Natural History and Clinical Characteristics of CKD in Type 1 and Type 2 Diabetes Mellitus Sally M. Marshall The nature of CKD in diabetes is changing. Diabetic glomerulosclerosis remains the cause of CKD in most type 1 diabetic individuals. However, the rate of progression of diabetic nephropathy has slowed because of improving glucose and blood pressure control. Most individuals with type 2 diabetes and 5% to 30% of those with type 1 diabetes with progressive CKD have normal urine albumin excretion or low-level microalbuminuria (albumin-to-creatinine ratio approximately ,100 mg/g), which does not progress despite the decline in glomerular filtration. People with progressive CKD but normal albuminuria have predominantly interstitial or vascular changes with much less glomerular changes. It seems likely that these histological abnormalities relate to blood pressure, aging, obesity, and intrarenal vascular disease. Initial studies suggested that 85% to 100% of diabetic individuals with microalbuminuria (Kidney Disease Improving Global Outcomes [KDIGO] CKD albuminuria A2) progressed to proteinuria (KDIGO CKD albuminuria A3). Recent data demonstrate that even after 2 to 3 years of persistent microalbuminuria, most will revert to normal albumin excretion (KDIGO CKD albuminuria A1). Regression is more likely at lower levels of microalbuminuria and with improved glucose, blood pressure, and lipid control. Thus, low levels of microalbuminuria cannot be considered as established diabetic nephropathy. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Diabetic nephropathy, Microalbuminuria/KDIGO CKD albuminuria A2, Proteinuria/KDIGO CKD albuminuria A3, CKD in diabetes, Natural history of diabetic nephropathy
Introduction Diabetic nephropathy has historically been considered to be a slowly progressive condition, developing over many years. The clinical characteristics of diabetic nephropathy are gradually increasing urine albumin excretion in parallel with rising blood pressure and increasing cardiovascular risk. Loss of glomerular filtration occurs relatively late, but it finally culminates in ESRD if the individual does not succumb to cardiovascular disease first. Underlying this clinical phenotype are the classical glomerulosclerosis changes of thickening glomerular basement membrane, mesangial expansion, nodular accumulation of extracellular matrix material, and podocyte changes with foot process widening, effacement, and loss. However, recent studies have elucidated an alternative clinical presentation of kidney disease in diabetes, particularly in individuals with type 2 diabetes. This review will concentrate first on describing the ‘‘classical’’ clinical phenotype and natural history of diabetic nephropathy and then focus on new data that have altered our perception of kidney disease in diabetes.
Diabetic Nephropathy—The Classical View What Is It? The first clinical indication of classical diabetic nephropathy is of slowly increasing urine albumin excretion that is initially only detectable by sensitive immunoassays. Microalbuminuria, or more recently Kidney Disease Improving Global Outcomes (KDIGO) CKD albuminuria A2,1 is the term used to describe increased urine albumin excretion above the normal range but less than that detected by conventional urine dipstick testing. This ‘‘microalbuminuria’’ appears 5 to 10 years after the diagnosis
of diabetes, and if untreated, it gradually increases over the next 10 to 15 years until conventional dipstickpositive proteinuria (clinical proteinuria, more recently KDIGO CKD albuminuria A3) is present. Glomerular filtration is initially normal or even high. Some individuals with diabetes have glomerular hyperfiltration during the first few years of diabetes. The reported prevalence varies widely from less than 25% to more than 75% in type 1 diabetes and from 0% to more than 40% in type 2 diabetes. Methodological and biological factors probably contribute to this variation. In most, the glomerular filtration rate (GFR) then falls into the normal range. However, in a small proportion, GFR remains above normal. It has been suggested that these individuals with persistent hyperfiltration are at greater risk of developing classical diabetic nephropathy; however, this remains controversial.2,3 Glomerular filtration begins to fall below the normal range at the stage of high microalbuminuria or early clinical proteinuria (albumin-to-creatinine ratio 300 mg/g). Untreated, the disease then progresses inexorably in approximately 9 years to ESRD. The initial data suggested that 85% to 100% of individuals who developed microalbuminuria progressed to clinical From Institute of Cellular Medicine, Newcastle University, Diabetes Research Group, Faculty of Clinical Medical Sciences, Newcastle upon Tyne, United Kingdom. Financial Disclosure: The author declares that there are no relevant financial interests. Address correspondence to Sally M. Marshall, MD, Diabetes Research Group, Institute of Cellular Medicine, Newcastle University, Floor 4, Leech Building, Faculty of Clinical Medical Sciences, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: sally.marshall@newcastle. ac.uk Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.03.007
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proteinuria and that virtually everyone with clinical proteinuria eventually reached ESRD.
Histological Characteristics
How Common Is Classical Diabetic Nephropathy? Older figures suggest that approximately 50% of individuals with type 1 or type 2 diabetes will have developed clinical proteinuria after a 25-year duration of diabetes.11 Unlike diabetic retinopathy, only a subset of individuals appears to be susceptible to developing diabetic nephropathy. This has suggested a genetic influence, which is supported by several other lines of evidence. In twins with type 1 diabetes, if the index twin develops nephropathy, then 83% of the second twins will also develop nephropathy. However, if the index twin does not have nephropathy, only 17% of the second twins will develop nephropathy.12 First-degree relatives of individuals with diabetic nephropathy have a similar clinical phenotype with increased blood pressure, insulin resistance, dyslipidemia, and high cardiovascular risk compared with first-degree relatives of diabetic individuals without diabetic nephropathy.13
The major histological feature of classical diabetic nephropathy is diabetic glomerulosclerosis. Widening of the glomerular basement membrane, mesangial matrix accumulation, podocyte foot process widening and effacement, and loss of podocytes all occur. The histological lesions tend to become more marked as urine albumin excretion increases.4 The fall in GFR relates to decreasing glomerular filtration surface area. These structural changes are accompanied by biochemical changes, including alterations in the glycosaminoglycans of the glomerular filtration barrier. Alterations in charge and in structure of the glomerular filtration barrier, perhaps with the formation of shunts, initially allow a selective increased passage of anionic albumin and then an unselected proteinuria.5 CLINICAL SUMMARY
Clinical Phenotype
The rate of progression of diabetic glomerulosclerosis has slowed in the past decades secondary to improving glucose and blood pressure control.
