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Diabetic kidney disease: Pathogenesis and epidemiology

Diabetic kidney disease: Pathogenesis and epidemiology
Authors:
Amy K Mottl, MD
Katherine R Tuttle, MD, FASN, FACP, FNKF
Section Editor:
George L Bakris, MD
Deputy Editor:
John P Forman, MD, MSc
Literature review current through: Dec 2022. | This topic last updated: Sep 14, 2021.

INTRODUCTION — Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States and worldwide. Diabetic kidney disease is a complex and heterogeneous disease with numerous overlapping etiologic pathways including changes in glomerular hemodynamics, oxidative stress and inflammation, and interstitial fibrosis and tubular atrophy.

The pathogenesis and epidemiology of diabetic kidney disease are reviewed here. Other topics discuss the following issues:

Manifestations, evaluation, and diagnosis of diabetic kidney disease (see "Diabetic kidney disease: Manifestations, evaluation, and diagnosis")

Treatment of diabetic kidney disease (see "Treatment of diabetic kidney disease")

Management of hypertension in patients with diabetes (see "Treatment of hypertension in patients with diabetes mellitus")

PATHOGENESIS — Diabetic kidney disease is a complex and heterogeneous disease with numerous overlapping etiologic pathways [1]. Hyperglycemia results in production of advanced glycation end-products (AGE) and reactive oxygen species. These aberrant metabolic products activate intercellular signaling for proinflammatory and profibrotic gene expression with production of a host of mediators for cellular injury [2,3]. While hyperglycemia undoubtedly plays a central role, hyperinsulinemia and insulin resistance also may incite pathogenic mechanisms, possibly accounting for variation in histopathology between type 1 and type 2 diabetes. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Manifestations and diagnosis' and "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Natural history'.)

Ultimately, alterations in glomerular hemodynamics, inflammation, and fibrosis are primary mediators of kidney tissue damage, although the relative contribution of these mechanisms likely varies between individuals and over the course of the natural history of diabetic kidney disease.

Glomerular hemodynamics — The diabetic milieu activates the renin-angiotensin-aldosterone system (RAAS) and numerous other downstream mediators, triggering kidney hypertrophy, increased renal plasma flow (RPF), and increased filtration fraction (FF), which together result in an abnormally elevated glomerular filtration rate (GFR) (figure 1) [4]. In the early stages of diabetes, "whole kidney GFR" and "single nephron GFR (SNGFR)" are increased. These states are often referred to as "glomerular hyperfiltration [5,6]." (See 'Glomerular hyperfiltration' below.)

While increased RPF and FF are partly due to an increase in kidney size, they are predominantly the result of disproportionately reduced afferent versus efferent arteriolar resistance [7]. Increased circulating vasodilators, such as atrial natriuretic peptide, nitric oxide, and prostanoids, and a relative deficiency or resistance to insulin have a preferential impact on reducing afferent arteriole resistance [5,6]. By contrast, an increase in circulating vasoconstrictors, including angiotensin II, thromboxane and endothelin 1, have a greater effect to increase efferent arteriole resistance. The imbalance in tone between afferent and efferent arterioles increases intraglomerular pressure that, over time, triggers a sclerotic response in diabetic kidney disease [4].

Tubular function also has an impact on glomerular hemodynamics, via tubuloglomerular feedback [1]. Diabetes is associated with a decrease in sodium delivery to the macula densa. This occurs early in the course of diabetes as the proximal tubule hypertrophies and there is upregulation of the sodium-glucose cotransporters (SGLT1 and SGLT2). Reabsorption of glucose and sodium are increased in relatively moderate hyperglycemia (>180 mg/dL), resulting in decreased sodium chloride delivery to the macula densa portion of the distal tubule. Consequently, afferent arteriolar tone is further decreased, thereby producing increases in RPF, FF, and GFR. The impact of tubular function on progression of diabetic kidney disease is further underscored by findings that inhibition of SGLT2 results in an initial, short-term decline in estimated GFR (eGFR) but a long-term delay in kidney disease progression [8-12]. This effect is presumably due, sequentially, to decreased reabsorption of sodium and glucose in the proximal nephron, increasing distal delivery of sodium to the macula densa, restoration of tubuloglomerular feedback, and a reduction in glomerular hyperfiltration [12]. The initial decrease in eGFR after SGLT2 inhibition has been variably observed among those with an eGFR <45 mL/min/1.73 m2. Regardless of this initial eGFR decline, these drugs slow CKD progression in this population [13-15].

Further exacerbation of glomerular hyperfiltration also occurs in diabetes due to impaired autoregulatory responses of the afferent arterioles to fluctuations in blood pressure [16]. Thus, increases in blood pressure, which would normally result in protective increases in vascular tone, are transmitted along to glomerular capillaries.

These anomalous vascular changes result in increased intraglomerular pressure and SNGFR, causing physical stress to capillary walls, podocytes, and mesangium, ultimately triggering a profibrotic response. As glomeruli become sclerosed and whole kidney GFR decreases, RPF is shunted to the remaining viable glomeruli, causing further increases in SNGFR of the less damaged glomeruli. Numerous studies in type 1 and type 2 diabetes have subsequently demonstrated an association between elevated estimated GFR (eGFR) and worsening albuminuria [5], although a direct link between hyperfiltration and worsening eGFR has not yet been demonstrated. (See 'Glomerular hyperfiltration' below.)

Glomerular hyperfiltration — Hyperfiltration can be defined at the level of the single nephron, wherein the ratio between GFR and effective RPF (ie, FF) is elevated due to either altered glomerular hemodynamics or glomerular damage with hypertrophy of remnant nephrons [5,6,17]. FF is difficult to measure in humans, and most studies of glomerular hyperfiltration have focused on "supraphysiologic" whole kidney GFR, generally defined as greater than two standard deviations above normal. Thus, glomerular hyperfiltration is usually defined between 120 and 140 mL/min/1.73 m2 [5]. There are shortcomings to ascribing a particular GFR cut point for hyperfiltration, including GFR differences by sex and race [18,19], but also variability in glomerular endowment, which can differ by nearly 10-fold [19,20]. Moreover, there is also significant intraindividual variability in GFR [21], which can be affected by transient physiologic states including hyperglycemia [22].

