Abstract
Background
The aim of this study was to determine whether a single moderate‐intensity exercise session induces renal injury based on various parameters that reflect kidney dysfunction, including urinary L‐type fatty acid‐binding protein (L‐FABP).
Methods
Adult outpatients (n = 31) with chronic kidney disease (CKD) not receiving renal replacement therapy participated in this study. Urine was collected before and after a single 20‐min moderate‐intensity exercise session. Urinary levels of L‐FABP, albumin, N‐acetyl‐β‐d‐glucosaminidase (NAG), and α1‐microglobrin (α1MG) were measured. In addition, 12 patients with estimated glomerular filtration fraction less than 30 ml/min/1.73 ml2 were selected from all patients and evaluated using the same analysis.
Results
Urinary values of L‐FABP, albumin, NAG, and α1MG did not increase significantly after exercise compared with before exercise (urinary L‐FABP, from 8.3 to 9.4 μg/g of creatinine; urinary albumin, from 293.1 to 333.7 mg/g of creatinine; urinary NAG, from 9.2 to 8.2 U/g of creatinine; urinary α1MG, from 11.4 to 9.8 mg/g of creatinine, not significant). Similar findings were seen in all patients, regardless of degree of renal dysfunction.
Conclusions
A single session of moderate‐intensity exercise was not associated with an increase in renal parameters used to assess renal damage.
Keywords: exercise, moderate‐intensity, chronic kidney disease, urinary L‐FABP, renal dysfunction
INTRODUCTION
The progression of chronic kidney disease (CKD) is known to be related to the degree of tubulointerstitial damage, rather than the degree of glomerular damage 1. Kidney hypoperfusion induces tubular hypoxia, which is an aggravating factor of tubulointerstitial damage and leads to the progression of CKD 2. Previous reports have shown that exercise increases blood flow and oxygen supply to muscles 3, decreases renal blood flow (RBF), induces kidney hypoperfusion, and decreases glomerular filtration rate (GFR; 4, 5. Therefore, it had been thought that exercise should be limited in patients with CKD.
However, recent clinical evidence has shown that exercise‐induced decreases in RBF and GFR were transient 6 and that prolonged moderate‐intensity exercise did not affect the progression of CKD 7, 8. Moreover, an experimental study showed that optimal exercise suppressed renal inflammation and renal fibrosis to improve CKD and emphasized the positive effect of exercise on CKD 9. Therefore, the Japanese guidelines for the treatment of CKD recommend moderate‐intensity exercise for improvements in physical function and prevention of cardiovascular complications 10.
Urinary L‐type fatty acid‐binding protein (L‐FABP) is a newly identified tubular biomarker of both CKD 11, 12, 13, 14, 15 and acute kidney injury 16, 17 and reflects not only the degree of tubulointerstitial damage, but also the decrease in RBF 2. Moreover, increases in urinary L‐FABP have been shown to be a risk factor for progression of CKD 11, 13, 15. Therefore, we consider that urinary L‐FABP may reflect renal hemodynamic changes and pathophysiological conditions due to exercise that cannot be detected by conventional markers, such as urinary albumin, urinary N‐acetyl‐β‐d‐glucosaminidase (NAG), and urinary α1‐microglobulin (α1MG). However, the influence of exercise on urinary L‐FABP levels has not been evaluated. This study assessed whether a single session of moderate‐intensity exercise induces changes in variables used to assess renal damage, including urinary L‐FABP levels as well as conventional parameters.
SUBJECTS AND METHODS
Subjects
Thirty‐one adult patients with CKD were recruited from the outpatient clinics at the Division of Nephrology & Hypertension, Department of Medicine, St. Marianna University School of Medicine Hospital (Kanagawa, Japan). Inclusion criteria included no use of hemodialysis, no central nervous system or musculoskeletal disorders, no gait apraxia, and no contraindications to exercise (i.e., unstable angina, uncontrolled heart failure, or uncontrolled hypertension).
This research was carried out according to the principles of the Declaration of Helsinki, and informed consent was obtained from all patients. Our institutional review board approved the study protocol. Table 1 summarizes the clinical characteristics and laboratory findings of the study participants.
Table 1.
