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Frontiers in Diabetic Kidney Disease: Introduction
Frontiers in Diabetic Kidney Disease: Introduction Robert C. Stanton, MD
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iabetes mellitus continues to increase at epidemic rates worldwide. The 2012 statistics from the World Health Organization state that an estimated 347 million people have diabetes, with the expectation that this number will double or triple over the next 20 years, depending on location.1 The impact of this illness is especially great in low- and middleincome countries, where .80% of diabetes cases occur. Moreover, deaths due to diabetes-related complications are expected to double from 2005 to 2030.1 Recently, a very concerning analysis reported that there could be a tripling of the number of cases of type 1 diabetes mellitus in youths (defined as ,20 years old) by 2050 and possibly a quadrupling of cases of type 2 diabetes, with the highest number of increased cases seen in minority race/ethnic populations.2 Of the complications of diabetes, the development of diabetic kidney disease may be the most devastating with respect to patients’ quality of life and survival. For example, as glomerular filtration rate (GFR) declines, there is a linear increase in mortality, with 2- to 5-fold increases in patient mortality when comparing a GFR . 60 mL/min to one , 45 mL/min.3 This increase in mortality rate is independently observed in people with increasing urine albumin levels, for which similarly highly significant linear increases in mortality are observed when comparing a range of urine albumin levels (reported as albumincreatinine ratio) from ,30 to .300 mg/g.3 Furthermore, a detailed analysis of the NHANES (National Health and Nutrition Examination Survey) database determined that most of the increased mortality (due to both cardiovascular disease and noncardiovascular causes) observed in people with diabetes, as compared with people without diabetes and without kidney disease, could be ascribed to the presence of kidney disease.4 There also is a highly significant independent association of increasing urine albumin levels and decreasing GFRs with worse cardiovascular outcomes.5 That is, as urine albumin levels increase, the risk for cardiovascular disease increases significantly. The direct association of increased risk for cardiovascular disease is observed even at very low urine albumin levels. An intriguing analysis of Framingham Heart Study patients who did not have diabetes or hypertension discovered that people at the higher end of the normal range of urine albumin excretion had higher rates of ischemic heart disease events compared with those at the lower end of normal.6 Thus, there appears to be a direct association Am J Kidney Dis. 2014;63(2)(suppl 2):S1-S2
between urine albumin level and cardiovascular events, and “normal” urine albumin levels may well be zero. A possible mechanistic explanation for this association is that urine albumin levels reflect endothelial dysfunction.7 If this hypothesis is correct, presumably the same factors causing endothelial dysfunction (eg, inflammatory mediators) also are responsible, at least in part, for increases in urine albumin levels. In addition to the associations of diabetic kidney disease with mortality and the macrovascular complication of cardiovascular disease, studies have shown close associations of diabetic kidney disease with the other diabetic microvascular complications of retinopathy and neuropathy.8 Hence, the development of diabetic kidney disease is not only concerning from the perspective of worsening kidney function, but also is a harbinger of (or possibly mechanistically related to) other diabetic complications. Early diagnosis and early aggressive management are of paramount importance to maintain the health of our patients. It also is clear that current approaches can slow the progression of diabetic kidney disease, but do not provide a cure. In this supplement, the reviews are intended to illustrate areas of interest to the clinical nephrologist, describing current diagnostic and management issues, as well as diagnostic and therapeutic forefronts. Glucose management in diabetic kidney disease is of critical importance to the health of the patient. Often, as kidney disease worsens, the nephrologist becomes the main care provider that the patient routinely sees. Hence, it is important that the nephrologist understand glucose management in patients with diabetic kidney disease. Mark Williams and Rajesh Garg9 have provided a comprehensive overview of this important subject. It also has become apparent that the current markers for the diagnosis (primarily GFR, urine albumin level, urinalysis, and history) and progression of kidney disease are not wholly adequate. As a result,
From the Kidney and Hypertension Division, Joslin Diabetes Center, Boston, MA. This article is part of a supplement that was developed with funding from Novo Nordisk. Address correspondence to Robert C. Stanton, MD, Kidney and Hypertension Division, Joslin Diabetes Center, One Joslin Pl, Boston, MA 02215. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.10.051 S1
Robert C. Stanton
there have been major efforts by a number of laboratories to develop better markers for the diagnosis and progression of diabetic kidney disease. The article on this subject by Richard MacIsaac, Elif Ekinci, and George Jerums10 delivers comprehensive background information, new marker information, and insights into future directions. Current treatments clearly are not adequate as the burden of diabetic kidney disease continues to increase worldwide, so there is a need for new treatments. There are a number of possible mechanistic targets for the drug treatments that have been discovered. The article by Shawn Badal and Farhad Danesh11 illustrates these important areas of research, from which diabetic kidney disease treatments of the future may arise. In addition, I have contributed a discussion on current issues in the diagnosis and management of diabetic kidney disease, with the intent of addressing areas that are either controversial or not fully defined.12 Hopefully these reviews will serve as a source of information, as well as inspiration.