The prevalence of glomerular hyperfiltration depends partly on the duration of diabetes. Among cohorts with at least 100 participants with type 1 diabetes of less than 10 years duration and measured GFR, the prevalence of hyperfiltration ranges between 34 and 67 percent [5]. Duration of diabetes is more difficult to assess and is generally not provided in studies of type 2 diabetes cohorts; however, prevalence of hyperfiltration in larger cohorts (n≥100) with measured GFR ranges between 6 and 23 percent [5]. Reasons for the lower prevalence of hyperfiltration in type 2 versus type 1 diabetes may include older age and resultant glomerulosclerosis from hypertension and/or age-related senescence of the kidney.

Numerous studies have probed the association between glomerular hyperfiltration and clinical outcomes of worsening albuminuria and GFR decline; associations with incident albuminuria are conflicting for both type 1 and type 2 diabetes, with few factors explaining the heterogeneity [5]:

A meta-analysis of 10 studies of patients with type 1 diabetes and measured GFR found that hyperfiltration was associated with a higher risk of moderately or severely increased albuminuria at 11 years (odds ratio 2.7, 95 percent CI 1.2-6.1) [23].

In a post-hoc analysis of 600 clinical trial participants with type 2 diabetes and repeated measures of GFR before and after initiation of an angiotensin converting enzyme (ACE) inhibitor found that, of the participants with baseline hyperfiltration, only those with persistent hyperfiltration after ACE inhibitor initiation were at increased risk for developing albuminuria [24]. In addition, the annual rate of GFR decline in those with baseline hyperfiltration that was normalized by ACE inhibitor use was slower than in those patients who had had persistent hyperfiltration despite taking ACE inhibitors (2.4 versus 5.2 mL/min/1.73 m2).

These data support the hypothesis that normalization of whole kidney hyperfiltration may slow the rate of CKD progression. This is considered to be one of the primary mechanisms by which ACE inhibitors and angiotensin receptor blockers (ARBs) mitigate kidney disease, as they preferentially decrease arteriolar resistance in the efferent compared with afferent arteriole, thereby lowering glomerular pressure [25]. Complementary physiologic effects of SGLT2 inhibitors may explain why this newer class of antihyperglycemic agents is protective for diabetic kidney disease [26]. (See "Treatment of diabetic kidney disease".)

Innate immunity, oxidative stress, and inflammation — Innate immunity is an increasingly recognized contributor to the pathogenesis of diabetic kidney disease. Integral to the innate immunity are oxidative stress and inflammation (figure 2). Hyperglycemia as well as insulin resistance and dyslipidemia cause increased formation of AGE, which, upon binding to AGE receptors (RAGE) located on multiple cell types in the kidney, induces production of numerous cytokines (tumor necrosis factor [TNF], interleukin 6 (IL-6), IL-1beta) via activation of nuclear transcription factors, such as NF-kappaB [27,28]. A similar signaling pathway occurs via stimulation of toll-like receptors by exposure to hyperglycemia and damaged cellular components (as occurs with oxidative stress). Oxidative stress and inflammation are tightly intertwined, creating a vicious cycle wherein one process begets the other [3,29].

Macrophage infiltration is a hallmark of diabetic kidney disease, the magnitude of which correlates with worsening disease [30,31]. Macrophages can be recruited and activated by hyperglycemic stress, angiotensin II, oxidized low-density lipoproteins, AGE, and kidney injury molecule 1 [32]. The result is increased oxidative stress and production of injurious cytokines including transforming growth factor (TGF)-beta and platelet derived growth factor. Macrophages are also a rich source of TNF-alpha, a pleiotropic cytokine resulting in renal hypertrophy, podocyte and tubular epithelial cell injury, and the triggering of a cascade of other cytokines [31,33].

Hyperglycemia also results in increased shunting of glucose through non-glycolytic pathways such as the polyol pathway, which increases oxidative stress. Protein kinase C (PKC) is also activated by a hyperglycemic environment, resulting in decreased production of endothelial nitric oxide synthase (eNOS) and increased levels of the endothelin 1 and vascular endothelial growth factor (VEGF), which promotes endothelial instability and NF-kappaB stimulated cytokine production.

Mesangial cell hypertrophy and matrix accumulation, hallmarks of diabetic glomerulosclerosis, are mediated by the transforming growth factor-beta (TGF-beta) system [34,35]. TGF-beta production by the mesangial cell is activated by a hyperglycemic environment and angiotensin II and has been found to not only trigger glomerular extracellular mesangial matrix production but also to decrease the production of matrix metalloproteinases, which are responsible for keeping extracellular matrix in check through degradation [34]. A primary mediator of TGF-beta on mesangial expansion is connective tissue growth factor (CTGF); however, CTGF can also be directly stimulated by hyperglycemia, mechanical strain, and AGE [36].

Vascular proliferation and endothelial permeability are increased in diabetic kidney disease and are thought to be mediated by VEGF [37], particularly when accompanied by diabetes-induced downregulation of endothelial nitric oxide production [38]. Angiopoietins (ANGPT) are also important regulators of endothelial function, necessitating a balance between ANGPT1, which stabilizes the endothelium, and ANGPT2, which promotes endothelial proliferation [39]. The ratio of ANGPT2 to ANGPT1 is consistently elevated in both experimental models of diabetic kidney disease as well as from tissue specimens from human diabetic glomerulopathy.