Clinical Characteristics and Laboratory Findings of Patients
| N | 31 |
| Sex (male/female) | 23/8 |
| Age (years) | 60 (52–66) |
| Height (cm) | 163 (158–170) |
| Weight (kg) | 65 (54–72) |
| Serum creatinine (mg/dl) | 1.42 (1.12–2.16) |
| eGFR (ml/min/1.73 m2) | 35.3 (20.2–49.1) |
| Hemoglobin (g/dl) | 12.7 (11.3–14.9) |
| Degree of CKD (n) | |
| Mild (eGFR 60–89 ml/min/1.73 m2) | 5 |
| Moderate (eGFR30–59 ml/min/1.73 m2) | 14 |
| Severe (eGFR15–29 ml/min/1.73 m2) | 9 |
| Kidney failure (eGFR <15 ml/min/1.73 m2) | 3 |
| Cause of CKD, n (%) | |
| Chronic glomerulonephritis | 11 (35) |
| Nephrosclerosis | 8 (26) |
| Diabetic nephropathy | 6 (20) |
| Unknown | 4 (13) |
| Other | 2 (6) |
| Medication, n (%) | |
| ARB | 21 (68) |
| ACEI | 7 (23) |
| β‐blockers | 7 (23) |
| Calcium antagonists | 19 (61) |
Values are medians (interquartile range).
eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; ARB, angiotensin‐receptor blocker; ACEI, angiotensin‐converting enzyme inhibitor.
Exercise Protocol
The moderate‐intensity exercise consisted of 20 min of treadmill walking (Treadmill MAT‐2500, Fukuda Denshi Co., Tokyo, Japan) after reaching the target heart rate. Target heart rate was calculated by the Karvonen formula using a range of 40–60% exercise intensity 18 in patients not receiving β‐blockers. For patients receiving β‐blockers, exercise intensity ranged from 11 to 13 on the Borg scale of rating of perceived exertion 19. Metabolic equivalents (METs), which represent the intensity of exercise, were expressed as the ratio of oxygen consumption between during exercise and at rest calculated by the following formula: oxygen consumption = {(0.1 × speed of treadmill) + (1.8 × its speed × slope of treadmill) + 3.5} 20. Heart rate and systolic blood pressure were measured during exercise and at rest (Medical telemeter WEP‐4202, Nihon Kohden Co., Tokyo, Japan).
Measurements
Urinary variables
Spot urine samples were obtained before and within 60 min after exercise. Urinary levels of L‐FABP in spot urine samples were measured by an enzyme linked immunosorbent assay (ELISA) using the Human L‐FABP ELISA Kit (CMIC, Tokyo, Japan; 15) and were expressed as a ratio to the level of urinary creatinine. Urinary creatinine, albumin, N‐acetyl‐β‐d‐glucosaminidase (NAG), and α1‐microgloburin (α1MG) were also measured.
Levels of urinary parameters in spot urine samples were expressed as a ratio to urinary creatinine levels. GFR was estimated using the new equation proposed by the Japanese Society of Nephrology as follows:
estimated GFR (eGFR; ml/min1/1.73 m2) = 194 × Cr−1.094 × Age−0.287 × 0.739 (if female) 21.
Blood variables
Blood samples were taken before exercise and serum creatinine and hemoglobin were measured.
Statistical Analysis
Levels of urinary parameters were given as medians (interquartile range, IQR). To compare two parameters before and after exercise, the Wilcoxon signed‐rank test (nonparametric distributions) were used for the paired data. Statistical analyses were performed using SPSS (version 12.0, SPSS SAS, Inc., Chicago, IL). P values <0.05 were considered statistically significant.
RESULTS
Urinary Parameters Before and After Treadmill Walking
Urinary values of L‐FABP, albumin, NAG, and α1MG did not increase significantly after exercise compared with before exercise (Table 2). Similar findings were seen in all patients, regardless of degree of renal dysfunction.
Table 2.
Clinical Urinary Parameters Before and After Exercise
| Before | After | ||
|---|---|---|---|
| exercise | exercise | P‐value | |
| All patients (n = 31) | |||
| Urinary L‐FABP (μg/g of creatinine) | 8.3 (4.6−29.5) | 9.4 (4.6−21.5) | 0.81 |
| Urinary albumin(mg/g of creatinine) | 293.1 (112.7−1167.6) | 337.7 (153.6−1462.9) | 0.92 |
| Urinary NAG (U/g of creatinine) | 9.2 (5.8−12.9) | 8.2 (5.5−12.3) | 0.88 |
| Urinary α1MG (mg/g of creatinine) | 11.4 (7.2−20.8) | 9.8 (5.2−21.8) | 0.51 |
| Patients with eGFR ≤ 30 ml/min/1.73 m2 (n = 12) | |||
| Urinary L‐FABP (μg/g of creatinine) | 23.0 (7.7−54.2) | 20.2 (4.8−52.2) | 0.53 |
| Urinary albumin (mg/g of creatinine) | 748.5 (110.3–1446.7) | 705.7 (106.7–1494.1) | 0.94 |
| Urinary NAG (U/g ofcreatinine) | 10.5 (4.9–13.8) | 9.3 (5.6–13.3) | 0.88 |
| Urinary α1MG (mg/g ofcreatinine) | 27.7 (11.0−35.2) | 22.0 (8.5−47.6) | 0.27 |
Values are medians (interquartile range).