ACKNOWLEDGEMENTS Support: The development of this journal supplement was funded by Novo Nordisk. Technical editing was provided by Watermeadow Medical, funded by Novo Nordisk. Costs associated with publication were funded by Novo Nordisk. The author received no remuneration for this work. Financial Disclosure: The author declares that he has no relevant financial interests.
REFERENCES 1. World Health Organization. Diabetes. 2012. http://www. who.int/mediacentre/factsheets/fs312/en/index.html. Accessed January 14, 2013.
S2
2. Imperatore G, Boyle JP, Thompson TJ, et al. Projections of type 1 and type 2 diabetes burden in the U.S. population aged ,20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care. 2012;35(12): 2515-2520. 3. Muntner P, Bowling CB, Gao L, et al. Age-specific association of reduced estimated glomerular filtration rate and albuminuria with all-cause mortality. Clin J Am Soc Nephrol. 2011;6(9):2200-2207. 4. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24(2):302-308. 5. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20(8): 1813-1821. 6. Arnlov J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation. 2005;112(7):969-975. 7. Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008;51(5):714-725. 8. Girach A, Manner D, Porta M. Diabetic microvascular complications: can patients at risk be identified? A review. Int J Clin Pract. 2006;60(11):1471-1483. 9. Williams ME, Garg R. Glycemic management in ESRD and earlier stages of CKD. Am J Kidney Dis. 2014;63(2)(suppl 2): S22-S38. 10. MacIsaac RJ, Ekinci EI, Jerums G. Markers of and risk factors for the development and progression of diabetic kidney disease. Am J Kidney Dis. 2014;63(2)(suppl 2):S39-S62. 11. Badal SS, Danesh FR. New insights into molecular mechanisms of diabetic kidney disease. Am J Kidney Dis. 2014;63(2)(suppl 2):S63-S83. 12. Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis. 2014;63(2) (suppl 2):S3-S21.
Am J Kidney Dis. 2014;63(2)(suppl 2):S1-S2
D
iabetes mellitus continues to increase at epidemic rates worldwide. The 2012 statistics from the World Health Organization state that an estimated 347 million people have diabetes, with the expectation that this number will double or triple over the next 20 years, depending on location.1 The impact of this illness is especially great in low- and middleincome countries, where .80% of diabetes cases occur. Moreover, deaths due to diabetes-related complications are expected to double from 2005 to 2030.1 Recently, a very concerning analysis reported that there could be a tripling of the number of cases of type 1 diabetes mellitus in youths (defined as ,20 years old) by 2050 and possibly a quadrupling of cases of type 2 diabetes, with the highest number of increased cases seen in minority race/ethnic populations.2 Of the complications of diabetes, the development of diabetic kidney disease may be the most devastating with respect to patients’ quality of life and survival. For example, as glomerular filtration rate (GFR) declines, there is a linear increase in mortality, with 2- to 5-fold increases in patient mortality when comparing a GFR . 60 mL/min to one , 45 mL/min.3 This increase in mortality rate is independently observed in people with increasing urine albumin levels, for which similarly highly significant linear increases in mortality are observed when comparing a range of urine albumin levels (reported as albumincreatinine ratio) from ,30 to .300 mg/g.3 Furthermore, a detailed analysis of the NHANES (National Health and Nutrition Examination Survey) database determined that most of the increased mortality (due to both cardiovascular disease and noncardiovascular causes) observed in people with diabetes, as compared with people without diabetes and without kidney disease, could be ascribed to the presence of kidney disease.4 There also is a highly significant independent association of increasing urine albumin levels and decreasing GFRs with worse cardiovascular outcomes.5 That is, as urine albumin levels increase, the risk for cardiovascular disease increases significantly. The direct association of increased risk for cardiovascular disease is observed even at very low urine albumin levels. An intriguing analysis of Framingham Heart Study patients who did not have diabetes or hypertension discovered that people at the higher end of the normal range of urine albumin excretion had higher rates of ischemic heart disease events compared with those at the lower end of normal.6 Thus, there appears to be a direct association Am J Kidney Dis. 2014;63(2)(suppl 2):S1-S2