Interstitial fibrosis and tubular atrophy (IFTA) — As diabetic kidney disease progresses, there is a clear relationship between the degree of interstitial fibrosis/tubular atrophy (IFTA) and decline in eGFR [40]. Hyperglycemia results in shunting of glucose through the hexosamine pathway and subsequently increased production of TGF-beta and plasminogen activator inhibitor 1 (PAI-1) [41]. Damage to the proximal tubular cell from AGE, angiotensin II, and albuminuria also results in increased TGF-beta with consequent conversion of pericytes into myofibroblasts (epithelial to mesenchymal transformation), infiltration of macrophages, and an excess of collagen and fibronectin deposition [1,42].

EPIDEMIOLOGY AND RISK FACTORS

Incidence and prevalence — Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States [43] and worldwide [44]. However, the true incidence and prevalence of CKD and kidney failure from diabetes is impossible to know, because kidney biopsies (the gold standard for diagnosis of diabetic kidney disease) are infrequently performed in patients with diabetes and CKD.

The burden of diabetic kidney disease is high, resulting in decreased quality of life and increased rates of disability and premature death [45]. Globally, the age-standardized incidence of diabetic kidney disease decreased by approximately 10 percent from 1990 to 2017; however, disability-adjusted life years and mortality increased over this period (by approximately 20 percent and 10 percent, respectively) [46]. Health care costs are also significantly increased in people with diabetic kidney disease [47].

Although the prevalence of diabetes in the United States has risen over the last 20 years from 6 to 10 percent, the proportion of people with diabetes who also have CKD has remained relatively stable (approximately 25 to 30 percent) [48]. However, the distribution of clinical manifestations of diabetic kidney disease has changed (see "Diabetic kidney disease: Manifestations, evaluation, and diagnosis") [48]:

The prevalence of persistent moderately to severely increased albuminuria (ie, a urine albumin-to-creatinine ratio ≥30 mg/g) in diabetic patients decreased from approximately 20 percent during the period from 1988 to 1994 to approximately 15 percent during the period from 2009 to 2014.

By contrast, the prevalence of decreased estimated glomerular filtration rate (eGFR), defined as an eGFR <60 mL/min/1.73 m2, increased from approximately 10 to 15 percent.

Despite the high prevalence of kidney disease among people with diabetes, CKD awareness is extremely poor even in the United States. Only 10 percent of people with stage 3 CKD (eGFR 30 to 59 mL/min/1.73 m2) are aware of their diagnosis; although this proportion is higher among people with stage 4 CKD (eGFR 15 to 29 mL/min/1.73 m2), less than 60 percent of patients overall are aware of their disease [43,49,50].

Diabetic kidney disease is a common cause of ESKD, but the incidence of ESKD among diabetic patients with CKD is relatively uncommon because most patients with diabetic kidney disease die before requiring kidney replacement therapy [51,52]. In the United States, more than 58,000 people have ESKD attributed to diabetes, accounting for nearly 50 percent of all patients with ESKD [43]. Worldwide, the annual incidence of ESKD attributed to diabetes is rising [53], perhaps due to greater overall survival. The incidence is increasing fastest in the African and Western Pacific regions and among lower-income groups. These data underscore the growing toll of diabetes on health and its disproportionate impact in underserved populations.

Type 1 versus type 2 diabetes — It is unclear whether the natural history and rate of progression of diabetic kidney disease differs according to diabetes type. In the vast majority of people with type 2 diabetes, disease onset is after the age of 40 years, and other factors such as age-related senescence of the kidney and hypertension can contribute to kidney function decline to varying degrees. In addition, type 2 diabetes can be asymptomatic for years, resulting in a delay in diagnosis; therefore, the true time of onset of the hyperglycemic exposure is usually unknown.

Few studies have directly compared rates of diabetic kidney disease according to diabetes type; in general, rates of albuminuria seem to be similar, but decreased eGFR is more common in patients with type 2 diabetes. A systematic review of studies with type 1 or type 2 diabetes and kidney disease found slightly higher annualized incidence rates of albuminuria among cohorts of type 2 (3.8 to 12.7 percent per year) compared with type 1 diabetes (1.3 to 3.8 percent per year) [54]. However, diabetes duration varied between the studies, potentially confounding the findings. A large population-based study in the United Kingdom found that, among those with preserved eGFR (≥60 mL/min/1.73 m2), the prevalence of increased albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) was similar (18 percent) in patients with type 1 and type 2 diabetes [55]. By contrast, the prevalence of decreased eGFR (<60 mL/min/1.73 m2) was less common in type 1 (14 percent) than in type 2 diabetes (25 percent).

The incidence of ESKD is variable and it is unknown if the rate differs according to diabetes type [56-58]. As an example, in one study of diabetic patients with albuminuria at baseline, the unadjusted incidence rates of ESKD were 18 and 47 cases per 1000 person-years in those with type 1 and type 2 diabetes, respectively [57]. Unadjusted mortality rates were also higher among patients with type 2 diabetes. However, after adjustment for age, sex, and baseline serum creatinine, there was no difference in ESKD or mortality risk by diabetes type.

By contrast, in a large registry of over one million patients, the incidence of ESKD was higher among type 1 compared with type 2 diabetes (1.9 versus 0.9 per 1000 person-years) [58]. The reasons why the rates of ESKD in this study were lower than in the previously mentioned study are unclear but may be due in part to a shorter diabetes duration at baseline.

Youth-onset type 2 diabetes — Although previously rare, type 2 diabetes among youth is now common and is a well-recognized result of the obesity pandemic [59]. Youth-onset type 2 diabetes appears to result in CKD complications earlier and with a more rapid rate of progression than in type 1 diabetes [60-62]. The SEARCH for Diabetes in Youth study, a longitudinal, cohort study of youth-onset type 1 and type 2 diabetes, found a higher prevalence of moderately increased albuminuria at eight years after diabetes diagnosis among participants with type 2 as compared with type 1 diabetes (20 versus 6 percent) [63]. Albuminuria was also more likely to progress and less likely to regress in those who had youth-onset type 2 as compared with type 1 diabetes. In another study, the incidence of ESKD at 16 years of diabetes duration was 2.3 percent among those with youth-onset type 2 diabetes (at a mean age of 30 years); by contrast, no individuals with youth-onset type 1 diabetes developed ESKD over the same follow-up period [61].