What Has Changed? Over the last decade, our understanding of the natural history of microalbuminuria (albuminuria A2), rates of progression of diabetic nephropathy, and the types of CKD that develop in diabetes has changed dramatically. The data underpinning these changes are described in the following subsections.
Classical diabetic nephropathy can develop in any type Most individuals with low-level microalbuminuria (KDIGO of diabetes. Cross-sectional CKD albuminuria A2; albumin-to-creatinine ratio approxistudies show that individuals mately ,100 mg/g) for 2 to 3 years will revert to normal with diabetic nephropathy urine albumin excretion (KDIGO CKD albuminuria A1). are more likely to be male; to Regression of microalbuminuria to normal urine albumin smoke; and to have poorer excretion is more likely at lower levels of microalbuminuria glycemic control, higher and with improved glucose, blood pressure, and lipid control. blood pressure, insulin resistance, dyslipidemia (high Most type 2 diabetic individuals with CKD have a triglycerides and low highprogressive decline in glomerular filtration but normal or Microalbuminuria/ low-level microalbuminuria, which does not progress, secdensity lipoprotein cholesAlbuminuria A2 ondary to kidney interstitial and vascular changes rather terol), and endothelial than glomerulosclerosis. dysfunction than their peers Initial studies suggested with normal albumin excrethat approximately 85% of tion.6 In general, the higher individuals who developed microalbuminuria would progress to clinical proteinuria the urine albumin excretion, the more marked the ab(albuminuria A3) over some 10 to 15 years, with the normalities. Other specific complications of diabetes, remainder continuing to have microalbuminuria. Microparticularly retinopathy, are also more common and albuminuria was thus regarded as the first clinical sign tend to progress in parallel.7 Rising blood pressure is of diabetic nephropathy. It quickly became apparent an integral part of the process, important from very that urine albumin excretion fluctuates widely from day early stages, although the blood pressure is not in the to day, with a coefficient of variability of at least 40%.14 ‘‘hypertensive range.’’8 The risk of premature death, primarily from cardiovascular disease, increases as Thus, more than 1 measurement of urine albumin excreurine albumin excretion increases and as glomerular tion is required to make a clinical diagnosis of raised filtration falls in an independent manner.9 Compared urine albumin excretion. Consensus arose that for a confident diagnosis, albumin excretion should be abnormal to type 2 diabetic individuals without CKD, the risk in a minimum of 2 of 3 urine samples collected over is increased approximately 2-fold in microalbuminuria, 3 months. However, more recent studies have demon5-fold in clinical proteinuria, and 12-fold when plasma strated in individuals who have microalbuminuria creatinine is 175 mmol/L or greater.10 Although the persistently over several years that most become excess of conventional cardiovascular risk factors assonormoalbuminuric (albuminuria A1) again.15,16 In 1 ciated with the clinical phenotype contributes to this increased risk, they do not fully explain it. study of type 1 diabetic individuals with persistent
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microalbuminuria over 2 years, 58% reverted to normal albumin excretion after a further 6 years of follow-up.16 Those who reverted to normal albumin excretion had lower hemoglobin A1c, blood pressure, cholesterol, and triglycerides than those with persistent microalbuminuria over the follow-up period. Thus, ‘‘persistent’’ microalbuminuria is not always a permanent state and is more likely to reverse in individuals with ideal blood glucose, blood pressure, and lipid management. It seems unlikely that reversal represents a structural change in the kidney, but it may reflect improved hemodynamics and/or endothelial function. Although this is clearly very good news, it does make it more difficult at the early microalbuminuric stage to be confident about an individual’s risk of progressing to clinical proteinuria and ESRD. It has been suggested that the rate of increase of microalbuminuria might be an indicator of the risk of progression to clinical proteinuria, but this has not been substantiated. However, the rate of change of urine albumin excretion is an independent predictor of cardiovascular disease.17,18 The level of urine albumin excretion is also probably important. The higher the urine albumin excretion within the ‘‘normal range,’’ the greater the chance of microalbuminuria developing.8,19 One early study suggests that this is also true of individuals with microalbuminuria: Individuals with a urine albumin excretion greater than 70 mg/minute (normal range # 20 mg/minute) were more likely to develop clinical proteinuria than those with baseline albumin excretion less than 70 mg/ minute.20 Individuals with stable microalbuminuria had stable GFR whereas GFR decreased in those with increasing urine albumin excretion.21 In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study, the level of urine albumin excretion rate at first presentation of persistent microalbuminuria was strongly associated with progression to proteinuria and weakly associated with regression to normal urine albumin excretion.22 The hazard ratio for progression to proteinuria was 1.98 in those with a urine albumin excretion of 50 to 99 mg/ 24 hours and 3.33 for those with a urine albumin excretion rate of 100 mg/24 hours or greater compared with those with an excretion rate of 30 to 49 mg/24 hours. Thus, low levels of microalbuminuria, perhaps an albumin-to-creatinine ratio less than 100 mg/g, particularly if the levels are not increasing, do not indicate a high risk of developing diabetic nephropathy over the subsequent 5 to 10 years. The longer-term fate of those individuals who revert from microalbuminuria to normal urine albumin excretion remains uncertain. It may be that with more prolonged follow-up they develop progressive microalbuminuria. A parallel might be drawn with the data from small trials of antihypertensive therapy in individuals with clinical proteinuria: Improving blood pressure control may substantially
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initially reduce urine albumin excretion, but in a proportion of patients albumin excretion eventually increases again.23,24 Thus, for the moment, low levels of microalbuminuria cannot be considered to be the earliest clinical sign of diabetic glomerulosclerosis. Instead, the presence of low-level microalbuminuria (albumin-to-creatinine ratio ,100 mg/g) reflects the need to improve glucose and blood pressure control. It is important to clinically monitor urine albumin excretion and glomerular filtration throughout the life of someone with diabetes because kidney disease may take decades to appear and progress. Implications for research may be that only individuals with clinical proteinuria can confidently be regarded as having diabetic nephropathy and that progression of urine albumin excretion from normal to microalbuminuria is not a robust study measure of the development of diabetic nephropathy. In diabetic individuals with reduced GFR but only minimally increased urine albumin excretion, changes in GFR can be regarded as ‘‘hard endpoints.’’