between urine albumin level and cardiovascular events, and “normal” urine albumin levels may well be zero. A possible mechanistic explanation for this association is that urine albumin levels reflect endothelial dysfunction.7 If this hypothesis is correct, presumably the same factors causing endothelial dysfunction (eg, inflammatory mediators) also are responsible, at least in part, for increases in urine albumin levels. In addition to the associations of diabetic kidney disease with mortality and the macrovascular complication of cardiovascular disease, studies have shown close associations of diabetic kidney disease with the other diabetic microvascular complications of retinopathy and neuropathy.8 Hence, the development of diabetic kidney disease is not only concerning from the perspective of worsening kidney function, but also is a harbinger of (or possibly mechanistically related to) other diabetic complications. Early diagnosis and early aggressive management are of paramount importance to maintain the health of our patients. It also is clear that current approaches can slow the progression of diabetic kidney disease, but do not provide a cure. In this supplement, the reviews are intended to illustrate areas of interest to the clinical nephrologist, describing current diagnostic and management issues, as well as diagnostic and therapeutic forefronts. Glucose management in diabetic kidney disease is of critical importance to the health of the patient. Often, as kidney disease worsens, the nephrologist becomes the main care provider that the patient routinely sees. Hence, it is important that the nephrologist understand glucose management in patients with diabetic kidney disease. Mark Williams and Rajesh Garg9 have provided a comprehensive overview of this important subject. It also has become apparent that the current markers for the diagnosis (primarily GFR, urine albumin level, urinalysis, and history) and progression of kidney disease are not wholly adequate. As a result,
From the Kidney and Hypertension Division, Joslin Diabetes Center, Boston, MA. This article is part of a supplement that was developed with funding from Novo Nordisk. Address correspondence to Robert C. Stanton, MD, Kidney and Hypertension Division, Joslin Diabetes Center, One Joslin Pl, Boston, MA 02215. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.10.051 S1
Robert C. Stanton
there have been major efforts by a number of laboratories to develop better markers for the diagnosis and progression of diabetic kidney disease. The article on this subject by Richard MacIsaac, Elif Ekinci, and George Jerums10 delivers comprehensive background information, new marker information, and insights into future directions. Current treatments clearly are not adequate as the burden of diabetic kidney disease continues to increase worldwide, so there is a need for new treatments. There are a number of possible mechanistic targets for the drug treatments that have been discovered. The article by Shawn Badal and Farhad Danesh11 illustrates these important areas of research, from which diabetic kidney disease treatments of the future may arise. In addition, I have contributed a discussion on current issues in the diagnosis and management of diabetic kidney disease, with the intent of addressing areas that are either controversial or not fully defined.12 Hopefully these reviews will serve as a source of information, as well as inspiration.
ACKNOWLEDGEMENTS Support: The development of this journal supplement was funded by Novo Nordisk. Technical editing was provided by Watermeadow Medical, funded by Novo Nordisk. Costs associated with publication were funded by Novo Nordisk. The author received no remuneration for this work. Financial Disclosure: The author declares that he has no relevant financial interests.
REFERENCES 1. World Health Organization. Diabetes. 2012. http://www. who.int/mediacentre/factsheets/fs312/en/index.html. Accessed January 14, 2013.
S2
2. Imperatore G, Boyle JP, Thompson TJ, et al. Projections of type 1 and type 2 diabetes burden in the U.S. population aged ,20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care. 2012;35(12): 2515-2520. 3. Muntner P, Bowling CB, Gao L, et al. Age-specific association of reduced estimated glomerular filtration rate and albuminuria with all-cause mortality. Clin J Am Soc Nephrol. 2011;6(9):2200-2207. 4. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24(2):302-308. 5. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20(8): 1813-1821. 6. Arnlov J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation. 2005;112(7):969-975. 7. Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008;51(5):714-725. 8. Girach A, Manner D, Porta M. Diabetic microvascular complications: can patients at risk be identified? A review. Int J Clin Pract. 2006;60(11):1471-1483. 9. Williams ME, Garg R. Glycemic management in ESRD and earlier stages of CKD. Am J Kidney Dis. 2014;63(2)(suppl 2): S22-S38. 10. MacIsaac RJ, Ekinci EI, Jerums G. Markers of and risk factors for the development and progression of diabetic kidney disease. Am J Kidney Dis. 2014;63(2)(suppl 2):S39-S62. 11. Badal SS, Danesh FR. New insights into molecular mechanisms of diabetic kidney disease. Am J Kidney Dis. 2014;63(2)(suppl 2):S63-S83. 12. Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis. 2014;63(2) (suppl 2):S3-S21.
Am J Kidney Dis. 2014;63(2)(suppl 2):S1-S2