The more aggressive diabetic kidney disease course in youth-onset type 2 diabetes may be related to social determinants of health. African Americans, Hispanic individuals, and American Indians are disproportionately affected with youth-onset type 2 diabetes [59] and are at higher risk for diabetic kidney disease [43,64,65]. However, in the SEARCH study mentioned above, ancestry and ethnicity did not completely explain the difference in albuminuria between youth-onset type 2 and youth-onset type 1 diabetes [60]. (See 'Ancestry/ethnicity' below.)

Risk factors for diabetic kidney disease — Diabetic kidney disease is a complex disease with multiple phenotypes. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis".)

Given the heterogeneity of disease and distinct biological pathways at play at different stages of disease, it is not surprising that epidemiologic studies have not consistently identified the same risk factors for diabetic kidney disease. It is clear, however, that while there is a strong genetic basis for diabetic kidney disease, both modifiable and nonmodifiable environmental risk factors play an important role via direct tissue damage and indirect or epigenetic modification.

Age — Increasing age is directly related to the prevalence of diabetic kidney disease with decreased eGFR, rising from 8 percent in the 5th decade to 19 percent in the 6th decade and 35 percent in the 7th decade of life [66]. The incidence rate of diabetic ESKD is 142, 274, 368, and 329 cases per 100,000 among diabetic persons aged <45, 45 to 64, 65 to 74, and ≥75 years, respectively [67]. This is likely due in part to age-related senescence of the kidney, which can contribute to CKD of any cause [68], and which may explain a rise in the prevalence of normoalbuminuric (rather than albuminuric) diabetic kidney disease starting in the 5th decade [69]. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Nonalbuminuric diabetic kidney disease'.)

However, the primary reason for increases in diabetic kidney disease prevalence with age is the typically indolent course of diabetic kidney damage, requiring decades of exposure to diabetes for progressive kidney disease to manifest.

Ancestry/ethnicity — Compared with White populations, African American, Hispanic American, and American Indian populations have higher rates of albuminuria, decreased eGFR, and ESKD [43,70,71]. The highest rates of ESKD were historically among American Indians; however, with public health interventions, rates have declined significantly in this population [72]. Incidence rates of diabetic ESKD among African Americans, Hispanic Americans, and White Americans are estimated at 409, 307, and 266 cases per 100,000 diabetic persons; although these rates appear to be declining among White patients, this does not appear to be the case in underrepresented populations and may actually be rising among the Mexican-American population [48,67].

Sex — Both CKD in general and diabetic kidney disease in particular are more common in females [43]. However, compared with females, males have a significantly higher risk of progression from late-stage CKD to ESKD (hazard ratio [HR] 1.37, 95% CI 1.17-1.62) [73]. The reasons for greater CKD prevalence in females, but higher risk of progression in males, are uncertain, but differences in genetic architecture, sex hormone exposure, body composition (eg, muscle mass), and lifestyle factors (eg, smoking, obesity, physical activity, and diet) have been proposed as possible mediators.

Low socioeconomic status — The disparity in diabetic kidney disease among underrepresented populations is explained in large part by socioeconomic status, which is tightly intertwined with educational attainment. Albuminuria and decreased eGFR (<60mL/min/1.72 m2) is more common among individuals with lower education level, even after controlling for sociodemographic and clinical factors [74]. After controlling for self-reported race, the incidence rate of ESKD in one study was 4.5-fold higher among populations in which more than 25 percent lived below the poverty level as compared with populations in which fewer than 5 percent lived below the poverty level [75]. Socioeconomic status in people with type 1 diabetes is also associated with pathogenic factors involved in diabetic kidney disease, including glomerular hyperfiltration and levels of certain cytokines [76].

Mediators of the association between low socioeconomic status and diabetic kidney disease are numerous. Access to care is a substantial issue and results from barriers to health insurance coverage, financial constraints in out-of-pocket medical costs, lack of transportation to healthcare providers, decreased language and literacy skills, personal beliefs (eg, focus on living in the present rather than future, destiny is driven by fate), and distrust in medical providers [77,78]. At the community level, poorer neighborhoods are at greater risk of environmental exposures (lead paint or tainted water), have fewer healthy food options and open spaces for physical activity to mitigate obesity, are more likely to have unhealthy behaviors (smoking, alcohol, illicit drugs), and often have less access to healthcare, particularly in underserved areas.

Obesity — Even in the absence of diabetes, obesity leads to a form of secondary focal segmental glomerulosclerosis (FSGS), termed "obesity-related glomerulopathy (ORG)" [79]. Notably, approximately 40 percent of these patients have features of diabetic kidney disease (mesangial expansion, glomerular basement membrane thickening, and nodular glomerulosclerosis), even in the absence of diabetes [80]. Obesity is a significant risk factor for type 2 diabetes and can often accompany type 1 diabetes due to the rising prevalence of obesity in the general population [81]. As a result, ORG and diabetic kidney disease often coexist and share many clinical and pathogenic features such as glomerular hyperfiltration, progressive albuminuria, podocyte injury, and FSGS [82]. Obesity results in activation of the renin-angiotensin-aldosterone system (RAAS), causing increased sodium retention, activation of the sympathetic nervous system, and increased intraglomerular capillary pressure, exacerbating the same processes caused by diabetes and also resulting in glomerulosclerosis [4].

