Diabetic kidney disease: Pathogenesis and epidemiology

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, insulin resistance, and lipotoxicity also may incite pathogenic mechanisms, possibly accounting for variation in histopathology between type 1 and type 2 diabetes [4]. (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) [5]. 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 [6,7]." (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 [8]. Increased circulating and local 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 [6,7]. By contrast, an increase in circulating and local 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 [5].

Tubular function also has an impact on glomerular hemodynamics, via tubuloglomerular feedback [1]. Diabetes is associated with a decrease in sodium, chloride, and solute 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, sodium, and chloride is increased in relatively moderate hyperglycemia (>180 mg/dL), resulting in decreased solute delivery to the macula densa portion of the distal tubule. Consequently, afferent arteriolar tone is reduced, 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 [9-11]. This effect is presumably due, sequentially, to decreased reabsorption of sodium and chloride along with glucose in the proximal tubule, thereby increasing distal delivery of solutes to the macula densa, restoration of tubuloglomerular feedback, and a reduction in glomerular hyperfiltration [12]. The initial decrease in eGFR after SGLT2 inhibition also occurs in those with low eGFR, and, ultimately, the rate of eGFR decline is slowed over time regardless of eGFR at initiation [13-16].

Further exacerbation of glomerular hyperfiltration also occurs in diabetes due to impaired autoregulatory responses of the afferent arterioles to fluctuations in blood pressure [17]. Thus, increases in blood pressure, which would result in protective increases in vascular tone under normal physiological circumstances, are transmitted along to glomerular capillaries in diabetes.

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 eGFR and worsening albuminuria [6], although a direct link between hyperfiltration and worsening albuminuria is more difficult to demonstrate, in part due to the long duration of follow-up that is required to observe such changes. (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 [6,7,18]. 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, depending on age [6]. There are shortcomings to ascribing a particular GFR cut point for hyperfiltration, including GFR differences by sex and age [19,20], but also variability in glomerular endowment, which can differ by nearly 10-fold [19,21]. Moreover, there is also significant intraindividual variability in GFR [22], which can be affected by transient physiologic states including hyperglycemia and hyperaminoacidemia, such as occurs after protein feeding [23-25].

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 [6]. 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 [6]. 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 worsening albuminuria, with most demonstrating a positive association [6]:

●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) [26].

●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 [27]. 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).

Few studies have examined the association of glomerular hyperfiltration with eGFR decline, and none included endpoints such as end-stage kidney disease (ESKD) or death attributed to kidney disease. As an example, in a study of 646 patients with type 1 diabetes followed for six years, baseline hyperfiltration (defined as eGFR ≥120 mL/min/1.73 m²) was associated with both rapid eGFR decline, defined as loss of ≥3 mL/min/1.73m² per year (odds ratio 5.0, 95% CI 3.0-8.3) and the incidence of an eGFR <60 mL/min/1.73 m² (odds ratio 16.0, 95% CI 2.3-114) [28].

These data support the hypothesis that normalization of whole kidney hyperfiltration may slow the rate of chronic kidney disease (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 [29]. Complementary physiologic effects of SGLT2 inhibitors may explain why this class of antihyperglycemic agents is also protective for diabetic kidney disease [30]. (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 [31,32]. 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 via multiple mediators [3,33,34].

Macrophage infiltration is a hallmark of diabetic kidney disease, the magnitude of which correlates with worsening disease [35,36]. Macrophages can be recruited and activated by hyperglycemic stress, angiotensin II, oxidized low-density lipoproteins, AGE, and kidney injury molecule 1 [37]. 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 kidney hypertrophy, podocyte and tubular epithelial cell injury, and the triggering of a cascade of other cytokines [36,38].

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 [39,40]. 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 [39]. 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 [41].

Vascular proliferation and endothelial permeability are increased in diabetic kidney disease and are thought to be mediated by VEGF [42], particularly when accompanied by diabetes-induced downregulation of endothelial nitric oxide production [43]. Angiopoietins (ANGPT) are also important regulators of endothelial function, necessitating a balance between ANGPT1, which stabilizes the endothelium, and ANGPT2, which promotes endothelial proliferation [44]. 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 [45]. Hyperglycemia results in shunting of glucose through the hexosamine pathway and subsequently increased production of TGF-beta and plasminogen activator inhibitor 1 (PAI-1) [46]. 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 [1,47].

EPIDEMIOLOGY AND RISK FACTORS

Incidence and prevalence — Diabetes is the leading ascribed cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States [48] and worldwide [49]. However, the true incidence and prevalence of diabetic kidney disease, CKD attributable to diabetes per se, is not clear, because kidney biopsies (the gold standard for diagnosis of diabetic kidney disease) are infrequently performed in patients with diabetes and CKD.

Nevertheless, the overall burden of diabetic kidney disease is high, resulting in decreased quality of life and increased rates of disability and premature death [50]. 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) [51]. Health care costs are also significantly increased in people with diabetic kidney disease [52].

Although the prevalence of diabetes in the United States has risen over the last 20 years from 6 to 11 percent, the proportion of people with diabetes who also have CKD has remained relatively stable (approximately 25 to 30 percent) [53]. However, the distribution of clinical manifestations of diabetic kidney disease has changed over time. (see "Diabetic kidney disease: Manifestations, evaluation, and diagnosis") [53]:

●The prevalence of persistent moderately to severely increased albuminuria (ie, a urine albumin-to-creatinine ratio ≥30 mg/g) in patients with diabetes 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 low 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 [48,54,55].

