NEWS & VIEWS DIABETIC NEPHROPATHY
How does exercise affect kidney disease in T1DM? George Jerums and Richard J. MacIsaac
In a prospective study of patients with type 1 diabetes mellitus, leisure time physical activity of low intensity at baseline (versus high intensity) was associated with the development and progression of nephropathy. This finding is consistent with previous reports that exercise delays the progression of chronic kidney disease in people with or without diabetes mellitus. A recent report from the FinnDiane study has explored how leisure time physical activity (LTPA) predicts onset and progression of nephropathy in patients with type 1 diabetes mellitus (T1DM).1 LTPA was assessed at baseline by a self-report questionnaire and analysed in four ways: total LTPA (sedentary, moderately active and active); LTPA intensity (low, moderate and high); LTPA frequency (2 episodes per week); and LTPA duration (60 min per episode).1
‘‘
…physical activity … might affect the initiation and progression of nephropathy
’’
Progression of nephropathy was defined by an increase in albuminuria from normo albuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria. The development of end-stage renal disease (ESRD; defined as commencement of dialysis or undergoing a renal transplantation) was also used as a marker of renal status. Whether glomerular filtration rate (GFR) declined at an early stage of nephropathy was not assessed. The study included 1,390 patients with T1DM and disease duration of at least 20 years. Over a mean followup of 6.4 years, 72 patients progressed from normoalbuminuria to microalbuminuria, 35 patients progressed from micro albuminuria to macroalbuminuria and 47 patients progressed to ESRD.
The progression of nephropathy was then related to the four categories of LTPA. Total LTPA and duration of LTPA were not related to progression of kidney disease. By contrast, LTPA intensity and frequency were closely related to progression of nephropathy. For intensity of LTPA, the 10‑year cumulative mean progression rate was 24.0%, 13.5% and 13.1% in patients with low, moderate or high intensity LTPA, respectively (P = 0.01). For the frequency of LTPA, the progression rate was 24.7%, 14.7% and 12.6% for patients with low, medium or high frequency LTPA, respectively (P = 0.003). The effects of low intensity LTPA were largely explained by worse control of glycaemia and blood pressure in these patients compared with those in the moderate and high intensity groups. The authors concluded that physical activity, in particular intensity of activity, might affect the initiation and progression of nephropathy. Whether a switch from low to high intensity LTPA could influence nephropathy requires further study in a randomized trial. A major difficulty in evaluating the relationship between LTPA and progression of nephropathy is the uneven distri bution of risk factors for nephropathy between individuals with baseline LTPA of different frequencies and intensities. For instance, low levels of LTPA were associated with abdominal obesity, worse glycaemic control, increased antihypertensive therapy and increased serum levels of triglycerides compared with moderate and high levels of LTPA. Progression of nephropathy in the
NATURE REVIEWS | ENDOCRINOLOGY
Ridofranz/iStock/Thinkstock
Refers to Waden, J. et al. Leisure time physical activity and development and progression of diabetic nephropathy in type 1 diabetes: the FinnDiane study. Diabetologia doi:10.1007/s00125-015-3499-6
low intensity LTPA subgroup was related to older age (threshold of 41 years, 38 years and 31 years for low, moderate and high intensity groups, respectively), male sex, obesity and hypertension. Furthermore, Cox regression analysis of the rate of progression to microalbuminuria or macroalbuminuria in patients with low versus moderate and high intensity LTPA showed that the hazard ratio for progression was no longer statistically significant after adjustment for duration of diabetes mellitus, smoking, sex and levels of HbA1c. Inclusion of mean arterial pressure, serum levels of triglycerides and BMI in the multivariate analysis further decreased the hazard ratio for progression of nephropathy when comparing the low intensity LTPA group to the moderate and high intensity LTPA groups. Over the past decade, studies have shown that exercise can either increase or decrease albuminuria. Three short-term studies have shown that albuminuria increases transiently after exercise.2–4 By contrast, one longer term study showed that microalbuminuria can be reduced after 6 months of aerobic exercise,5 which is consistent with the findings of this report from the FinnDiane study.1 Of interest, the EURODIAB Prospective Complications Study of 3,250 patients with T1DM detected a borderline inverse associ ation between physical activity and incident cardiovascular disease in women. 6 This finding raises the possibility that the beneficial effects of exercise in patients with T1DM might not be limited to albuminuria or the kidney. VOLUME 11 | JUNE 2015
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS A literature review published in 2012 examined the health benefits of physical activity in patients with T1DM.7 Results from randomized controlled trials strongly indicated that physical exercise improved control of glucose and lipid levels, whilst non-randomized trials and case series demonstrated improvements in control of blood pressure. However, prospective trials included in this review found no evidence to suggest that microvascular complications, including nephropathy, are improved by physical activity. In contrast, a previous report from the FinnDiane Study noted that the presence of diabetic complications, particularly impaired renal function, increasing proteinuria, retinopathy and cardiovascular disease, were associated with reduced physical activity.8 However, this association could be explained by patients with complications being less able to undertake exercise than patients without complications, rather than exercise decreasing the risk of developing complications of diabetes mellitus.