Visceral obesity has a greater association with incident and progressive diabetic kidney disease than general obesity [83], possibly due to increased adipocyte cytokine production. On the other hand, adiponectin production from adipocytes is reduced, resulting in reduced AMP-activated protein kinase (AMPK) activation and ultimately increased oxidative stress and podocyte injury [84]. There is also increased production of tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and leptin in obese individuals, which results in greater transforming growth factor (TGF)-beta production [85,86].

Smoking — Even in the absence of diabetes, smoking can result in nodular sclerosis of the kidney that is similar to diabetic glomerulosclerosis. In addition, smoking triggers many of the same pathogenic pathways that are active in diabetic kidney disease, such as endothelial dysfunction, oxidative stress, and inflammation [87]. (See 'Innate immunity, oxidative stress, and inflammation' above.)

Studies of smoking and diabetic kidney disease have yielded conflicting results, likely due to different study designs and specific definitions of smoking and diabetic kidney disease, although the majority report a higher risk of kidney disease among smokers [88-90]. As an example, in a meta-analysis of nine cohorts and more than 200,000 individuals, cigarette smoking was modestly associated with diabetic kidney disease, defined as moderately or severely increased albuminuria or an eGFR <60 mL/min/1.73 m2 (HR 1.07, 95% CI 1.01-1.13) [88].

Hyperglycemia — There is overwhelming evidence that glycemic control impacts the risk for incident and progressive diabetic kidney disease [91,92]. In addition, restoration of normal glycemic control with pancreatic transplantation in patients with type 1 diabetes can improve kidney disease in the long term [93,94]. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications" and 'Pathogenesis' above.)

Observational studies of both type 1 and type 2 diabetes have demonstrated that lower HbA1c levels are associated with reversal of hyperfiltration [95,96], increased albuminuria regression [97,98], reductions in worsening albuminuria [63,99,100], rapid eGFR decline [101,102], and the development of stage 3 CKD [103]. Such improvements can be observed, even in later stages of diabetic kidney disease, including severely increased albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) [103] and eGFR <60 mL/min/1.73 m2 [103].

Glycemic targets in patients with diabetes are discussed elsewhere. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus" and "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Glycemic targets' and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Treatment goals'.)

Hypertension — Blood pressure control is important to the pathogenesis and progression of diabetic kidney disease. Similar to the effect of hyperglycemia, there is a linear relationship between blood pressure and the risk for adverse kidney outcomes [104,105]. A systolic blood pressure greater than 140 mmHg has consistently been found to increase the risk for the development of severely increased albuminuria and stage 3 CKD [104]. A full discussion of randomized trials targeting different blood pressures can be found separately. (See "Treatment of hypertension in patients with diabetes mellitus".)

Genetic factors — Environmental factors may explain some of the disparities in diabetic kidney disease among African American, Hispanic American, and American Indian populations [106]. Familial clustering of diabetic kidney disease and diabetic ESKD has long been recognized [107], with heritability estimates ranging from 0.30 to 0.75 depending upon the population (eg, ancestry, ethnicity, diabetes type) and trait under study (eg, albuminuria, eGFR, ESKD) [108].

Despite the apparent heritability of diabetic kidney disease, the quest to identify genetic etiologies remains elusive. Several candidate genes were initially implicated in the susceptibility and progression of diabetic kidney disease, but subsequent studies failed to replicate the findings [109]. Several large genome-wide association studies identified genes and gene regions for various diabetic kidney disease phenotypes in both type 1 and type 2 diabetes [110-113]; however, few loci were replicated among these studies. Overlapping, yet distinct, biologic pathways are active at various stages of diabetic kidney disease progression, which complicates genetic analyses. In addition, diabetic kidney disease is a highly heterogeneous disease. As such, studies based upon the assumption that people with diabetic kidney disease have a homogenous disease are likely to fail to identify a genetic basis for disease.

The apolipoprotein 1 (APOL1) gene has been found to explain much of the disparity in nondiabetic ESKD among Black individuals but has not born out as a causative factor for diabetic kidney disease [114]. However, APOL1 variants are associated with an increased risk for progression of diabetic kidney disease in Black patients. (See "Epidemiology of chronic kidney disease".)

Acute kidney injury — Diabetes, particularly if accompanied by diabetic kidney disease, is a risk factor for various types of acute kidney injury (AKI) [115,116]. Conversely, AKI is increasingly recognized as a risk factor for CKD due to maladaptive repair processes that become chronic. In diabetic kidney disease, these AKI-induced injuries involve the podocyte and endothelium of the glomerulus and induce myofibroblast transformation of tubular cells. As a result, both the glomerulopathy and tubulointerstitial fibrosis associated with diabetic kidney disease may be accelerated by AKI.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient education: Diabetic kidney disease (Beyond the Basics)")

SUMMARY

Diabetic kidney disease is a complex and heterogeneous disease with numerous overlapping etiologic pathways. Hyperglycemia results in production of advanced glycation end-products (AGE) and reactive oxygen species. While hyperglycemia undoubtedly plays a central role, hyperinsulinemia and insulin resistance also may incite pathogenic mechanisms, possibly accounting for variation in histopathology between type 1 and type 2 diabetes. Ultimately, alterations in glomerular hemodynamics, inflammation, and fibrosis are primary mediators of kidney tissue damage (figure 1), although the relative contribution of these mechanisms likely varies between individuals and over the course of the natural history of diabetic kidney disease. (See 'Glomerular hemodynamics' above and 'Innate immunity, oxidative stress, and inflammation' above and 'Interstitial fibrosis and tubular atrophy (IFTA)' above.)

Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States and worldwide. The proportion of people with diabetes who also have CKD has remained relatively stable (approximately 25 to 30 percent) over the past 20 years, although the distribution of clinical manifestations of diabetic kidney disease has changed. The prevalence of persistent albuminuria is declining, but the prevalence of decreased estimated glomerular filtration rate (eGFR) is rising. (See 'Incidence and prevalence' above.)