Rate of Progression of Classical Diabetic Nephropathy The rate of progression of classical diabetic nephropathy in type 1 diabetes appears to have slowed over the last 2 decades.25 Initial studies demonstrated that most individuals who developed clinical proteinuria did so within 30 years of diabetes duration, with the peak incidence of first appearance of proteinuria at 16 years of duration and with almost no new cases after 35 to 40 years of duration.26 The cumulative incidence of clinical proteinuria was 41% after a 40-year diabetes duration. In more recent studies, the incidence of proteinuria is extremely variable, but it generally does appear to have fallen at 25 to 30 years of diabetes duration to 13% to 32%.27-30 Reports from Finland and Sweden indicate a cumulative incidence of ESRD of 2.5% to 7.8%.31,32 Although it is tempting to interpret these new data as prevention of proteinuria and thus irreversible diabetic nephropathy, it remains possible that the data represent a delay in the appearance of proteinuria. The recent studies report a lower, but more constant, incidence of clinical proteinuria at 19 to 30 years of diabetes duration28,32 in contrast to the peak incidence at 16 years of duration reported in the original study.26 However, summation of the annual incidence into cumulative incidence to duration of diabetes greater than 30 years suggests that the cumulative incidence of nephropathy in the more recent studies appears to at least equal that of the older studies but with a 5- to 15-year delay in the appearance of proteinuria.25 Thus, the onset of proteinuria in individuals with diabetes susceptible to diabetic nephropathy may be delayed rather than prevented. Screening for CKD should be continued
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indefinitely throughout the individual’s life, regardless of diabetes duration.
Young-Onset Type 2 Diabetes With changes to lifestyle resulting in obesity and physical inactivity, type 2 diabetes is being diagnosed at a much younger age, particularly in Asian and Black ethnic minorities. Chronic complications of diabetes may occur at a younger age and shorter duration of diabetes.33 Some cross-sectional studies report a higher prevalence of increased urine albumin excretion in young people with type 2 compared with type 1 diabetes.34-36 A recent large study suggested that young people with type 2 diabetes were 4 times as likely as young people with type 1 diabetes to have ESRD and to have a significantly poorer survival.37 Data are currently sparse, but clearly further studies are urgently needed.
Nonclassical Diabetic Kidney Disease Over the last few years, it has become clear that many individuals with diabetes who develop progressive CKD do so without following the classical pattern of increasing urine protein excretion with a relatively late decline in GFR (Fig 1). Most have normal albumin excretion or low-level microalbuminuria, which does not progress, whereas glomerular filtration steadily declines. The exact prevalence of nonproteinuric progressive CKD varies with the population studied. Most individuals with type 2 diabetes and progressive CKD do not have significant microalbuminuria or proteinuria.38-40 In type 1 diabetes, the incidence is much less, but it still accounts for 20% to 30% of individuals with progressive CKD.15,41 The rapid increase in individuals with diabetes requiring renal replacement therapy over the last few years appears to be mainly due to individuals with type 2 diabetes older than 65 years of age, most of whom have CKD without proteinuria. What is the cause of this progressive CKD specifically in diabetes without proteinuria? There are very few studies to guide us. The United Kingdom Prospective Diabetes Study suggested that individuals with diabetes and reduced GFR in the absence of increased urine albumin excretion were more likely to be female with lower waist circumference, higher insulin sensitivity, and older age than those with increased excretion.38 Fioretto and colleagues reported a small study of individuals with type 2 diabetes and microalbuminuria but preserved GFR.42 Histological changes were heterogeneous, with normal or near-normal structure, predominately classical glomerular changes or severe interstitial, tubular, or vascular damage with few or no glomerular changes. A more recent small study suggests that type 2 diabetic individuals with microalbuminuria or proteinuria are more likely to have typical glomerular changes whereas those with normal albumin excretion but low GFR have
Figure 1. A comparison of previous and current thinking about progression of diabetic nephropathy. In the older view, almost all individuals who developed microalbuminuria progressed to clinical proteinuria and eventually to ESRD. More recent data suggest that, at least in type 1 diabetes, most of those who develop microalbuminuria revert to normal albumin excretion at least for some years. Few progress to clinical proteinuria and eventually ESRD. However, the rate of progression is much slower than previously observed, and some individuals may regress. A substantial number of individuals with diabetes, particularly those with type 2 diabetes, will develop ESRD with normal albumin excretion or low-level microalbuminuria.