‘‘
…exercise should be a strong component of the management of patients with T1DM…
’’
The benefits of physical activity in preventing the progression of nephropathy might not be specific to diabetes mellitus. Over the past few years, physical activity has also been linked to a reduction in the rate of progression of chronic kidney disease of different aetiologies. In the Seattle Kidney Study of 256 patients with chronic kidney disease, of whom 139 had type 2 diabetes mellitus, the mean baseline cystatin C‑derived estimated GFR was 42 ml/min/1.73 m2. During 3.7 years of follow-up, the mean change in estimated
JUNE 2015 | VOLUME 11
GFR was –6.2% per year in participants who engaged in >150 min of physical activity per week, compared with –9.6% per year in inactive participants. Results were similar in participants with or without diabetes mellitus.9 In a multivariate analysis, each 60 min increase in duration of physical activity was associated with a 0.5% slower decline in estimated GFR per year (P = 0.04). Furthermore, a study from Singapore followed up ~60,000 adults (only 8% with diabetes mellitus) for 15 years and collected information on physical activity from a structured questionnaire. The risk of ESRD was 24% lower in participants undertaking any level of physical activity than in those who reported no physical activity. The magnitude in the reduction of risk of ESRD was also associated with the level of intensity of exercise, with adjusted hazard ratios of 0.81 and 0.58 for moderate and strenuous activity levels, respectively.10 A prospective, randomized trial is needed to clarify the influence of physical activity on the evolution of nephropathy in patients with T1DM. Participants randomized to intensive or non-intensive LTPA would require regular, objective documentation of physical activity, albuminuria and GFR, as well as control of glycaemia and blood pressure. In the meantime, exercise should be a strong component of the management of patients with T1DM, as it can have important effects on glycaemic control and body weight. Endocrine Centre, Austin Health & University of Melbourne, 300 Waterdale Road, Heidelberg West, VIC 3081, Australia (G.J.). Department of Endocrinology & Diabetes, St Vincent’s Hospital Melbourne & University of Melbourne, 35 Victoria Parade, Fitzroy, VIC 3065, Australia (R.J.M.). Correspondence to: G.J. [email protected]
doi:10.1038/nrendo.2015.46 Published online 17 March 2015 Competing interests The authors declare no competing interests. 1.
Wadén, J. et al. Leisure-time physical activity and development and progression of diabetic nephropathy in type 1 diabetes: the FinnDiane Study. Diabetologia http://dx.doi.org/ 10.1007/s00125-015-3499-6. 2. Kornhauser, C., Malacara, J. M., MacíasCervantes, M. H. & Rivera-Cisneros, A. E. Effect of exercise intensity on albuminuria in adolescents with type 1 diabetes mellitus. Diabet. Med. 29, 70–73 (2012). 3. Koh, K. H. et al. Effect of exercise on albuminuria in people with diabetes. Nephrology (Carlton) 16, 704–709 (2011). 4. Lane, J. T., Ford, T. C., Larson, L. R., Chambers, W. A. & Lane, P. H. Acute effects of different intensities of exercise in normoalbuminuric/normotensive patients with type 1 diabetes. Diabetes Care 27, 28–32 (2004). 5. Lazarevic, G. et al. Effects of aerobic exercise on microalbuminuria and enzymuria in type 2 diabetic patients. Ren. Fail. 29, 199–205 (2007). 6. Tielemans, S. M. et al. Association of physical activity with all-cause mortality and incident and prevalent cardiovascular disease among patients with type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetologia 56, 82–91 (2013). 7. Chimen, M. et al. What are the health benefits of physical activity in type 1 diabetes mellitus? A literature review. Diabetologia 55, 542–551 (2012). 8. Wadén, J. et al. Physical activity and diabetes complications in patients with type 1 diabetes: the Finnish Diabetic Nephropathy (FinnDiane) Study. Diabetes Care 31, 230–232 (2008). 9. Robinson-Cohen, C. et al. Physical activity and change in estimated GFR among persons with CKD. J. Am. Soc. Nephrol. 25, 399–406 (2014). 10. Jafar, T. H., Jin, A., Koh, W. P., Yuan, J. M., Chow, K. Y. Physical activity and risk of endstage kidney disease in the Singapore Chinese Health Study. Nephrology (Carlton) 20, 61–67 (2015).