It is unclear whether the natural history and rate of progression of diabetic kidney disease differs according to diabetes type. In the vast majority of people with type 2 diabetes, disease onset is after the age of 40 years, and other factors such as age-related senescence of the kidney and hypertension can participate in kidney function decline to varying degrees. In addition, type 2 diabetes can be asymptomatic for years, resulting in a delay in diagnosis; therefore, the true time of onset of the hyperglycemic exposure is usually unknown. (See 'Type 1 versus type 2 diabetes' above.)

Although previously rare, type 2 diabetes among youth is now common and is a well-recognized result of the obesity pandemic. Youth-onset type 2 diabetes appears to result in CKD complications earlier and with a more rapid rate of progression than with youth-onset type 1 diabetes. (See 'Youth-onset type 2 diabetes' above.)

Among patients with diabetes, risk factors for diabetic kidney disease include older age, African American or American Indian ancestry, Hispanic ethnicity, low socioeconomic status, obesity, smoking, poor glycemic and blood pressure control, and genetic factors. (See 'Risk factors for diabetic kidney disease' above.)

  1. Vallon V, Komers R. Pathophysiology of the diabetic kidney. Compr Physiol 2011; 1:1175.
  2. Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002; 288:2579.
  3. Pichler R, Afkarian M, Dieter BP, Tuttle KR. Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets. Am J Physiol Renal Physiol 2017; 312:F716.
  4. Hostetter TH. Hyperfiltration and glomerulosclerosis. Semin Nephrol 2003; 23:194.
  5. Tonneijck L, Muskiet MH, Smits MM, et al. Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol 2017; 28:1023.
  6. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol 2012; 8:293.
  7. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int 1996; 49:1774.
  8. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380:2295.
  9. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375:323.
  10. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380:347.
  11. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644.
  12. van Bommel EJM, Lytvyn Y, Perkins BA, et al. Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function. Kidney Int 2020; 97:631.
  13. Dekkers CCJ, Wheeler DC, Sjöström CD, et al. Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b-4 chronic kidney disease. Nephrol Dial Transplant 2018; 33:2005.
  14. Bakris GL. Major Advancements in Slowing Diabetic Kidney Disease Progression: Focus on SGLT2 Inhibitors. Am J Kidney Dis 2019; 74:573.
  15. Kraus BJ, Weir MR, Bakris GL, et al. Characterization and implications of the initial estimated glomerular filtration rate 'dip' upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial. Kidney Int 2021; 99:750.
  16. Hill JV, Findon G, Appelhoff RJ, Endre ZH. Renal autoregulation and passive pressure-flow relationships in diabetes and hypertension. Am J Physiol Renal Physiol 2010; 299:F837.
  17. Hostetter TH. Diabetic nephropathy. Metabolic versus hemodynamic considerations. Diabetes Care 1992; 15:1205.
  18. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012; 367:20.
  19. Denic A, Mathew J, Lerman LO, et al. Single-Nephron Glomerular Filtration Rate in Healthy Adults. N Engl J Med 2017; 376:2349.
  20. Hoy WE, Douglas-Denton RN, Hughson MD, et al. A stereological study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int Suppl 2003; :S31.
  21. Kwong YT, Stevens LA, Selvin E, et al. Imprecision of urinary iothalamate clearance as a gold-standard measure of GFR decreases the diagnostic accuracy of kidney function estimating equations. Am J Kidney Dis 2010; 56:39.
  22. Cherney DZ, Sochett EB, Dekker MG, Perkins BA. Ability of cystatin C to detect acute changes in glomerular filtration rate provoked by hyperglycaemia in uncomplicated Type 1 diabetes. Diabet Med 2010; 27:1358.
  23. Magee GM, Bilous RW, Cardwell CR, et al. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia 2009; 52:691.
  24. Ruggenenti P, Porrini EL, Gaspari F, et al. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 2012; 35:2061.
  25. Ibrahim HN, Rosenberg ME, Hostetter TH. Role of the renin-angiotensin-aldosterone system in the progression of renal disease: a critical review. Semin Nephrol 1997; 17:431.
  26. Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 2018; 94:26.
  27. Bierhaus A, Humpert PM, Morcos M, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005; 83:876.
  28. Tang SCW, Yiu WH. Innate immunity in diabetic kidney disease. Nat Rev Nephrol 2020; 16:206.
  29. Hojs R, Ekart R, Bevc S, Hojs N. Markers of Inflammation and Oxidative Stress in the Development and Progression of Renal Disease in Diabetic Patients. Nephron 2016; 133:159.
  30. Nguyen D, Ping F, Mu W, et al. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology (Carlton) 2006; 11:226.
  31. Tesch GH. Macrophages and diabetic nephropathy. Semin Nephrol 2010; 30:290.
  32. Humphreys BD, Xu F, Sabbisetti V, et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 2013; 123:4023.
  33. Awad AS, You H, Gao T, et al. Macrophage-derived tumor necrosis factor-α mediates diabetic renal injury. Kidney Int 2015; 88:722.
  34. Border WA, Brees D, Noble NA. Transforming growth factor-beta and extracellular matrix deposition in the kidney. Contrib Nephrol 1994; 107:140.
  35. Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A 2000; 97:8015.
  36. Riser BL, Denichilo M, Cortes P, et al. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol 2000; 11:25.
  37. Cooper ME, Vranes D, Youssef S, et al. Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 1999; 48:2229.
