Epidemiology and Risk Factors for Diabetic Kidney Disease Valma Harjutsalo and Per-Henrik Groop Prevalence rates of diabetic kidney disease (DKD) are increasing in parallel with the incidence rates of diabetes mellitus. DKD has already become a significant health problem worldwide. Without radical improvements in prevention and treatment, DKD prevalence will continue to climb. The pathogenesis of DKD is complex and multifactorial, with genetic and environmental factors involved. Several nonmodifiable risk factors contribute to DKD, including genetics, sex, age, age at onset, and duration of diabetes. However, there are also several modifiable risk factors that have a strong effect on the risk of DKD. Traditional modifiable factors include glycemic control, blood pressure, lipids, and smoking. Other recently discovered modifiable risk factors include chronic low-grade inflammation, advanced glycation end products, and lack of physical activity. Efficient management of these modifiable risk factors may improve the prognosis of diabetic patients at risk of DKD. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Diabetic kidney disease, CKD, ESRD, Risk factors, Epidemiology
Introduction The number of individuals being diagnosed with diabetic kidney disease (DKD) has increased steeply along with the diabetes epidemic. It is currently estimated that a total of 382 million have diabetes in 2013, and the number is expected to rise to 592 million by 2035.1 Because the incidence rates of type 1 diabetes (T1D) and type 2 diabetes (T2D) are rising, the numbers of patients with severe complications such as DKD are also increasing.1a The pathogenesis of DKD is complex and multifactorial with genetic and environmental factors involved. It is a progressive disease characterized by gradual increases in urinary albumin excretion, decreases in glomerular filtration rate (GFR), and elevation of arterial blood pressure (BP). However, kidney disease can also develop in patients without albuminuria or in patients with minimal albuminuria,2 especially in elderly patients
with T2D. Of note, kidney disease in T2D is not necessarily DKD as seen in T1D because a large proportion of the patients may have CKD that is related to hypertensive nephrosclerosis or other etiologies.3,4 These patients are best identified by the lack of simultaneous diabetic retinopathy.5 Overall, patients with diabetes account for 30% to 45% of those with ESRD. The risk of DKD increases with the duration of diabetes, with a peak incidence after 15 to 20 years of diabetes.6,7 In T2D, DKD can be detected at the time of diagnosis of diabetes; a large proportion of the patients may have had undiagnosed diabetes, and the true duration of diabetes is unknown. In such cases, T2D and DKD may be diagnosed at the same time.
Epidemiology of DKD Incidence of DKD
From Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Folkh€alsan Institute of Genetics, Folkh€alsan Research Center, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland; Diabetes and Obesity Research Program, Research Program’s Unit, University of Helsinki, Helsinki; and the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Support: This research was supported by grants from the Folkh€alsan Research Foundation, the Academy of Finland (134379), the Wilhelm and Else Stockmann Foundation, the Liv och H€alsa Foundation, and the Novo Nordisk Foundation. The sponsor had no role in the design and conduct of this review. P.-H.G. has received lecture honorariums from Boehringer Ingelheim, Eli Lilly, Genzyme, Medscape, MSD, Novartis, and Novo Nordisk. P.-H.G. is an advisory board member of Boehringer Ingelheim, Eli Lilly, Novartis, AbbVie, Abbott, and Cebix. P.-H.G. has received investigator-initiated study grants from Eli Lilly and Roche. No other potential conflicts of interest relevant to this article are reported. Address correspondence to Per-Henrik Groop, MD, DMSc, FRCPE, Division of Nephrology, Department of Medicine, Helsinki University Hospital, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, FIN-00014 Helsinki, Finland. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.03.009
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Although the absolute number of patients with DKD has increased, the incidence rate has decreased in T1D because of improved diabetes management since the 1980s. Major milestones include self-monitoring of blood glucose, multiple insulin injections with long- and rapidacting insulin, semisynthetic and synthetic human insulin, and measurement of hemoglobin A1c (HbA1c). In addition, aggressive management of hypertension and dyslipidemia has become a routine intervention. Such improvements are presumed to manifest as improved prognosis and a reduced incidence of diabetic complications over the last 2 decades. In T1D, the cumulative incidence of DKD is 20% to 40% after 20 to 25 years of diabetes.6,7 Bojestig and colleagues8 were among the first to report a dramatic decline in the incidence of DKD in T1D in Sweden. Other studies have also observed similar findings,9,10 but some studies have reported contradictory results.11,12 A nationwide study from Iceland did not show any decline in the cumulative incidence over time when
Advances in Chronic Kidney Disease, Vol 21, No 3 (May), 2014: pp 260-266
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patients were compared according to the year of onset of T1D.11 DKD is a more common complication in T2D than in T1D; approximately half of all patients with T2D seen by general practitioners had CKD in an Australian study.13 In the Echantillon National Temoin Representatif des Personnes Diabetiques study (ENTRED) survey in France, approximately 1/3 of the patients with T2D had CKD, but the authors stated that this number is likely an underestimate.14 It is noteworthy that despite a decreased incidence of albuminuria, probably due to the management of hyperglycemia and hypertension, the distribution of estimated GFR remained unchanged in Pima Indians with T2D.15 It is important to note that in contrast to patients with T1D, the incidence of DKD has not decreased in patients with T2D.16,17
Incidence of DKD in Young-Onset T2D
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that the rates of ESRD due to T2D have risen the most in the youngest age group of 30 to 44 years.21
Incidence and Trends in ESRD The cumulative risk of ESRD differs between populations from less than 1% to as high as 13% at 20 years of diabetes duration.22-24 In a cohort from Allegheny County, Pennsylvania, the cumulative incidence was 13% 20 years after the diagnosis of T1D.25 In Finland, the corresponding figure was 2.4%, but it reached 7.8% at 30 years.23 The Finnish study also showed a timeperiod effect with a decline in the cumulative incidence over time (1965-1999). The major improvement was seen in those diagnosed after the 1960s. Further improvements were seen in those diagnosed from 1980 to 1999, but this cohort has had too short of a follow-up to confirm the conclusion. In Sweden, the cumulative incidence of ESRD was surprisingly low—3.3% at 30 years.22 Divergent trends in the incidence of ESRD between T1D and T2D have been observed. Although the incidence for T1D has gradually declined in Europe, Canada, and Australia, it has increased for T2D.21