predominately interstitial or vascular changes.43 This ‘‘nonclassical’’ CKD is not due to other specifically treatable kidney diseases, which should be excluded by simple clinical and laboratory investigations such as kidney tract ultrasound, autoantibodies, and immunoglobulins. Most published studies regarding these individuals without increased urine albumin excretion are crosssectional in nature. We have little information about the rate of progression of kidney disease in these diabetic individuals, although simple clinical observation confirms that they do have progressive CKD. High-quality cohort studies in people with diabetes and reduced GFR in the absence of increased urine albumin excretion are urgently needed to improve our understanding of the natural history of kidney disease in these individuals. The presence of nonproteinuric CKD in individuals with diabetes has important implications for clinical practice and research. The implications for screening and diagnosis of CKD in diabetes are that measurement of urine albumin excretion and serum creatinine for calculation of estimated GFR is necessary to identify all individuals with and at high risk of CKD. In research studies, individuals with and without increased urine albumin excretion should be considered separately.
Conclusions Recent data have changed our view of the clinical phenotype of CKD in diabetes with important implications for clinical practice and research (Fig 1, Table 1). Individuals with low-level microalbuminuria may not necessarily have established diabetic nephropathy; instead, they should be regarded as being at high risk of vascular
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CKD in Diabetes
Table 1. Recent Changes in Perceptions Regarding CKD in Diabetes, With Implications for Clinical Practice and Research Older Data Microalbuminuria Permanent Progresses to proteinuria in most
Newer Data Reversible in majority Higher levels more likely to progress to proteinuria
Rate of progression of diabetic nephropathy Peak incidence 16-y duration Incidence relatively uniform from 19- to 30-y duration of diabetes Cumulative incidence after 30-y duration may not be lower than previously Common clinical phenotype of CKD in diabetes Progressive increase in urine albumin Progressive decrease in GFR without excretion, followed by declining GFR significant microalbuminuria in a subset
Implications
Not necessarily a marker of established diabetic nephropathy Indicates need to improve glucose and blood pressure control Need duration of diabetes .25 y to be certain that an individual is unlikely to develop diabetic nephropathy
Few incident cases after 35-y duration
Age at diagnosis of diabetes Older CKD uncommon at younger ages
Younger CKD commoner at earlier age in type 2 diabetes
Measure urine albumin excretion and serum creatinine Separately consider individuals with the different clinical phenotypes Screening for CKD important, even at young age Natural history of CKD in younger-onset diabetes unclear
Abbreviation: GFR, glomerular filtration rate.
disease and of developing diabetic nephropathy. Cardiovascular risk factors should be aggressively managed. Glucose and blood pressure control are probably the key management factors in increasing the likelihood of low-level microalbuminuria reverting to normal urine albumin excretion. Only if urine albumin excretion continues to increase is underlying established diabetic nephropathy likely to be present. It is currently unclear whether or not we can be certain that an individual has progressive diabetic nephropathy before the stage of dipstick-positive proteinuria, although it seems likely that higher levels of microalbuminuria (albumin-to-creatinine ratio .100 mg/g) and progression of microalbuminuria are poor prognostic features. Therefore, careful longitudinal follow-up of urine albumin excretion is vital. Detailed clinical phenotyping of individuals participating in research studies is of even greater paramount importance. Participants with classical diabetic nephropathy may need to be considered separately from those without significant albuminuria. Individuals with lowlevel microalbuminuria cannot be assumed to have progressive diabetic nephropathy; therefore, they may need to be considered more carefully in studies of established diabetic nephropathy. However, this does not imply that individuals with low-level microalbuminuria cannot provide useful information; they simply need to be considered separately. The development of microalbuminuria after a longer duration of diabetes and the suggestions that the rate of progression of diabetic nephropathy is slowing make the description of ‘‘control’’ individuals at very low risk
of developing diabetic nephropathy more difficult to define: It may be prudent to use a duration of diabetes greater than 25 years as opposed to using a lesser duration, as has been used in previous studies.