  38. Nakagawa T, Sato W, Kosugi T, Johnson RJ. Uncoupling of VEGF with endothelial NO as a potential mechanism for abnormal angiogenesis in the diabetic nephropathy. J Diabetes Res 2013; 2013:184539.
  39. Gnudi L. Angiopoietins and diabetic nephropathy. Diabetologia 2016; 59:1616.
  40. An Y, Xu F, Le W, et al. Renal histologic changes and the outcome in patients with diabetic nephropathy. Nephrol Dial Transplant 2015; 30:257.
  41. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005; 54:1615.
  42. Bonventre JV. Can we target tubular damage to prevent renal function decline in diabetes? Semin Nephrol 2012; 32:452.
  43. United States Renal Data System. USRDS 2018 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, editor, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 2017.
  44. International Diabetes Federation. IDF Diabetes Atlas. International Diabetes Federation, editor, Brussels, Belgium 2017.
  45. Wyld MLR, Morton RL, Aouad L, et al. The impact of comorbid chronic kidney disease and diabetes on health-related quality-of-life: a 12-year community cohort study. Nephrol Dial Transplant 2021; 36:1048.
  46. Li H, Lu W, Wang A, et al. Changing epidemiology of chronic kidney disease as a result of type 2 diabetes mellitus from 1990 to 2017: Estimates from Global Burden of Disease 2017. J Diabetes Investig 2021; 12:346.
  47. Nichols GA, Ustyugova A, Déruaz-Luyet A, et al. Health Care Costs by Type of Expenditure across eGFR Stages among Patients with and without Diabetes, Cardiovascular Disease, and Heart Failure. J Am Soc Nephrol 2020; 31:1594.
  48. Afkarian M, Zelnick LR, Hall YN, et al. Clinical Manifestations of Kidney Disease Among US Adults With Diabetes, 1988-2014. JAMA 2016; 316:602.
  49. Duru OK, Middleton T, Tewari MK, Norris K. The Landscape of Diabetic Kidney Disease in the United States. Curr Diab Rep 2018; 18:14.
  50. Chu CD, McCulloch CE, Banerjee T, et al. CKD Awareness Among US Adults by Future Risk of Kidney Failure. Am J Kidney Dis 2020; 76:174.
  51. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013; 24:302.
  52. Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380:1662.
  53. Cheng HT, Xu X, Lim PS, Hung KY. Worldwide Epidemiology of Diabetes-Related End-Stage Renal Disease, 2000-2015. Diabetes Care 2021; 44:89.
  54. Koye DN, Shaw JE, Reid CM, et al. Incidence of chronic kidney disease among people with diabetes: a systematic review of observational studies. Diabet Med 2017; 34:887.
  55. Hill CJ, Cardwell CR, Patterson CC, et al. Chronic kidney disease and diabetes in the national health service: a cross-sectional survey of the U.K. national diabetes audit. Diabet Med 2014; 31:448.
  56. Cusick M, Chew EY, Hoogwerf B, et al. Risk factors for renal replacement therapy in the Early Treatment Diabetic Retinopathy Study (ETDRS), Early Treatment Diabetic Retinopathy Study Report No. 26. Kidney Int 2004; 66:1173.
  57. Hadjadj S, Cariou B, Fumeron F, et al. Death, end-stage renal disease and renal function decline in patients with diabetic nephropathy in French cohorts of type 1 and type 2 diabetes. Diabetologia 2016; 59:208.
  58. Koye DN, Magliano DJ, Reid CM, et al. Trends in Incidence of ESKD in People With Type 1 and Type 2 Diabetes in Australia, 2002-2013. Am J Kidney Dis 2019; 73:300.
  59. Mayer-Davis EJ, Lawrence JM, Dabelea D, et al. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012. N Engl J Med 2017; 376:1419.
  60. Dabelea D, Stafford JM, Mayer-Davis EJ, et al. Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood. JAMA 2017; 317:825.
  61. Dart AB, Sellers EA, Martens PJ, et al. High burden of kidney disease in youth-onset type 2 diabetes. Diabetes Care 2012; 35:1265.
  62. Krakoff J, Lindsay RS, Looker HC, et al. Incidence of retinopathy and nephropathy in youth-onset compared with adult-onset type 2 diabetes. Diabetes Care 2003; 26:76.
  63. Kahkoska AR, Isom S, Divers J, et al. The early natural history of albuminuria in young adults with youth-onset type 1 and type 2 diabetes. J Diabetes Complications 2018; 32:1160.
  64. Hsu CY, Lin F, Vittinghoff E, Shlipak MG. Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States. J Am Soc Nephrol 2003; 14:2902.
  65. Derose SF, Rutkowski MP, Crooks PW, et al. Racial differences in estimated GFR decline, ESRD, and mortality in an integrated health system. Am J Kidney Dis 2013; 62:236.
  66. Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System - United States 2018 [June 19, 2019]. Available from: http://www.cdc.gov/ckd.
  67. Burrows NR, Li Y, Geiss LS. Incidence of treatment for end-stage renal disease among individuals with diabetes in the U.S. continues to decline. Diabetes Care 2010; 33:73.
  68. Denic A, Glassock RJ, Rule AD. Structural and Functional Changes With the Aging Kidney. Adv Chronic Kidney Dis 2016; 23:19.
  69. Mottl AK, Kwon KS, Mauer M, et al. Normoalbuminuric diabetic kidney disease in the U.S. population. J Diabetes Complications 2013; 27:123.
  70. Bryson CL, Ross HJ, Boyko EJ, Young BA. Racial and ethnic variations in albuminuria in the US Third National Health and Nutrition Examination Survey (NHANES III) population: associations with diabetes and level of CKD. Am J Kidney Dis 2006; 48:720.
  71. Narres M, Claessen H, Droste S, et al. The Incidence of End-Stage Renal Disease in the Diabetic (Compared to the Non-Diabetic) Population: A Systematic Review. PLoS One 2016; 11:e0147329.
  72. Pavkov ME, Knowler WC, Bennett PH, et al. Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians. Kidney Int 2006; 70:1840.
  73. Tsai WC, Wu HY, Peng YS, et al. Risk Factors for Development and Progression of Chronic Kidney Disease: A Systematic Review and Exploratory Meta-Analysis. Medicine (Baltimore) 2016; 95:e3013.