L‐FABP, liver‐type fatty acid‐binding protein; NAG, N‐acetyl‐β‐d‐glucosaminidase; α1MG, α1‐microglobulin; eGFR, estimated glomerular filtration rate.
Treadmill Indicators
Table 3 shows the speed and the slope of treadmill and METs performed in this study. Patients’ maximum heart rate and systolic blood pressure for exercise were significantly higher than those at rest (P < 0.01).
Table 3.
Treadmill Indicators and Physical Findings of Patients During Treadmill Walking
| Speed (km/h) | 5.0 (4.2–5.0) |
|---|---|
| Slope (%) | 2 (2–3) |
| Exercise intensity (METs) | 4.11 (3.27–4.61) |
| Heart rate at rest (bpm/min) | 73 (68–81) |
| Maximum heart rate (bpm/min) | 115 (105–123)* |
| Systolic blood pressure at rest (mmHg) | 133 (121–140) |
| Maximum systolic blood pressure (mmHg) | 154 (140–170)* |
| Diastolic blood pressure at rest (mmHg) | 80 (71–90) |
| Maximum diastolic blood pressure (mmHg) | 80 (70–90) |
Values are medians (interquartile range).
*P < 0.01 versus at rest.
METs, metabolic equivalents.
DISCUSSION
The exercise‐intensity performed in this study was considered to be moderate based on METS values that ranged from 3 to 5 22. Because urinary levels of L‐FABP, albumin, NAG, and α1MG did not differ significantly between before and after a single session of moderate‐intensity exercise, this type of exercise is not thought to influence renal function. This finding was maintained even in patients with severe CKD.
Moderate‐intensity exercise has beneficial effects on obesity 23, hypertension 24, and glycemic control 25. With regard to CKD, although moderate‐intensity exercise is recommended 10, 26, no study to date has suggested a detailed exercise program or has shown a direct positive effect of such an exercise on progression of CKD with sufficient power to be definitive. However, increases in urinary excretion of total protein or albumin were shown to be significantly correlated with exercise intensity in healthy men 27. Therefore, the valuable effect of exercise may depend not only on the optimal type, frequency, and duration of exercise, but also the intensity of exercise.
Urinary L‐FABP is a newly identified tubular biomarker that reflects the degree of tubulointerstitial damage 12. In a clinical study of patients receiving living‐related kidney transplants, urinary L‐FABP levels in virgin urine obtained after anastomosis of the renal artery and vein of the transplanted kidney was established and was significantly correlated with ischemic time, defined as the period between the time point of clamping the donor's renal artery and the time point of the appearance of virgin urine from the recipient's ureter 2. Moreover, only the decrease in urinary L‐FABP, and not urinary NAG and α1MG, correlated with the gradual increase in peritubular capillary blood flow after initiation of reperfusion 2. From these results, urinary L‐FABP was considered to be a biomarker that represents renal hemodynamic changes such as tubular hypoxia. Because significant increases in urinary L‐FABP levels were not observed in virgin urine obtained after the exercise performed in this study, moderate‐intensity exercise was considered not to induce tubular hypoxia.
The primary limitation of the present study is that only a single session of moderate‐intensity exercise was assessed. It is unknown whether prolonged moderate‐intensity exercise or high‐intensity exercise will increase urinary L‐FABP levels or promote or inhibit the progression of CKD. We are planning an interventional study to determine the effects of prolonged moderate‐intensity exercise on CKD progression.
In conclusion, a single session of moderate‐intensity exercise in patients with CKD was not associated with an increase in any renal parameter measured, regardless of the level of kidney dysfunction.
CONFLICT OF INTEREST
None of the other authors have conflicts of interest or financial disclosures of any relevance to the present study.
ACKNOWLEDGMENTS
We thank Seiko Hoshino and Aya Sakamaki for assistance with the collection of urine.
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