References 1. Stevens PE, Levin A, Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825-830. 2. Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 2009;52(4): 691-697. 3. Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ. The clinical significance of hyperfiltration in diabetes. Diabetologia. 2010;53(10): 2093-2104. 4. Ponchiardi C, Mauer M, Najafian B. Temporal profile of diabetic nephropathy pathologic changes. Curr Diab Rep. 2013;13(4):592-599. 5. Suh JH, Miner JH. The glomerular basement membrane as a barrier to albumin. Nat Rev Nephrol. 2013;9(8):470-477. 6. Marshall SM, Flyvbjerg A. Prevention and early detection of vascular complications in diabetes. BMJ. 2006;333(7566):475-480. 7. Kramer CK, Retnakaran R. Concordance of retinopathy and nephropathy over time in Type 1 diabetes: an analysis of data from the Diabetes Control and Complications Trial. Diabetic Med. 2013;30(11):1333-1341. 8. The Microalbuminuria Collaborative Study Group. Risk factors for development of microalbuminuria in insulin-dependent diabetic patients: a cohort study. BMJ. 1993;306(6867):1235-1239. 9. Amin AP, Whaley-Connell AT, Li S, Chen SC, McCullough PA, Kosiborod MN, KEEP Investigators. The synergistic relationship between estimated GFR and microalbuminuria in predicting long term progression to ESRD or death in patients with diabetes: results
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26. Andersen AR, Sandahl Christiansen J, Andersen LK, Kreiner S, Deckert T. Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia. 1983;25(6):496-501. 27. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group. Modern-day clinical course of type 1 diabetes mellitus after 30 years. Arch Intern Med. 2009;169(14):1307-1316. 28. Pambianco G, Costacou T, Ellis D, Becker DJ, Klein R, Orchard T. The 30-year natural history of type 1 diabetes complications. Diabetes. 2006;55(5):1463-1469. 29. Hovind P, Tarnow L, Rossing K, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care. 2003;26(4):1258-1264. 30. Nordwall M, Bojestig M, Arnqvist HJ, Ludvigsson J, Linkoping Diabetes Complications Study. Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of type 1 diabetes-the Linkoping Diabetes Complications Study. Diabetologia. 2004;47(7):1266-1272. 31. Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-Riska C. Incidence of end-stage renal disease in patients with type 1 diabetes. J Am Med Assoc. 2005;294(14):1782-1787. 32. Mollsten A, Svensson M, Waernbaum I, et al. Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes. Diabetes. 2010; 59:1803-1808. 33. Pinhas-Hamiel O, Zeitler P. Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet. 2007;369(9575):1823-1831. 34. Scott A, Toomath R, Bouchier D, et al. First national audit of outcomes of care in young people with diabetes in New Zealand: high prevalence of nephropathy in Maori and Pacific Islanders. N Z Med J. 2006;119(1235):U2015. 35. Eppens MC, Craig ME, Jones TW, Silink M, Ong S, Ping YJ. International Diabetes Federation Western Pacific Region Steering Committee. Type 2 diabetes in youth from the Western Pacific region: glycaemic control, diabetes care and complications. Curr Med Res Opin. 2006;22(5):1013-1020. 36. Maahs DM, Snively BM, Bell RA, et al. Higher prevalence of elevated albumin excretion in youth with type 2 than type 1 diabetes. Diabetes Care. 2007;30(10):2593-2598. 37. Dart AB, Selleres EA, Martens PJ, Rigatio C, Brownell MD, Dean HJ. High burden of kidney disease in youth-onset type 2 diabetes. Diabetes Care. 2012;35(6):1265-1271. 38. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes study 74. Diabetes. 2006;55(6):1832-1839. 39. Kramer HJ, Nguyen QD, Curham G, Hsu CY. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. J Am Med Assoc. 2003;289(24):3273-3277. 40. MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G. Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care. 2004;27(1):195-200. 41. Costacou T, Ellis P, Fried L, Orchard TJ. Sequence of progression of albuminuria and decreased GFR in persons with type 1 diabetes: a cohort study. Am J Kidney Dis. 2007;50(5):721-732. 42. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminruia. Diabetologia. 1996;39(12): 1569-1576. 43. Ekinci EI, Jerums G, Skene A, et al. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care. 2013;36(11):3620-3626.
Introduction Diabetic nephropathy has historically been considered to be a slowly progressive condition, developing over many years. The clinical characteristics of diabetic nephropathy are gradually increasing urine albumin excretion in parallel with rising blood pressure and increasing cardiovascular risk. Loss of glomerular filtration occurs relatively late, but it finally culminates in ESRD if the individual does not succumb to cardiovascular disease first. Underlying this clinical phenotype are the classical glomerulosclerosis changes of thickening glomerular basement membrane, mesangial expansion, nodular accumulation of extracellular matrix material, and podocyte changes with foot process widening, effacement, and loss. However, recent studies have elucidated an alternative clinical presentation of kidney disease in diabetes, particularly in individuals with type 2 diabetes. This review will concentrate first on describing the ‘‘classical’’ clinical phenotype and natural history of diabetic nephropathy and then focus on new data that have altered our perception of kidney disease in diabetes.
Diabetic Nephropathy—The Classical View What Is It? The first clinical indication of classical diabetic nephropathy is of slowly increasing urine albumin excretion that is initially only detectable by sensitive immunoassays. Microalbuminuria, or more recently Kidney Disease Improving Global Outcomes (KDIGO) CKD albuminuria A2,1 is the term used to describe increased urine albumin excretion above the normal range but less than that detected by conventional urine dipstick testing. This ‘‘microalbuminuria’’ appears 5 to 10 years after the diagnosis
of diabetes, and if untreated, it gradually increases over the next 10 to 15 years until conventional dipstickpositive proteinuria (clinical proteinuria, more recently KDIGO CKD albuminuria A3) is present. Glomerular filtration is initially normal or even high. Some individuals with diabetes have glomerular hyperfiltration during the first few years of diabetes. The reported prevalence varies widely from less than 25% to more than 75% in type 1 diabetes and from 0% to more than 40% in type 2 diabetes. Methodological and biological factors probably contribute to this variation. In most, the glomerular filtration rate (GFR) then falls into the normal range. However, in a small proportion, GFR remains above normal. It has been suggested that these individuals with persistent hyperfiltration are at greater risk of developing classical diabetic nephropathy; however, this remains controversial.2,3 Glomerular filtration begins to fall below the normal range at the stage of high microalbuminuria or early clinical proteinuria (albumin-to-creatinine ratio 300 mg/g). Untreated, the disease then progresses inexorably in approximately 9 years to ESRD. The initial data suggested that 85% to 100% of individuals who developed microalbuminuria progressed to clinical From Institute of Cellular Medicine, Newcastle University, Diabetes Research Group, Faculty of Clinical Medical Sciences, Newcastle upon Tyne, United Kingdom. Financial Disclosure: The author declares that there are no relevant financial interests. Address correspondence to Sally M. Marshall, MD, Diabetes Research Group, Institute of Cellular Medicine, Newcastle University, Floor 4, Leech Building, Faculty of Clinical Medical Sciences, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: sally.marshall@newcastle. ac.uk Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.03.007
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proteinuria and that virtually everyone with clinical proteinuria eventually reached ESRD.