www.nature.com/nrendo © 2015 Macmillan Publishers Limited. All rights reserved
How does exercise affect kidney disease in T1DM? George Jerums and Richard J. MacIsaac
In a prospective study of patients with type 1 diabetes mellitus, leisure time physical activity of low intensity at baseline (versus high intensity) was associated with the development and progression of nephropathy. This finding is consistent with previous reports that exercise delays the progression of chronic kidney disease in people with or without diabetes mellitus. A recent report from the FinnDiane study has explored how leisure time physical activity (LTPA) predicts onset and progression of nephropathy in patients with type 1 diabetes mellitus (T1DM).1 LTPA was assessed at baseline by a self-report questionnaire and analysed in four ways: total LTPA (sedentary, moderately active and active); LTPA intensity (low, moderate and high); LTPA frequency (2 episodes per week); and LTPA duration (60 min per episode).1
‘‘
…physical activity … might affect the initiation and progression of nephropathy
’’
Progression of nephropathy was defined by an increase in albuminuria from normo albuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria. The development of end-stage renal disease (ESRD; defined as commencement of dialysis or undergoing a renal transplantation) was also used as a marker of renal status. Whether glomerular filtration rate (GFR) declined at an early stage of nephropathy was not assessed. The study included 1,390 patients with T1DM and disease duration of at least 20 years. Over a mean followup of 6.4 years, 72 patients progressed from normoalbuminuria to microalbuminuria, 35 patients progressed from micro albuminuria to macroalbuminuria and 47 patients progressed to ESRD.
The progression of nephropathy was then related to the four categories of LTPA. Total LTPA and duration of LTPA were not related to progression of kidney disease. By contrast, LTPA intensity and frequency were closely related to progression of nephropathy. For intensity of LTPA, the 10‑year cumulative mean progression rate was 24.0%, 13.5% and 13.1% in patients with low, moderate or high intensity LTPA, respectively (P = 0.01). For the frequency of LTPA, the progression rate was 24.7%, 14.7% and 12.6% for patients with low, medium or high frequency LTPA, respectively (P = 0.003). The effects of low intensity LTPA were largely explained by worse control of glycaemia and blood pressure in these patients compared with those in the moderate and high intensity groups. The authors concluded that physical activity, in particular intensity of activity, might affect the initiation and progression of nephropathy. Whether a switch from low to high intensity LTPA could influence nephropathy requires further study in a randomized trial. A major difficulty in evaluating the relationship between LTPA and progression of nephropathy is the uneven distri bution of risk factors for nephropathy between individuals with baseline LTPA of different frequencies and intensities. For instance, low levels of LTPA were associated with abdominal obesity, worse glycaemic control, increased antihypertensive therapy and increased serum levels of triglycerides compared with moderate and high levels of LTPA. Progression of nephropathy in the
NATURE REVIEWS | ENDOCRINOLOGY
Ridofranz/iStock/Thinkstock
Refers to Waden, J. et al. Leisure time physical activity and development and progression of diabetic nephropathy in type 1 diabetes: the FinnDiane study. Diabetologia doi:10.1007/s00125-015-3499-6
low intensity LTPA subgroup was related to older age (threshold of 41 years, 38 years and 31 years for low, moderate and high intensity groups, respectively), male sex, obesity and hypertension. Furthermore, Cox regression analysis of the rate of progression to microalbuminuria or macroalbuminuria in patients with low versus moderate and high intensity LTPA showed that the hazard ratio for progression was no longer statistically significant after adjustment for duration of diabetes mellitus, smoking, sex and levels of HbA1c. Inclusion of mean arterial pressure, serum levels of triglycerides and BMI in the multivariate analysis further decreased the hazard ratio for progression of nephropathy when comparing the low intensity LTPA group to the moderate and high intensity LTPA groups. Over the past decade, studies have shown that exercise can either increase or decrease albuminuria. Three short-term studies have shown that albuminuria increases transiently after exercise.2–4 By contrast, one longer term study showed that microalbuminuria can be reduced after 6 months of aerobic exercise,5 which is consistent with the findings of this report from the FinnDiane study.1 Of interest, the EURODIAB Prospective Complications Study of 3,250 patients with T1DM detected a borderline inverse associ ation between physical activity and incident cardiovascular disease in women. 6 This finding raises the possibility that the beneficial effects of exercise in patients with T1DM might not be limited to albuminuria or the kidney. VOLUME 11 | JUNE 2015
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS A literature review published in 2012 examined the health benefits of physical activity in patients with T1DM.7 Results from randomized controlled trials strongly indicated that physical exercise improved control of glucose and lipid levels, whilst non-randomized trials and case series demonstrated improvements in control of blood pressure. However, prospective trials included in this review found no evidence to suggest that microvascular complications, including nephropathy, are improved by physical activity. In contrast, a previous report from the FinnDiane Study noted that the presence of diabetic complications, particularly impaired renal function, increasing proteinuria, retinopathy and cardiovascular disease, were associated with reduced physical activity.8 However, this association could be explained by patients with complications being less able to undertake exercise than patients without complications, rather than exercise decreasing the risk of developing complications of diabetes mellitus.