T2D has become conspicuously more common in young people. However, only a few studies have addressed the prevalence of DKD in young-onset T2D. These recent studies have shown that young individuals with T2D are more prone to develop DKD than individuals CLINICAL SUMMARY Modifiable Risk diagnosed with T1D at the Factors for DKD 18-20 same age. DKD is an increasing global health problem. A relatively large study Glycemic Control Genetic risk factors may play a major role in the from Canada reported that development of DKD. 27% of youth with T2D Table 1 shows the risk fac Aggressive treatment of modifiable risk factors may had persistent microalbutors for DKD. Poor glyceprevent DKD. minuria and 4.7% had macmic control is the major roalbuminuria after only modifiable risk factor. 1.6 years of diabetes.18 Consequently, the beneficial effects of improved Youth with T2D were 4 glycemic control have been convincingly shown in 2 times more likely to develop kidney failure than those landmark studies: the Diabetes Control and Complicawith T1D.18 A similarly high burden of DKD among pations Trial (DCCT) study in patients with T1D and the tients with young-onset T2D has been found in other U.K. Protective Diabetes Study (UKPDS) in patients studies.19,20 A Japanese long-term study showed that with T2D. These studies showed that intensive glucosethe patients with T2D had 2.7 times higher risk than the lowering therapy considerably reduced the risk of diapatients with T1D despite a similar duration of diabetes; betic complications.26 The DCCT follow-up study, the the 30-year cumulative incidence was 44.4% in T2D and 16 20.2% in T1D. Furthermore, they reported that the inciEpidemiology of Diabetes Interventions and Complications study, showed sustained benefits of improved glydence of DKD among patients with T1D has declined cemic control. At closeout of the DCCT, there was a during the past 2 decades, but not among the patients significant difference in HbA1c between the intensively with T2D. and conventionally treated groups—7% vs 9%. However, Young people with T2D show typical clusters of risk after the closeout, the levels merged, resulting in no diffactors, such as obesity, insulin resistance, hypertension, ference between the groups. Nevertheless, the better glyand dyslipidemia. These factors are also risk factors for cemic control during the DCCT was translated into a DKD; therefore, it is not unexpected that young people lower risk of DKD. This phenomenon is known as ‘‘metawith T2D are more prone to develop DKD than those bolic memory.’’ In the UKPDS, similar benefits were with T1D. It is of great concern that the incidence of shown, although there was a modest difference (0.9%) young-onset T2D has increased and that the first signs in HbA1c between the intensively and the conventionally of DKD may emerge shortly after the diagnosis of diatreated groups. This phenomenon has been called the betes. Given the young age of T2D onset, the lifetime ‘‘legacy effect.’’27 Because UKPDS involved newly risk of ESRD will be much higher. Of significance is
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Table 1. Risk Factors for Diabetic Kidney Disease Nonmodifiable Genetic factors Male sex Age at onset of diabetes between 5 and 15 years Long duration of diabetes Increasing age Family history of diabetic kidney disease, type 2 diabetes, hypertension, and insulin resistance Modifiable Poor glycemic control Hypertension Lipid abnormalities Smoking Metabolic syndrome Insulin resistance Low-grade inflammation Endotoxins Advanced glycation end products Low intensity of physical activity Salt intake
diagnosed patients, the study clearly showed that hyperglycemia is the trigger for diabetic tissue damage.28 The mechanism that mediates the tissue damage in the kidney may involve mesangial cells in the glomerulus, which are vulnerable to hyperglycemia, because the glucose transport rate does not decline in the mesangial cells as it does in most other cell types during hyperglycemia. This leads to high intracellular glucose and activation of several deleterious cascades.29 The effect of hyperglycemia is related not only to the absolute values of HbA1c but also to HbA1c variability. Despite identical mean HbA1c, patients may show a wide variation in their long-term glycemic profiles. The DCCT data indicated that variation in long-term glycemia added to the predictive value of HbA1c.30 Later, in the Finnish Diabetic Nephropathy (FinnDiane) study, the effect of HbA1c variability was confirmed.31 The highest incidence of DKD was observed when the mean and the standard deviation of the HbA1c were above the median.
Hypertension An increase in the systolic BP is a classical indicator of kidney complications. There is actually an interactive relationship between the kidney and BP: kidney disease causes an increase in BP; on the other hand, high BP accelerates the loss of kidney function. BP rises in parallel with the increase in urinary albumin excretion rate, although some data show that high BP might even precede the onset of DKD.32 BP lowering and blockade of the reninangiotensin system (RAS) are cornerstones in the treatment and prevention of DKD because large interventional studies such as Reduction in Endpoints in NoninsulinDependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan
Diabetic Nephropathy Trial (IDNT) showed retardation of DKD with effective BP control and RAS blockade.33 In clinical practice, it may be difficult to reach optimal BP targets despite aggressive treatment. The FinnDiane study showed a high rate of resistant hypertension, defined as failure to reach the BP target of 130/85 mmHg despite the use of 3 or more antihypertensive drugs from different classes, 1 of which was a diuretic. The prevalence of resistant hypertension was 1.2% in the normoalbuminuric group, 4.7% in the microalbuminuric group, 28.1% in the macroalbuminuric group, 36.6% in the dialysis group, and 26.3% in the kidney transplant group.34
Lipid Abnormalities Dyslipidemia is another major independent risk factor for the development and progression of DKD.35 Patients with DKD present with several lipoprotein abnormalities such as higher plasma levels of very low-density lipoprotein (VLDL), intermediate-density lipoprotein, lowdensity lipoprotein (LDL) and triglycerides, and lower high-density lipoprotein (HDL) concentrations.36 Patients with T1D but without DKD typically have normal or even elevated HDL cholesterol. The lipid abnormalities related to DKD are not necessarily the same at all DKD stages. Thus, high triglycerides, apolipoprotein (Apo) B, ApoA-II, and HDL3-cholesterol predict incident microalbuminuria whereas high triglycerides and ApoB predict the progression to macroalbuminuria.37 However, conventional lipids and lipoproteins do not fully account for the complex lipid abnormalities in DKD. Lipoproteins are heterogeneous in size, density, and composition.36 Nuclear magnetic resonance has paved the way to retrieve additional information beyond that gained from the conventional lipid profile by quantification of the particle sizes and concentrations of the various lipoprotein subclasses. These features might play an even greater role in the pathogenesis of DKD than the actual quantity of the major lipoproteins. A detailed nuclear magnetic resonance analysis in the DCCT revealed that high intermediate-density lipoprotein and high LDL particle concentrations, as well as a shift from larger toward smaller LDL, ApoB, and small HDL, were all associated with DKD, especially in men.36 Another study focusing on the various stages of DKD found that triglycerides and cholesterol in the large VLDL particles were associated with incident albuminuria whereas triglycerides and cholesterol in the medium-sized VLDL were associated with progression from microalbuminuria.38 However, it is still not clear which lipoproteins are the most important in the pathogenesis of DKD.