  74. Choi AI, Weekley CC, Chen SC, et al. Association of educational attainment with chronic disease and mortality: the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2011; 58:228.
  75. Volkova N, McClellan W, Klein M, et al. Neighborhood poverty and racial differences in ESRD incidence. J Am Soc Nephrol 2008; 19:356.
  76. Cummings LAM, Clarke A, Sochett E, et al. Social Determinants of Health Are Associated with Markers of Renal Injury in Adolescents with Type 1 Diabetes. J Pediatr 2018; 198:247.
  77. McClellan WM, Casey MT, Hughley J, Freund E. Population-based interventions to reduce socioeconomic disparities in chronic kidney disease. Semin Nephrol 2010; 30:33.
  78. Nicholas SB, Kalantar-Zadeh K, Norris KC. Socioeconomic disparities in chronic kidney disease. Adv Chronic Kidney Dis 2015; 22:6.
  79. D'Agati VD, Chagnac A, de Vries AP, et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol 2016; 12:453.
  80. Choung HG, Bomback AS, Stokes MB, et al. The spectrum of kidney biopsy findings in patients with morbid obesity. Kidney Int 2019; 95:647.
  81. Corbin KD, Driscoll KA, Pratley RE, et al. Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact, and Mechanisms. Endocr Rev 2018; 39:629.
  82. Bayliss G, Weinrauch LA, D'Elia JA. Pathophysiology of obesity-related renal dysfunction contributes to diabetic nephropathy. Curr Diab Rep 2012; 12:440.
  83. Hu J, Yang S, Zhang A, et al. Abdominal Obesity Is More Closely Associated With Diabetic Kidney Disease Than General Obesity. Diabetes Care 2016; 39:e179.
  84. Sharma K, Ramachandrarao S, Qiu G, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008; 118:1645.
  85. Wolf G, Ziyadeh FN. Leptin and renal fibrosis. Contrib Nephrol 2006; 151:175.
  86. Aroor AR, McKarns S, Demarco VG, et al. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism 2013; 62:1543.
  87. Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol 2014; 34:509.
  88. Liao D, Ma L, Liu J, Fu P. Cigarette smoking as a risk factor for diabetic nephropathy: A systematic review and meta-analysis of prospective cohort studies. PLoS One 2019; 14:e0210213.
  89. Feodoroff M, Harjutsalo V, Forsblom C, et al. Smoking and progression of diabetic nephropathy in patients with type 1 diabetes. Acta Diabetol 2016; 53:525.
  90. Zitt E, Pscheidt C, Concin H, et al. Anthropometric and Metabolic Risk Factors for ESRD Are Disease-Specific: Results from a Large Population-Based Cohort Study in Austria. PLoS One 2016; 11:e0161376.
  91. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977.
  92. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405.
  93. Fioretto P, Sutherland DE, Najafian B, Mauer M. Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients. Kidney Int 2006; 69:907.
  94. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339:69.
  95. Tuttle KR, Bruton JL, Perusek MC, et al. Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N Engl J Med 1991; 324:1626.
  96. Tuttle KR, Bruton JL. Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes. Kidney Int 1992; 42:167.
  97. Perkins BA, Ficociello LH, Silva KH, et al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003; 348:2285.
  98. Gaede P, Tarnow L, Vedel P, et al. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria. Nephrol Dial Transplant 2004; 19:2784.
  99. de Boer IH, Rue TC, Cleary PA, et al. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med 2011; 171:412.
  100. Retnakaran R, Cull CA, Thorne KI, et al. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 2006; 55:1832.
  101. Skupien J, Warram JH, Smiles AM, et al. The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease. Kidney Int 2012; 82:589.
  102. Zoppini G, Targher G, Chonchol M, et al. Predictors of estimated GFR decline in patients with type 2 diabetes and preserved kidney function. Clin J Am Soc Nephrol 2012; 7:401.
  103. de Boer IH, Afkarian M, Rue TC, et al. Renal outcomes in patients with type 1 diabetes and macroalbuminuria. J Am Soc Nephrol 2014; 25:2342.
  104. Ku E, McCulloch CE, Mauer M, et al. Association Between Blood Pressure and Adverse Renal Events in Type 1 Diabetes. Diabetes Care 2016; 39:2218.
  105. Rossing K, Christensen PK, Hovind P, et al. Progression of nephropathy in type 2 diabetic patients. Kidney Int 2004; 66:1596.
  106. Lipworth L, Mumma MT, Cavanaugh KL, et al. Incidence and predictors of end stage renal disease among low-income blacks and whites. PLoS One 2012; 7:e48407.
  107. Seaquist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989; 320:1161.
  108. Satko SG, Sedor JR, Iyengar SK, Freedman BI. Familial clustering of chronic kidney disease. Semin Dial 2007; 20:229.
  109. Williams WW, Salem RM, McKnight AJ, et al. Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy. Diabetes 2012; 61:2187.
  110. Guan M, Keaton JM, Dimitrov L, et al. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans. Hum Genomics 2019; 13:21.
  111. Iyengar SK, Sedor JR, Freedman BI, et al. Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND). PLoS Genet 2015; 11:e1005352.
  112. Sandholm N, Salem RM, McKnight AJ, et al. New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet 2012; 8:e1002921.
  113. van Zuydam NR, Ahlqvist E, Sandholm N, et al. A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes. Diabetes 2018; 67:1414.
  114. Kruzel-Davila E, Wasser WG, Aviram S, Skorecki K. APOL1 nephropathy: from gene to mechanisms of kidney injury. Nephrol Dial Transplant 2016; 31:349.
  115. Zuk A, Bonventre JV. Recent advances in acute kidney injury and its consequences and impact on chronic kidney disease. Curr Opin Nephrol Hypertens 2019; 28:397.
  116. Yu SM, Bonventre JV. Acute Kidney Injury and Progression of Diabetic Kidney Disease. Adv Chronic Kidney Dis 2018; 25:166.
Topic 3103 Version 38.0

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