Histological Characteristics
How Common Is Classical Diabetic Nephropathy? Older figures suggest that approximately 50% of individuals with type 1 or type 2 diabetes will have developed clinical proteinuria after a 25-year duration of diabetes.11 Unlike diabetic retinopathy, only a subset of individuals appears to be susceptible to developing diabetic nephropathy. This has suggested a genetic influence, which is supported by several other lines of evidence. In twins with type 1 diabetes, if the index twin develops nephropathy, then 83% of the second twins will also develop nephropathy. However, if the index twin does not have nephropathy, only 17% of the second twins will develop nephropathy.12 First-degree relatives of individuals with diabetic nephropathy have a similar clinical phenotype with increased blood pressure, insulin resistance, dyslipidemia, and high cardiovascular risk compared with first-degree relatives of diabetic individuals without diabetic nephropathy.13
The major histological feature of classical diabetic nephropathy is diabetic glomerulosclerosis. Widening of the glomerular basement membrane, mesangial matrix accumulation, podocyte foot process widening and effacement, and loss of podocytes all occur. The histological lesions tend to become more marked as urine albumin excretion increases.4 The fall in GFR relates to decreasing glomerular filtration surface area. These structural changes are accompanied by biochemical changes, including alterations in the glycosaminoglycans of the glomerular filtration barrier. Alterations in charge and in structure of the glomerular filtration barrier, perhaps with the formation of shunts, initially allow a selective increased passage of anionic albumin and then an unselected proteinuria.5 CLINICAL SUMMARY
Clinical Phenotype
The rate of progression of diabetic glomerulosclerosis has slowed in the past decades secondary to improving glucose and blood pressure control.
What Has Changed? Over the last decade, our understanding of the natural history of microalbuminuria (albuminuria A2), rates of progression of diabetic nephropathy, and the types of CKD that develop in diabetes has changed dramatically. The data underpinning these changes are described in the following subsections.
Classical diabetic nephropathy can develop in any type Most individuals with low-level microalbuminuria (KDIGO of diabetes. Cross-sectional CKD albuminuria A2; albumin-to-creatinine ratio approxistudies show that individuals mately ,100 mg/g) for 2 to 3 years will revert to normal with diabetic nephropathy urine albumin excretion (KDIGO CKD albuminuria A1). are more likely to be male; to Regression of microalbuminuria to normal urine albumin smoke; and to have poorer excretion is more likely at lower levels of microalbuminuria glycemic control, higher and with improved glucose, blood pressure, and lipid control. blood pressure, insulin resistance, dyslipidemia (high Most type 2 diabetic individuals with CKD have a triglycerides and low highprogressive decline in glomerular filtration but normal or Microalbuminuria/ low-level microalbuminuria, which does not progress, secdensity lipoprotein cholesAlbuminuria A2 ondary to kidney interstitial and vascular changes rather terol), and endothelial than glomerulosclerosis. dysfunction than their peers Initial studies suggested with normal albumin excrethat approximately 85% of tion.6 In general, the higher individuals who developed microalbuminuria would progress to clinical proteinuria the urine albumin excretion, the more marked the ab(albuminuria A3) over some 10 to 15 years, with the normalities. Other specific complications of diabetes, remainder continuing to have microalbuminuria. Microparticularly retinopathy, are also more common and albuminuria was thus regarded as the first clinical sign tend to progress in parallel.7 Rising blood pressure is of diabetic nephropathy. It quickly became apparent an integral part of the process, important from very that urine albumin excretion fluctuates widely from day early stages, although the blood pressure is not in the to day, with a coefficient of variability of at least 40%.14 ‘‘hypertensive range.’’8 The risk of premature death, primarily from cardiovascular disease, increases as Thus, more than 1 measurement of urine albumin excreurine albumin excretion increases and as glomerular tion is required to make a clinical diagnosis of raised filtration falls in an independent manner.9 Compared urine albumin excretion. Consensus arose that for a confident diagnosis, albumin excretion should be abnormal to type 2 diabetic individuals without CKD, the risk in a minimum of 2 of 3 urine samples collected over is increased approximately 2-fold in microalbuminuria, 3 months. However, more recent studies have demon5-fold in clinical proteinuria, and 12-fold when plasma strated in individuals who have microalbuminuria creatinine is 175 mmol/L or greater.10 Although the persistently over several years that most become excess of conventional cardiovascular risk factors assonormoalbuminuric (albuminuria A1) again.15,16 In 1 ciated with the clinical phenotype contributes to this increased risk, they do not fully explain it. study of type 1 diabetic individuals with persistent
CKD in Diabetes