Chronic Inflammation Recent studies have suggested that DKD may be an inflammatory disease. In clinical studies, concentrations
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of circulating inflammatory markers have been found in patients with T1D and T2D, and these markers seem to predict the onset and progression of diabetic complications. The FinnDiane study showed that C-reactive protein and interleukin (IL)-6 concentrations are increased in T1D patients with DKD.39 Declining kidney function has been further associated with increased serum cytokine levels, such as those of IL-6, IL-8, and tumor necrosis factor-a.40 In a recent study in patients with T2D, an increase in IL-6 was associated not only with DKD, but also with glomerular basement membrane thickening, a crucial lesion of DKD and a strong predictor of declining kidney function.41 IL-6 is a proinflammatory cytokine and an important mediator of cell proliferation, endothelial cell permeability, and matrix overproduction.35 T2D per se is also associated with inflammation, but inflammation also importantly contributes to the development of DKD.41
Metabolic Syndrome The metabolic syndrome (MS) is characterized by abdominal obesity, dyslipidemia, high BP, insulin resistance, and hyperglycemia. Of note, MS and its components were associated with the development of DKD in patients with T1D because approximately 40% of the patients fulfilled the criteria for MS. Moreover, the proportion of MS increased with increasing severity of DKD; in normoalbuminuric patients, the proportion was the same as in the general population whereas in patients with ESRD it was 68%. The MS was also more prevalent with worsening kidney function and was associated with a 3.75-fold odds ratio for DKD after adjustment for traditional risk factors.42
Smoking Several studies have shown that smoking promotes onset and progression at all stages of DKD in T1D and T2D.43 The prevalence of DKD is progressively higher with increasing pack-years of cigarette consumption.44 It is interesting to note that conspicuous differences between men and women were recently observed regarding the effects of smoking on the development of DKD. This difference was particularly obvious in the ex-smokers: In men, the risk of progression was slightly decreased and similar to the risk in nonsmokers whereas in women the risk in ex-smokers remained the same as in the current smokers. This suggests that smoking may have more harmful long-term and irreversible effects on the development of DKD in women.45 Why does smoking increase the risk of DKD? Smoking increases oxidative stress, lipid accumulation, and accumulation of advanced glycation end products (AGEs) while decreasing nitric oxide production, all of which lead to thickening of the glomerular basement mem-
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brane, mesangial expansion, progression of glomerulosclerosis, and interstitial fibrosis.46
Physical Activity Although some of the patients with T1D show decreased aerobic capacity, the data related to physical activity and its effect on the risk of DKD are scarce and contradictory.47,48 However, it is of note that physical activity was reduced already in patients with T1D and microalbuminuria compared with normoalbuminuric patients, although microalbuminuria in itself is unlikely to cause exercise restrictions.47 In contrast, it might be that low physical activity contributes to the development of microalbuminuria (for example, through sympathetic activation and low baroreflex sensitivity).49 More importantly, recent data show that it is the intensity of the exercise that might be the determining factor for the initiation and progression of DKD.50 Other possible mechanisms by which physical activity may prevent the development of DKD are lowering of BP, improvement of the lipid profile, glycemic control, insulin sensitivity, and endothelial function.
AGEs Formation of AGEs is increased in patients with diabetes because of hyperglycemia. Long-term exposure to AGEs increases the risk of DKD because AGEs accelerate the aging process in tissues. Furthermore, direct in vivo exposure to AGEs is able to generate lesions similar to those seen in DKD.51 In addition to hyperglycemia, the primary sources of AGEs are dietary, including food cooked at high temperature (grilling, frying, and roasting) and cola drinks. Reducing dietary intake of AGEs through food choices and modified cooking techniques may be beneficial.
Nonmodifiable Risk Factors for DKD Age, Gender, Age at Onset of Diabetes, and Duration of Diabetes Age, gender, and age at onset of diabetes are typically unmodifiable risk factors of DKD (Table 1). Aging is the most common risk factor. Even in adults without diabetes in the general population, kidney function declines approximately 1 mL/minute per year beyond the age of 40 years.52 The risk of DKD is generally reduced or delayed among patients diagnosed with diabetes at younger than 5 years of age and in those with their diabetes onset after puberty. This is in contrast to those whose diagnosis occurred during puberty or a few years before puberty who have an increased risk.23,53 Men are more susceptible to DKD than women in T1D and T2D,54 although there are studies that have not been able to
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show a male preponderance.55 It is interesting to note that the adverse effect of the male gender on the risk of ESRD is also related to the age at onset of T1D, being apparent with pubertal onset and remaining high with onset after age 15.56 It is known that sex hormones and high glucose can trigger epigenetic modifications regulating gene expression without changing DNA sequences.57,58 Timing and order of hyperglycemia and changes in prepubertal and pubertal hormones may lead to epigenetic effects and thus different risk profiles of ESRD according to age at onset and sex. After sexual maturation, sex hormone profiles may play a role in the risk of DKD in adulthood. Women with T1D may have reduced circulating estradiol levels and elevated testosterone levels54 whereas men with T1D have either increased or reduced free testosterone and increased estradiol levels.54 However, the results have been inconclusive, and the most consistent finding has been an imbalance between the sex hormones rather than deviations in the absolute levels. Regarding the age at onset of T2D, it is possible to delay the onset and even prevent the manifestation of T2D by intensive lifestyle interventions59; thus, the age at onset of diabetes in T2D is not a totally nonmodifiable risk factor as it is in T1D.