‘‘
…exercise should be a strong component of the management of patients with T1DM…
’’
The benefits of physical activity in preventing the progression of nephropathy might not be specific to diabetes mellitus. Over the past few years, physical activity has also been linked to a reduction in the rate of progression of chronic kidney disease of different aetiologies. In the Seattle Kidney Study of 256 patients with chronic kidney disease, of whom 139 had type 2 diabetes mellitus, the mean baseline cystatin C‑derived estimated GFR was 42 ml/min/1.73 m2. During 3.7 years of follow-up, the mean change in estimated
JUNE 2015 | VOLUME 11
GFR was –6.2% per year in participants who engaged in >150 min of physical activity per week, compared with –9.6% per year in inactive participants. Results were similar in participants with or without diabetes mellitus.9 In a multivariate analysis, each 60 min increase in duration of physical activity was associated with a 0.5% slower decline in estimated GFR per year (P = 0.04). Furthermore, a study from Singapore followed up ~60,000 adults (only 8% with diabetes mellitus) for 15 years and collected information on physical activity from a structured questionnaire. The risk of ESRD was 24% lower in participants undertaking any level of physical activity than in those who reported no physical activity. The magnitude in the reduction of risk of ESRD was also associated with the level of intensity of exercise, with adjusted hazard ratios of 0.81 and 0.58 for moderate and strenuous activity levels, respectively.10 A prospective, randomized trial is needed to clarify the influence of physical activity on the evolution of nephropathy in patients with T1DM. Participants randomized to intensive or non-intensive LTPA would require regular, objective documentation of physical activity, albuminuria and GFR, as well as control of glycaemia and blood pressure. In the meantime, exercise should be a strong component of the management of patients with T1DM, as it can have important effects on glycaemic control and body weight. Endocrine Centre, Austin Health & University of Melbourne, 300 Waterdale Road, Heidelberg West, VIC 3081, Australia (G.J.). Department of Endocrinology & Diabetes, St Vincent’s Hospital Melbourne & University of Melbourne, 35 Victoria Parade, Fitzroy, VIC 3065, Australia (R.J.M.). Correspondence to: G.J. [email protected]
doi:10.1038/nrendo.2015.46 Published online 17 March 2015 Competing interests The authors declare no competing interests. 1.
Wadén, J. et al. Leisure-time physical activity and development and progression of diabetic nephropathy in type 1 diabetes: the FinnDiane Study. Diabetologia http://dx.doi.org/ 10.1007/s00125-015-3499-6. 2. Kornhauser, C., Malacara, J. M., MacíasCervantes, M. H. & Rivera-Cisneros, A. E. Effect of exercise intensity on albuminuria in adolescents with type 1 diabetes mellitus. Diabet. Med. 29, 70–73 (2012). 3. Koh, K. H. et al. Effect of exercise on albuminuria in people with diabetes. Nephrology (Carlton) 16, 704–709 (2011). 4. Lane, J. T., Ford, T. C., Larson, L. R., Chambers, W. A. & Lane, P. H. Acute effects of different intensities of exercise in normoalbuminuric/normotensive patients with type 1 diabetes. Diabetes Care 27, 28–32 (2004). 5. Lazarevic, G. et al. Effects of aerobic exercise on microalbuminuria and enzymuria in type 2 diabetic patients. Ren. Fail. 29, 199–205 (2007). 6. Tielemans, S. M. et al. Association of physical activity with all-cause mortality and incident and prevalent cardiovascular disease among patients with type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetologia 56, 82–91 (2013). 7. Chimen, M. et al. What are the health benefits of physical activity in type 1 diabetes mellitus? A literature review. Diabetologia 55, 542–551 (2012). 8. Wadén, J. et al. Physical activity and diabetes complications in patients with type 1 diabetes: the Finnish Diabetic Nephropathy (FinnDiane) Study. Diabetes Care 31, 230–232 (2008). 9. Robinson-Cohen, C. et al. Physical activity and change in estimated GFR among persons with CKD. J. Am. Soc. Nephrol. 25, 399–406 (2014). 10. Jafar, T. H., Jin, A., Koh, W. P., Yuan, J. M., Chow, K. Y. Physical activity and risk of endstage kidney disease in the Singapore Chinese Health Study. Nephrology (Carlton) 20, 61–67 (2015).
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