The prevalence of ESKD more than doubled from 2000 to 2019 to nearly 800,000 people, primarily driven by diabetes [56]. As of 2019, more than 307,000 people in the United States had ESKD primarily attributed to diabetes, accounting for nearly 40 percent of all patients with ESKD [56]. However, most people with diabetes and CKD die before requiring kidney replacement therapy [57-59].

Worldwide, the annual incidence of ESKD attributed to diabetes is rising [60]. 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) [61]. 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 [62]. 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 [63-65]. As an example, in one study of people with diabetes and 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 [64]. 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) [65]. 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 less recognized, type 2 diabetes among youth is common and is a result of the obesity pandemic [66]. 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 [67-69]. 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) [70]. 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 [68].

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 [66] and are at higher risk for diabetic kidney disease [48,71,72]. 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 [67]. (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 risk factors for diabetic kidney disease. It is clear, however, that while there is a genetic predisposition 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 5^th decade to 19 percent in the 6^th decade and 35 percent in the 7^th decade of life [73]. 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 [74]. This may be due to age-related senescence of the kidney, which can contribute to CKD of any cause [75], and which may explain a rise in the prevalence of normoalbuminuric (rather than albuminuric) diabetic kidney disease starting in the 5^th decade [76]. (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 [48,77,78]. The highest rates of ESKD were historically among American Indians; however, with public health interventions, rates have declined significantly in this population [79]. 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 may be declining among White patients, this does not appear to be the case in other populations and may actually be rising among the Mexican American population [53,74].

Sex — Males are more likely to develop CKD in diabetes and have significantly higher risk of progression from late-stage CKD to ESKD (hazard ratio [HR] 1.37, 95% CI 1.17-1.62) [80,81]. Differences in genetic architecture, sex hormones, body composition (eg, muscle mass), and lifestyle factors (eg, smoking, obesity, physical activity, and diet) have been proposed as possible mediators for different CKD risks in males and females with diabetes.

Low socioeconomic status — The disparity in diabetic kidney disease among disadvantaged populations is explained in large part by social determinants of health. Albuminuria and decreased eGFR (<60 mL/min/1.72 m²) is more common among individuals with lower education level, even after controlling for other social, demographic, and clinical factors [82]. After controlling for self-identified 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 [83]. 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 various cytokines [84].

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 [85,86]. 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 health care.

Obesity — Even in the absence of diabetes, obesity may lead to secondary focal segmental glomerulosclerosis (FSGS), termed "obesity-related glomerulopathy (ORG)" [87]. Notably, approximately 40 percent of these patients without diabetes have features of diabetic kidney disease (mesangial expansion, glomerular basement membrane thickening, and nodular glomerulosclerosis) [88]. Obesity is a significant risk factor for type 2 diabetes and can often accompany type 1 diabetes [89]. 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 [90]. 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 similar processes caused by diabetes and also resulting in glomerulosclerosis [5].

Visceral obesity has a greater association with incident and progressive diabetic kidney disease than general obesity [91], 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 [92]. 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 [93,94].

Smoking — Smoking can result in nodular sclerosis of the kidney that is similar to diabetic glomerulosclerosis irrespective of diabetes status. 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 [95]. (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 [96-98]. 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) [96].

Hyperglycemia — There is overwhelming evidence that glycemic control impacts the risk for incident and progressive diabetic kidney disease [99,100]. In addition, restoration of normal glycemic control with pancreatic transplantation in patients with type 1 diabetes can improve kidney disease, including resolution of structural damage, in the long term [101,102]. (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 [24,25], increased albuminuria regression [103,104], reductions in worsening albuminuria [70,105,106], rapid eGFR decline [107,108], and the development of stage 3 CKD [109]. 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) [109] and eGFR <60 mL/min/1.73 m² [109].

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 [110,111]. 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 [110]. 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 [112]. Familial clustering of diabetic kidney disease and diabetic ESKD has long been recognized [113], 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) [114].

The quest to identify specific genetic etiologies of diabetic kidney disease has been challenging. Several candidate genes were initially implicated in the susceptibility and progression of diabetic kidney disease, but subsequent studies failed to replicate the findings [115]. 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 [116-119]; however, consistent associations for only a few loci were replicated in subsequent studies.

Complex conditions, particularly "diseases within diseases," like development of kidney disease in diabetes, present major challenges for deciphering genetic associations [120,121]. However, genome-wide association studies using large data sets have yielded insights about genetic predisposition to diabetic kidney disease. As an example, one variant in the Col4A3 gene (the same gene associated with Alport syndrome) was associated with protection from clinical diabetic kidney disease in individuals with type 1 diabetes; in the subset who underwent kidney biopsy, this variant was also associated with less severe glomerular pathology. Variants in other genes related to collagen pathophysiology and kidney fibrosis (DDR1, COLEC11, BMP7) are, similarly, associated with various phenotypes of diabetic kidney disease.

The apolipoprotein 1 (APOL1) gene explains much of the disparity in nondiabetic ESKD among Black individuals but has not born out as a causative factor for diabetic kidney disease [122]. 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) [123,124]. 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" and "Society guideline links: Diabetic kidney disease".)

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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

●Pathogenesis – 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.)

●Epidemiology – Diabetes is the leading cause of chronic kidney disease (CKD) 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), 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.)

Type 2 diabetes among youth is common and another 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.)