Genetic Risk Factors Despite a long list of modifiable and nonmodifiable risk factors, it is quite clear that even when all factors are considered together they cannot explain all of the risk of DKD. Therefore, it is very likely that genetic factors also play an important role. Such a view is supported by the observation of familial clustering of DKD in T1D and T2D.53 In addition, genes associated with many modifiable factors such as glycemic control, BP, and lipids plausibly may play a role in a background of DKD predisposition. Snieder and colleagues60 have shown in a study of twins that even HbA1c levels are partly genetically determined. Correspondingly, hypertension has a firm genetic background.61 Parental history of hypertension, type 2 diabetes, cardiovascular disease, and insulin resistance appear to be risk factors of DKD in patients with diabetes, suggesting that DKD may be linked by a complex interrelated genetic predisposition also to these disorders.62,63
Summary DKD is an increasing global health problem that is associated with increased premature mortality, increased risk of cardiovascular events, increased risk of ending up on dialysis, increased risk of severe hypoglycemia, and escalating health-care costs. The major reason why DKD has become more common is the rapid increase in the number of patients with diabetes. However, many modifiable and nonmodifiable risk factors also contribute to the risk
of DKD. Nonmodifiable risk factors such as age, sex, duration of diabetes, and potential susceptibility genes seem to play an important role, but it is of course not possible to fully avoid the effects of these factors until diabetes itself can be prevented. However, the good news is that many of the modifiable risk factors have a strong effect on the risk of DKD, and efficient management of these factors may not only save kidney function but also strongly improve the prognosis of diabetic patients at risk of DKD.
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16. Yokoyama H, Okudaira M, Otani T, et al. Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Kidney Int. 2000;58(1):302-311. 17. Larson TS, Santanello N, Shahinfar S, et al. Trends in persistent proteinuria in adult-onset diabetes: a population-based study. Diabetes Care. 2000;23(1):51-56. 18. Dart AB, Sellers EA, Martens PJ, Rigatto C, Brownell MD, Dean HJ. High burden of kidney disease in youth-onset type 2 diabetes. Diabetes Care. 2012;35(6):1265-1271. 19. Eppens MC, Craig ME, Cusumano J, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care. 2006;29(6):1300-1306. 20. Maahs DM, Snively BM, Bell RA, et al. Higher prevalence of elevated albumin excretion in youth with type 2 than type 1 diabetes: the SEARCH for Diabetes in Youth study. Diabetes Care. 2007;30(10):2593-2598. 21. Group EIS, Stewart JH, McCredie MR, Williams SM. Divergent trends in the incidence of end-stage renal disease due to type 1 and type 2 diabetes in Europe, Canada and Australia during 1998-2002. Diabetic Med. 2006;23(12):1364-1369. 22. 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. A nationwide population based cohort study. Diabetes. 2010;59(7):1803-1808. 23. Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-Riska C. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA. 2005;294(14):1782-1787. 24. Krolewski M, Eggers PW, Warram JH. Magnitude of end-stage renal disease in IDDM: a 35 year follow-up study. Kidney Int. 1996;50(6):2041-2046. 25. Matsushima M, Tajima N, LaPorte RE, et al. Markedly increased renal disease mortality and incidence of renal replacement therapy among IDDM patients in Japan in contrast to Allegheny County, Pennsylvania, USA. Diabetes Epidemiology Research International (DERI) U.S.-Japan Mortality Study Group. Diabetologia. 1995;38(2): 236-243. 26. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47(6):1703-1720. 27. Murray P, Chune GW, Raghavan VA. Legacy effects from DCCT and UKPDS: what they mean and implications for future diabetes trials. Curr Atheroscler Rep. 2010;12(6):432-439. 28. Genuth S, Eastman R, Kahn R, et al. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 2003;26(suppl 1):S28-S32. 29. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615-1625. 30. The Diabetes Control and Complications Trial Research Group (DCCT). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986. 31. Waden J, Forsblom C, Thorn LM, et al. A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes. 2009;58(11): 2649-2655. 32. Fagerudd JA, Tarnow L, Jacobsen P, et al. Predisposition to essential hypertension and development of diabetic nephropathy in IDDM patients. Diabetes. 1998;47(3):439-444. 33. Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004;351(19):1941-1951. 34. Lithovius R, Harjutsalo V, Forsblom C, Saraheimo M, Groop PH, FinnDiane Study. Antihypertensive treatment and resistant hypertension in patients with type 1 diabetes by stages of diabetic nephropathy. Diabetes Care. 2014;37(3):709-717. 35. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93(1):137-188.