microalbuminuria over 2 years, 58% reverted to normal albumin excretion after a further 6 years of follow-up.16 Those who reverted to normal albumin excretion had lower hemoglobin A1c, blood pressure, cholesterol, and triglycerides than those with persistent microalbuminuria over the follow-up period. Thus, ‘‘persistent’’ microalbuminuria is not always a permanent state and is more likely to reverse in individuals with ideal blood glucose, blood pressure, and lipid management. It seems unlikely that reversal represents a structural change in the kidney, but it may reflect improved hemodynamics and/or endothelial function. Although this is clearly very good news, it does make it more difficult at the early microalbuminuric stage to be confident about an individual’s risk of progressing to clinical proteinuria and ESRD. It has been suggested that the rate of increase of microalbuminuria might be an indicator of the risk of progression to clinical proteinuria, but this has not been substantiated. However, the rate of change of urine albumin excretion is an independent predictor of cardiovascular disease.17,18 The level of urine albumin excretion is also probably important. The higher the urine albumin excretion within the ‘‘normal range,’’ the greater the chance of microalbuminuria developing.8,19 One early study suggests that this is also true of individuals with microalbuminuria: Individuals with a urine albumin excretion greater than 70 mg/minute (normal range # 20 mg/minute) were more likely to develop clinical proteinuria than those with baseline albumin excretion less than 70 mg/ minute.20 Individuals with stable microalbuminuria had stable GFR whereas GFR decreased in those with increasing urine albumin excretion.21 In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study, the level of urine albumin excretion rate at first presentation of persistent microalbuminuria was strongly associated with progression to proteinuria and weakly associated with regression to normal urine albumin excretion.22 The hazard ratio for progression to proteinuria was 1.98 in those with a urine albumin excretion of 50 to 99 mg/ 24 hours and 3.33 for those with a urine albumin excretion rate of 100 mg/24 hours or greater compared with those with an excretion rate of 30 to 49 mg/24 hours. Thus, low levels of microalbuminuria, perhaps an albumin-to-creatinine ratio less than 100 mg/g, particularly if the levels are not increasing, do not indicate a high risk of developing diabetic nephropathy over the subsequent 5 to 10 years. The longer-term fate of those individuals who revert from microalbuminuria to normal urine albumin excretion remains uncertain. It may be that with more prolonged follow-up they develop progressive microalbuminuria. A parallel might be drawn with the data from small trials of antihypertensive therapy in individuals with clinical proteinuria: Improving blood pressure control may substantially
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initially reduce urine albumin excretion, but in a proportion of patients albumin excretion eventually increases again.23,24 Thus, for the moment, low levels of microalbuminuria cannot be considered to be the earliest clinical sign of diabetic glomerulosclerosis. Instead, the presence of low-level microalbuminuria (albumin-to-creatinine ratio ,100 mg/g) reflects the need to improve glucose and blood pressure control. It is important to clinically monitor urine albumin excretion and glomerular filtration throughout the life of someone with diabetes because kidney disease may take decades to appear and progress. Implications for research may be that only individuals with clinical proteinuria can confidently be regarded as having diabetic nephropathy and that progression of urine albumin excretion from normal to microalbuminuria is not a robust study measure of the development of diabetic nephropathy. In diabetic individuals with reduced GFR but only minimally increased urine albumin excretion, changes in GFR can be regarded as ‘‘hard endpoints.’’
Rate of Progression of Classical Diabetic Nephropathy The rate of progression of classical diabetic nephropathy in type 1 diabetes appears to have slowed over the last 2 decades.25 Initial studies demonstrated that most individuals who developed clinical proteinuria did so within 30 years of diabetes duration, with the peak incidence of first appearance of proteinuria at 16 years of duration and with almost no new cases after 35 to 40 years of duration.26 The cumulative incidence of clinical proteinuria was 41% after a 40-year diabetes duration. In more recent studies, the incidence of proteinuria is extremely variable, but it generally does appear to have fallen at 25 to 30 years of diabetes duration to 13% to 32%.27-30 Reports from Finland and Sweden indicate a cumulative incidence of ESRD of 2.5% to 7.8%.31,32 Although it is tempting to interpret these new data as prevention of proteinuria and thus irreversible diabetic nephropathy, it remains possible that the data represent a delay in the appearance of proteinuria. The recent studies report a lower, but more constant, incidence of clinical proteinuria at 19 to 30 years of diabetes duration28,32 in contrast to the peak incidence at 16 years of duration reported in the original study.26 However, summation of the annual incidence into cumulative incidence to duration of diabetes greater than 30 years suggests that the cumulative incidence of nephropathy in the more recent studies appears to at least equal that of the older studies but with a 5- to 15-year delay in the appearance of proteinuria.25 Thus, the onset of proteinuria in individuals with diabetes susceptible to diabetic nephropathy may be delayed rather than prevented. Screening for CKD should be continued
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indefinitely throughout the individual’s life, regardless of diabetes duration.
Young-Onset Type 2 Diabetes With changes to lifestyle resulting in obesity and physical inactivity, type 2 diabetes is being diagnosed at a much younger age, particularly in Asian and Black ethnic minorities. Chronic complications of diabetes may occur at a younger age and shorter duration of diabetes.33 Some cross-sectional studies report a higher prevalence of increased urine albumin excretion in young people with type 2 compared with type 1 diabetes.34-36 A recent large study suggested that young people with type 2 diabetes were 4 times as likely as young people with type 1 diabetes to have ESRD and to have a significantly poorer survival.37 Data are currently sparse, but clearly further studies are urgently needed.
