0.8 0.505 (0.366–0.512)

3.3 1 0.7 3.7 1 0.8 0.505 (0.072–0.574)

2.9 1 0.6 3.3 1 0.8 0.505 (0.265–0.591)