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36. Jenkins AJ, Lyons TJ, Zheng D, et al. Lipoproteins in the DCCT/ EDIC cohort: associations with diabetic nephropathy. Kidney Int. 2003;64(3):817-828. 37. Tolonen N, Forsblom C, Thorn L, et al. Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes. Diabetologia. 2009;52(12):2522-2530. 38. Makinen VP, Soininen P, Kangas AJ, et al. Triglyceride-cholesterol imbalance across lipoprotein subclasses predicts diabetic kidney disease and mortality in type 1 diabetes: the FinnDiane study. J Intern Med. 2013;273(4):383-395. 39. Saraheimo M, Teppo AM, Forsblom C, Fagerudd J, Groop PH. Diabetic nephropathy is associated with low-grade inflammation in type 1 diabetic patients. Diabetologia. 2003;46(10):1402-1407. 40. Nakanishi I, Moutabarrik A, Okada N, et al. Interleukin-8 in chronic renal failure and dialysis patients. Nephrol Dial Transplant. 1994;9(10):1435-1442. 41. Dalla Vestra M, Mussap M, Gallina P, et al. Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes. J Am Soc Nephrol. 2005;16(suppl 1):S78-S82. 42. Thorn LM, Forsblom C, Fagerudd J, et al. Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care. 2005;28(8):20192024. 43. Orth SR. Smoking and the kidney. J Am Soc Nephrol. 2002;13(6):1663-1672. 44. Sawicki PT, Didjurgeit U, Muhlhauser I, Bender R, Heinemann L, Berger M. Smoking is associated with progression of diabetic nephropathy. Diabetes Care. 1994;17(2):126-131. 45. Feodoroff M, Harjutsalo V, Forsblom C, et al. Smoking increases the incidence of diabetic nephropathy and end stage renal disease in patients with type 1 diabetes. Paper presented at: 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD); September 23-27, 2013; Barcelona, Spain. 46. Chakkarwar VA. Smoking in diabetic nephropathy: sparks in the fuel tank? World J Diabetes. 2012;3(12):186-195. 47. Waden J, Forsblom C, Thorn LM, et al. Physical activity and diabetes complications in patients with type 1 diabetes: the Finnish Diabetic Nephropathy (FinnDiane) study. Diabetes Care. 2008;31(2): 230-232. 48. Makura CB, Nirantharakumar K, Girling AJ, Saravanan P, Narendran P. Effects of physical activity on the development and progression of microvascular complications in type 1 diabetes: retrospective analysis of the DCCT study. BMC Endocr Disord. 2013;13(1):37. 49. Rosengard-Barlund M, Bernardi L, Sandelin A, Forsblom C, Groop PH, FinnDiane Study Group. Baroreflex sensitivity and its response to deep breathing predict increase in blood pressure in type 1 diabetes in a 5-year follow-up. Diabetes Care. 2011;34(11): 2424-2430. 50. Tikkanen H, Waden J, Forsblom C, et al. Intensity of physical activity predicts the development and progression of diabetic nephropathy. Paper presented at: World Diabetes Congress (IDF); December 2-6, 2013; Melbourne, Australia. 51. Forbes JM, Cooper ME, Oldfield MD, Thomas MC. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol. 2003;14(8 suppl 3):S254-S258. 52. MacGregor MS. How common is early chronic kidney disease? A background paper prepared for the UK Consensus Conference on early chronic kidney disease. Nephrol Dial Transplant. 2007;22(suppl 9):ix8-ix18. 53. Harjutsalo V, Katoh S, Sarti C, Tajima N, Tuomilehto J. Populationbased assessment of familial clustering of diabetic nephropathy in type 1 diabetes. Diabetes. 2004;53(9):2449-2454. 54. Maric C. Sex, diabetes and the kidney. Am J Physiol Renal Physiol. 2009;296(4):F680-F688. 55. Rossing P, Hougaard P, Parving HH. Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic
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58. 59.
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patients: a 10-year prospective observational study. Diabetes Care. 2002;25(5):859-864. Harjutsalo V, Maric C, Forsblom C, Thorn L, Waden J, Groop PH. Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes. Diabetologia. 2011;54(8):1992-1999. El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205(10):2409-2417. Kaminsky Z, Wang SC, Petronis A. Complex disease, gender and epigenetics. Ann Med. 2006;38(8):530-544. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-1350.
60. Snieder H, Sawtell PA, Ross L, Walker J, Spector TD, Leslie RD. HbA(1c) levels are genetically determined even in type 1 diabetes: evidence from healthy and diabetic twins. Diabetes. 2001;50(12): 2858-2863. 61. Lind JM, Chiu CL. Genetic discoveries in hypertension: steps on the road to therapeutic translation. Heart. 2013;99(22):1645-1651. 62. Earle K, Walker J, Hill C, Viberti G. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med. 1992;326(10):673-677. 63. Fagerudd JA, Pettersson-Fernholm KJ, Gronhagen-Riska C, Groop PH. The impact of a family history of type II (non-insulindependent) diabetes mellitus on the risk of diabetic nephropathy in patients with type I (insulin-dependent) diabetes mellitus. Diabetologia. 1999;42(5):519-526.
Introduction The number of individuals being diagnosed with diabetic kidney disease (DKD) has increased steeply along with the diabetes epidemic. It is currently estimated that a total of 382 million have diabetes in 2013, and the number is expected to rise to 592 million by 2035.1 Because the incidence rates of type 1 diabetes (T1D) and type 2 diabetes (T2D) are rising, the numbers of patients with severe complications such as DKD are also increasing.1a The pathogenesis of DKD is complex and multifactorial with genetic and environmental factors involved. It is a progressive disease characterized by gradual increases in urinary albumin excretion, decreases in glomerular filtration rate (GFR), and elevation of arterial blood pressure (BP). However, kidney disease can also develop in patients without albuminuria or in patients with minimal albuminuria,2 especially in elderly patients
with T2D. Of note, kidney disease in T2D is not necessarily DKD as seen in T1D because a large proportion of the patients may have CKD that is related to hypertensive nephrosclerosis or other etiologies.3,4 These patients are best identified by the lack of simultaneous diabetic retinopathy.5 Overall, patients with diabetes account for 30% to 45% of those with ESRD. The risk of DKD increases with the duration of diabetes, with a peak incidence after 15 to 20 years of diabetes.6,7 In T2D, DKD can be detected at the time of diagnosis of diabetes; a large proportion of the patients may have had undiagnosed diabetes, and the true duration of diabetes is unknown. In such cases, T2D and DKD may be diagnosed at the same time.