Nonclassical Diabetic Kidney Disease Over the last few years, it has become clear that many individuals with diabetes who develop progressive CKD do so without following the classical pattern of increasing urine protein excretion with a relatively late decline in GFR (Fig 1). Most have normal albumin excretion or low-level microalbuminuria, which does not progress, whereas glomerular filtration steadily declines. The exact prevalence of nonproteinuric progressive CKD varies with the population studied. Most individuals with type 2 diabetes and progressive CKD do not have significant microalbuminuria or proteinuria.38-40 In type 1 diabetes, the incidence is much less, but it still accounts for 20% to 30% of individuals with progressive CKD.15,41 The rapid increase in individuals with diabetes requiring renal replacement therapy over the last few years appears to be mainly due to individuals with type 2 diabetes older than 65 years of age, most of whom have CKD without proteinuria. What is the cause of this progressive CKD specifically in diabetes without proteinuria? There are very few studies to guide us. The United Kingdom Prospective Diabetes Study suggested that individuals with diabetes and reduced GFR in the absence of increased urine albumin excretion were more likely to be female with lower waist circumference, higher insulin sensitivity, and older age than those with increased excretion.38 Fioretto and colleagues reported a small study of individuals with type 2 diabetes and microalbuminuria but preserved GFR.42 Histological changes were heterogeneous, with normal or near-normal structure, predominately classical glomerular changes or severe interstitial, tubular, or vascular damage with few or no glomerular changes. A more recent small study suggests that type 2 diabetic individuals with microalbuminuria or proteinuria are more likely to have typical glomerular changes whereas those with normal albumin excretion but low GFR have
Figure 1. A comparison of previous and current thinking about progression of diabetic nephropathy. In the older view, almost all individuals who developed microalbuminuria progressed to clinical proteinuria and eventually to ESRD. More recent data suggest that, at least in type 1 diabetes, most of those who develop microalbuminuria revert to normal albumin excretion at least for some years. Few progress to clinical proteinuria and eventually ESRD. However, the rate of progression is much slower than previously observed, and some individuals may regress. A substantial number of individuals with diabetes, particularly those with type 2 diabetes, will develop ESRD with normal albumin excretion or low-level microalbuminuria.
predominately interstitial or vascular changes.43 This ‘‘nonclassical’’ CKD is not due to other specifically treatable kidney diseases, which should be excluded by simple clinical and laboratory investigations such as kidney tract ultrasound, autoantibodies, and immunoglobulins. Most published studies regarding these individuals without increased urine albumin excretion are crosssectional in nature. We have little information about the rate of progression of kidney disease in these diabetic individuals, although simple clinical observation confirms that they do have progressive CKD. High-quality cohort studies in people with diabetes and reduced GFR in the absence of increased urine albumin excretion are urgently needed to improve our understanding of the natural history of kidney disease in these individuals. The presence of nonproteinuric CKD in individuals with diabetes has important implications for clinical practice and research. The implications for screening and diagnosis of CKD in diabetes are that measurement of urine albumin excretion and serum creatinine for calculation of estimated GFR is necessary to identify all individuals with and at high risk of CKD. In research studies, individuals with and without increased urine albumin excretion should be considered separately.
Conclusions Recent data have changed our view of the clinical phenotype of CKD in diabetes with important implications for clinical practice and research (Fig 1, Table 1). Individuals with low-level microalbuminuria may not necessarily have established diabetic nephropathy; instead, they should be regarded as being at high risk of vascular
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CKD in Diabetes
Table 1. Recent Changes in Perceptions Regarding CKD in Diabetes, With Implications for Clinical Practice and Research Older Data Microalbuminuria Permanent Progresses to proteinuria in most
Newer Data Reversible in majority Higher levels more likely to progress to proteinuria
Rate of progression of diabetic nephropathy Peak incidence 16-y duration Incidence relatively uniform from 19- to 30-y duration of diabetes Cumulative incidence after 30-y duration may not be lower than previously Common clinical phenotype of CKD in diabetes Progressive increase in urine albumin Progressive decrease in GFR without excretion, followed by declining GFR significant microalbuminuria in a subset
Implications
Not necessarily a marker of established diabetic nephropathy Indicates need to improve glucose and blood pressure control Need duration of diabetes .25 y to be certain that an individual is unlikely to develop diabetic nephropathy
Few incident cases after 35-y duration
Age at diagnosis of diabetes Older CKD uncommon at younger ages
Younger CKD commoner at earlier age in type 2 diabetes
Measure urine albumin excretion and serum creatinine Separately consider individuals with the different clinical phenotypes Screening for CKD important, even at young age Natural history of CKD in younger-onset diabetes unclear
Abbreviation: GFR, glomerular filtration rate.
disease and of developing diabetic nephropathy. Cardiovascular risk factors should be aggressively managed. Glucose and blood pressure control are probably the key management factors in increasing the likelihood of low-level microalbuminuria reverting to normal urine albumin excretion. Only if urine albumin excretion continues to increase is underlying established diabetic nephropathy likely to be present. It is currently unclear whether or not we can be certain that an individual has progressive diabetic nephropathy before the stage of dipstick-positive proteinuria, although it seems likely that higher levels of microalbuminuria (albumin-to-creatinine ratio .100 mg/g) and progression of microalbuminuria are poor prognostic features. Therefore, careful longitudinal follow-up of urine albumin excretion is vital. Detailed clinical phenotyping of individuals participating in research studies is of even greater paramount importance. Participants with classical diabetic nephropathy may need to be considered separately from those without significant albuminuria. Individuals with lowlevel microalbuminuria cannot be assumed to have progressive diabetic nephropathy; therefore, they may need to be considered more carefully in studies of established diabetic nephropathy. However, this does not imply that individuals with low-level microalbuminuria cannot provide useful information; they simply need to be considered separately. The development of microalbuminuria after a longer duration of diabetes and the suggestions that the rate of progression of diabetic nephropathy is slowing make the description of ‘‘control’’ individuals at very low risk
of developing diabetic nephropathy more difficult to define: It may be prudent to use a duration of diabetes greater than 25 years as opposed to using a lesser duration, as has been used in previous studies.
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