Epidemiology of DKD Incidence of DKD
From Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Folkh€alsan Institute of Genetics, Folkh€alsan Research Center, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland; Diabetes and Obesity Research Program, Research Program’s Unit, University of Helsinki, Helsinki; and the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Support: This research was supported by grants from the Folkh€alsan Research Foundation, the Academy of Finland (134379), the Wilhelm and Else Stockmann Foundation, the Liv och H€alsa Foundation, and the Novo Nordisk Foundation. The sponsor had no role in the design and conduct of this review. P.-H.G. has received lecture honorariums from Boehringer Ingelheim, Eli Lilly, Genzyme, Medscape, MSD, Novartis, and Novo Nordisk. P.-H.G. is an advisory board member of Boehringer Ingelheim, Eli Lilly, Novartis, AbbVie, Abbott, and Cebix. P.-H.G. has received investigator-initiated study grants from Eli Lilly and Roche. No other potential conflicts of interest relevant to this article are reported. Address correspondence to Per-Henrik Groop, MD, DMSc, FRCPE, Division of Nephrology, Department of Medicine, Helsinki University Hospital, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, FIN-00014 Helsinki, Finland. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.03.009
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Although the absolute number of patients with DKD has increased, the incidence rate has decreased in T1D because of improved diabetes management since the 1980s. Major milestones include self-monitoring of blood glucose, multiple insulin injections with long- and rapidacting insulin, semisynthetic and synthetic human insulin, and measurement of hemoglobin A1c (HbA1c). In addition, aggressive management of hypertension and dyslipidemia has become a routine intervention. Such improvements are presumed to manifest as improved prognosis and a reduced incidence of diabetic complications over the last 2 decades. In T1D, the cumulative incidence of DKD is 20% to 40% after 20 to 25 years of diabetes.6,7 Bojestig and colleagues8 were among the first to report a dramatic decline in the incidence of DKD in T1D in Sweden. Other studies have also observed similar findings,9,10 but some studies have reported contradictory results.11,12 A nationwide study from Iceland did not show any decline in the cumulative incidence over time when
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patients were compared according to the year of onset of T1D.11 DKD is a more common complication in T2D than in T1D; approximately half of all patients with T2D seen by general practitioners had CKD in an Australian study.13 In the Echantillon National Temoin Representatif des Personnes Diabetiques study (ENTRED) survey in France, approximately 1/3 of the patients with T2D had CKD, but the authors stated that this number is likely an underestimate.14 It is noteworthy that despite a decreased incidence of albuminuria, probably due to the management of hyperglycemia and hypertension, the distribution of estimated GFR remained unchanged in Pima Indians with T2D.15 It is important to note that in contrast to patients with T1D, the incidence of DKD has not decreased in patients with T2D.16,17
Incidence of DKD in Young-Onset T2D
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that the rates of ESRD due to T2D have risen the most in the youngest age group of 30 to 44 years.21
Incidence and Trends in ESRD The cumulative risk of ESRD differs between populations from less than 1% to as high as 13% at 20 years of diabetes duration.22-24 In a cohort from Allegheny County, Pennsylvania, the cumulative incidence was 13% 20 years after the diagnosis of T1D.25 In Finland, the corresponding figure was 2.4%, but it reached 7.8% at 30 years.23 The Finnish study also showed a timeperiod effect with a decline in the cumulative incidence over time (1965-1999). The major improvement was seen in those diagnosed after the 1960s. Further improvements were seen in those diagnosed from 1980 to 1999, but this cohort has had too short of a follow-up to confirm the conclusion. In Sweden, the cumulative incidence of ESRD was surprisingly low—3.3% at 30 years.22 Divergent trends in the incidence of ESRD between T1D and T2D have been observed. Although the incidence for T1D has gradually declined in Europe, Canada, and Australia, it has increased for T2D.21
T2D has become conspicuously more common in young people. However, only a few studies have addressed the prevalence of DKD in young-onset T2D. These recent studies have shown that young individuals with T2D are more prone to develop DKD than individuals CLINICAL SUMMARY Modifiable Risk diagnosed with T1D at the Factors for DKD 18-20 same age. DKD is an increasing global health problem. A relatively large study Glycemic Control Genetic risk factors may play a major role in the from Canada reported that development of DKD. 27% of youth with T2D Table 1 shows the risk fac Aggressive treatment of modifiable risk factors may had persistent microalbutors for DKD. Poor glyceprevent DKD. minuria and 4.7% had macmic control is the major roalbuminuria after only modifiable risk factor. 1.6 years of diabetes.18 Consequently, the beneficial effects of improved Youth with T2D were 4 glycemic control have been convincingly shown in 2 times more likely to develop kidney failure than those landmark studies: the Diabetes Control and Complicawith T1D.18 A similarly high burden of DKD among pations Trial (DCCT) study in patients with T1D and the tients with young-onset T2D has been found in other U.K. Protective Diabetes Study (UKPDS) in patients studies.19,20 A Japanese long-term study showed that with T2D. These studies showed that intensive glucosethe patients with T2D had 2.7 times higher risk than the lowering therapy considerably reduced the risk of diapatients with T1D despite a similar duration of diabetes; betic complications.26 The DCCT follow-up study, the the 30-year cumulative incidence was 44.4% in T2D and 16 20.2% in T1D. Furthermore, they reported that the inciEpidemiology of Diabetes Interventions and Complications study, showed sustained benefits of improved glydence of DKD among patients with T1D has declined cemic control. At closeout of the DCCT, there was a during the past 2 decades, but not among the patients significant difference in HbA1c between the intensively with T2D. and conventionally treated groups—7% vs 9%. However, Young people with T2D show typical clusters of risk after the closeout, the levels merged, resulting in no diffactors, such as obesity, insulin resistance, hypertension, ference between the groups. Nevertheless, the better glyand dyslipidemia. These factors are also risk factors for cemic control during the DCCT was translated into a DKD; therefore, it is not unexpected that young people lower risk of DKD. This phenomenon is known as ‘‘metawith T2D are more prone to develop DKD than those bolic memory.’’ In the UKPDS, similar benefits were with T1D. It is of great concern that the incidence of shown, although there was a modest difference (0.9%) young-onset T2D has increased and that the first signs in HbA1c between the intensively and the conventionally of DKD may emerge shortly after the diagnosis of diatreated groups. This phenomenon has been called the betes. Given the young age of T2D onset, the lifetime ‘‘legacy effect.’’27 Because UKPDS involved newly risk of ESRD will be much higher. Of significance is
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Table 1. Risk Factors for Diabetic Kidney Disease Nonmodifiable Genetic factors Male sex Age at onset of diabetes between 5 and 15 years Long duration of diabetes Increasing age Family history of diabetic kidney disease, type 2 diabetes, hypertension, and insulin resistance Modifiable Poor glycemic control Hypertension Lipid abnormalities Smoking Metabolic syndrome Insulin resistance Low-grade inflammation Endotoxins Advanced glycation end products Low intensity of physical activity Salt intake
diagnosed patients, the study clearly showed that hyperglycemia is the trigger for diabetic tissue damage.28 The mechanism that mediates the tissue damage in the kidney may involve mesangial cells in the glomerulus, which are vulnerable to hyperglycemia, because the glucose transport rate does not decline in the mesangial cells as it does in most other cell types during hyperglycemia. This leads to high intracellular glucose and activation of several deleterious cascades.29 The effect of hyperglycemia is related not only to the absolute values of HbA1c but also to HbA1c variability. Despite identical mean HbA1c, patients may show a wide variation in their long-term glycemic profiles. The DCCT data indicated that variation in long-term glycemia added to the predictive value of HbA1c.30 Later, in the Finnish Diabetic Nephropathy (FinnDiane) study, the effect of HbA1c variability was confirmed.31 The highest incidence of DKD was observed when the mean and the standard deviation of the HbA1c were above the median.
Hypertension An increase in the systolic BP is a classical indicator of kidney complications. There is actually an interactive relationship between the kidney and BP: kidney disease causes an increase in BP; on the other hand, high BP accelerates the loss of kidney function. BP rises in parallel with the increase in urinary albumin excretion rate, although some data show that high BP might even precede the onset of DKD.32 BP lowering and blockade of the reninangiotensin system (RAS) are cornerstones in the treatment and prevention of DKD because large interventional studies such as Reduction in Endpoints in NoninsulinDependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan
Diabetic Nephropathy Trial (IDNT) showed retardation of DKD with effective BP control and RAS blockade.33 In clinical practice, it may be difficult to reach optimal BP targets despite aggressive treatment. The FinnDiane study showed a high rate of resistant hypertension, defined as failure to reach the BP target of 130/85 mmHg despite the use of 3 or more antihypertensive drugs from different classes, 1 of which was a diuretic. The prevalence of resistant hypertension was 1.2% in the normoalbuminuric group, 4.7% in the microalbuminuric group, 28.1% in the macroalbuminuric group, 36.6% in the dialysis group, and 26.3% in the kidney transplant group.34
Lipid Abnormalities Dyslipidemia is another major independent risk factor for the development and progression of DKD.35 Patients with DKD present with several lipoprotein abnormalities such as higher plasma levels of very low-density lipoprotein (VLDL), intermediate-density lipoprotein, lowdensity lipoprotein (LDL) and triglycerides, and lower high-density lipoprotein (HDL) concentrations.36 Patients with T1D but without DKD typically have normal or even elevated HDL cholesterol. The lipid abnormalities related to DKD are not necessarily the same at all DKD stages. Thus, high triglycerides, apolipoprotein (Apo) B, ApoA-II, and HDL3-cholesterol predict incident microalbuminuria whereas high triglycerides and ApoB predict the progression to macroalbuminuria.37 However, conventional lipids and lipoproteins do not fully account for the complex lipid abnormalities in DKD. Lipoproteins are heterogeneous in size, density, and composition.36 Nuclear magnetic resonance has paved the way to retrieve additional information beyond that gained from the conventional lipid profile by quantification of the particle sizes and concentrations of the various lipoprotein subclasses. These features might play an even greater role in the pathogenesis of DKD than the actual quantity of the major lipoproteins. A detailed nuclear magnetic resonance analysis in the DCCT revealed that high intermediate-density lipoprotein and high LDL particle concentrations, as well as a shift from larger toward smaller LDL, ApoB, and small HDL, were all associated with DKD, especially in men.36 Another study focusing on the various stages of DKD found that triglycerides and cholesterol in the large VLDL particles were associated with incident albuminuria whereas triglycerides and cholesterol in the medium-sized VLDL were associated with progression from microalbuminuria.38 However, it is still not clear which lipoproteins are the most important in the pathogenesis of DKD.
Chronic Inflammation Recent studies have suggested that DKD may be an inflammatory disease. In clinical studies, concentrations
Diabetic Kidney Disease
of circulating inflammatory markers have been found in patients with T1D and T2D, and these markers seem to predict the onset and progression of diabetic complications. The FinnDiane study showed that C-reactive protein and interleukin (IL)-6 concentrations are increased in T1D patients with DKD.39 Declining kidney function has been further associated with increased serum cytokine levels, such as those of IL-6, IL-8, and tumor necrosis factor-a.40 In a recent study in patients with T2D, an increase in IL-6 was associated not only with DKD, but also with glomerular basement membrane thickening, a crucial lesion of DKD and a strong predictor of declining kidney function.41 IL-6 is a proinflammatory cytokine and an important mediator of cell proliferation, endothelial cell permeability, and matrix overproduction.35 T2D per se is also associated with inflammation, but inflammation also importantly contributes to the development of DKD.41
Metabolic Syndrome The metabolic syndrome (MS) is characterized by abdominal obesity, dyslipidemia, high BP, insulin resistance, and hyperglycemia. Of note, MS and its components were associated with the development of DKD in patients with T1D because approximately 40% of the patients fulfilled the criteria for MS. Moreover, the proportion of MS increased with increasing severity of DKD; in normoalbuminuric patients, the proportion was the same as in the general population whereas in patients with ESRD it was 68%. The MS was also more prevalent with worsening kidney function and was associated with a 3.75-fold odds ratio for DKD after adjustment for traditional risk factors.42
Smoking Several studies have shown that smoking promotes onset and progression at all stages of DKD in T1D and T2D.43 The prevalence of DKD is progressively higher with increasing pack-years of cigarette consumption.44 It is interesting to note that conspicuous differences between men and women were recently observed regarding the effects of smoking on the development of DKD. This difference was particularly obvious in the ex-smokers: In men, the risk of progression was slightly decreased and similar to the risk in nonsmokers whereas in women the risk in ex-smokers remained the same as in the current smokers. This suggests that smoking may have more harmful long-term and irreversible effects on the development of DKD in women.45 Why does smoking increase the risk of DKD? Smoking increases oxidative stress, lipid accumulation, and accumulation of advanced glycation end products (AGEs) while decreasing nitric oxide production, all of which lead to thickening of the glomerular basement mem-
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brane, mesangial expansion, progression of glomerulosclerosis, and interstitial fibrosis.46
Physical Activity Although some of the patients with T1D show decreased aerobic capacity, the data related to physical activity and its effect on the risk of DKD are scarce and contradictory.47,48 However, it is of note that physical activity was reduced already in patients with T1D and microalbuminuria compared with normoalbuminuric patients, although microalbuminuria in itself is unlikely to cause exercise restrictions.47 In contrast, it might be that low physical activity contributes to the development of microalbuminuria (for example, through sympathetic activation and low baroreflex sensitivity).49 More importantly, recent data show that it is the intensity of the exercise that might be the determining factor for the initiation and progression of DKD.50 Other possible mechanisms by which physical activity may prevent the development of DKD are lowering of BP, improvement of the lipid profile, glycemic control, insulin sensitivity, and endothelial function.
AGEs Formation of AGEs is increased in patients with diabetes because of hyperglycemia. Long-term exposure to AGEs increases the risk of DKD because AGEs accelerate the aging process in tissues. Furthermore, direct in vivo exposure to AGEs is able to generate lesions similar to those seen in DKD.51 In addition to hyperglycemia, the primary sources of AGEs are dietary, including food cooked at high temperature (grilling, frying, and roasting) and cola drinks. Reducing dietary intake of AGEs through food choices and modified cooking techniques may be beneficial.
Nonmodifiable Risk Factors for DKD Age, Gender, Age at Onset of Diabetes, and Duration of Diabetes Age, gender, and age at onset of diabetes are typically unmodifiable risk factors of DKD (Table 1). Aging is the most common risk factor. Even in adults without diabetes in the general population, kidney function declines approximately 1 mL/minute per year beyond the age of 40 years.52 The risk of DKD is generally reduced or delayed among patients diagnosed with diabetes at younger than 5 years of age and in those with their diabetes onset after puberty. This is in contrast to those whose diagnosis occurred during puberty or a few years before puberty who have an increased risk.23,53 Men are more susceptible to DKD than women in T1D and T2D,54 although there are studies that have not been able to
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show a male preponderance.55 It is interesting to note that the adverse effect of the male gender on the risk of ESRD is also related to the age at onset of T1D, being apparent with pubertal onset and remaining high with onset after age 15.56 It is known that sex hormones and high glucose can trigger epigenetic modifications regulating gene expression without changing DNA sequences.57,58 Timing and order of hyperglycemia and changes in prepubertal and pubertal hormones may lead to epigenetic effects and thus different risk profiles of ESRD according to age at onset and sex. After sexual maturation, sex hormone profiles may play a role in the risk of DKD in adulthood. Women with T1D may have reduced circulating estradiol levels and elevated testosterone levels54 whereas men with T1D have either increased or reduced free testosterone and increased estradiol levels.54 However, the results have been inconclusive, and the most consistent finding has been an imbalance between the sex hormones rather than deviations in the absolute levels. Regarding the age at onset of T2D, it is possible to delay the onset and even prevent the manifestation of T2D by intensive lifestyle interventions59; thus, the age at onset of diabetes in T2D is not a totally nonmodifiable risk factor as it is in T1D.
Genetic Risk Factors Despite a long list of modifiable and nonmodifiable risk factors, it is quite clear that even when all factors are considered together they cannot explain all of the risk of DKD. Therefore, it is very likely that genetic factors also play an important role. Such a view is supported by the observation of familial clustering of DKD in T1D and T2D.53 In addition, genes associated with many modifiable factors such as glycemic control, BP, and lipids plausibly may play a role in a background of DKD predisposition. Snieder and colleagues60 have shown in a study of twins that even HbA1c levels are partly genetically determined. Correspondingly, hypertension has a firm genetic background.61 Parental history of hypertension, type 2 diabetes, cardiovascular disease, and insulin resistance appear to be risk factors of DKD in patients with diabetes, suggesting that DKD may be linked by a complex interrelated genetic predisposition also to these disorders.62,63
Summary DKD is an increasing global health problem that is associated with increased premature mortality, increased risk of cardiovascular events, increased risk of ending up on dialysis, increased risk of severe hypoglycemia, and escalating health-care costs. The major reason why DKD has become more common is the rapid increase in the number of patients with diabetes. However, many modifiable and nonmodifiable risk factors also contribute to the risk
of DKD. Nonmodifiable risk factors such as age, sex, duration of diabetes, and potential susceptibility genes seem to play an important role, but it is of course not possible to fully avoid the effects of these factors until diabetes itself can be prevented. However, the good news is that many of the modifiable risk factors have a strong effect on the risk of DKD, and efficient management of these factors may not only save kidney function but also strongly improve the prognosis of diabetic patients at risk of DKD.
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