Diabetic Kidney Disease - Pathogenesis and Epidemiology - UpToDate

18/4/2021 Diabetic kidney disease: Pathogenesis and epidemiology - UpToDate
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Enfermedad renal diabética: patogenia y epidemiología

Autores: Amy K Mottl, doctora en Medicina, Katherine R Tuttle, MD, FASN, FACP, FNKF
Editor de sección: Dr. George L Bakris
Editor adjunto: John P Forman, MD, MSc
Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de revisión por
pares .
Revisión de literatura vigente hasta: marzo de 2021. | Este tema se actualizó por última vez: 19 de agosto de 2019.
INTRODUCCIÓN
La diabetes es la principal causa de enfermedad renal crónica (ERC) y enfermedad renal en etapa
terminal (ERT) en los Estados Unidos y en todo el mundo. La enfermedad renal diabética es una
enfermedad compleja y heterogénea con numerosas vías etiológicas superpuestas que incluyen
cambios en la hemodinámica glomerular, estrés oxidativo e inflamación, fibrosis intersticial y atrofia
tubular.
Aquí se revisan la patogenia y la epidemiología de la enfermedad renal diabética. Otros temas discuten
los siguientes temas:
● Manifestaciones, evaluación y diagnóstico de la enfermedad renal diabética (consulte "Enfermedad

renal diabética: manifestaciones, evaluación y diagnóstico" )
● Tratamiento de la enfermedad renal diabética (ver "Tratamiento de la enfermedad renal diabética" )
● Manejo de la hipertensión en pacientes con diabetes (ver "Tratamiento de la hipertensión en

pacientes con diabetes mellitus" )
PATOGÉNESIS
La enfermedad renal diabética es una enfermedad compleja y heterogénea con numerosas vías
etiológicas superpuestas [ 1 ]. La hiperglucemia da como resultado la producción de productos finales
de glicación avanzada (AGE) y especies reactivas de oxígeno. Estos productos metabólicos aberrantes
activan la señalización intercelular para la expresión génica proinflamatoria y profibrótica con la
producción de una serie de mediadores para la lesión celular ( Figura 1) [ 2,3 ]. Si bien la
hiperglucemia indudablemente juega un papel central, la hiperinsulinemia y la resistencia a la insulina
también pueden incitar mecanismos patogénicos, posiblemente explicando la variación en la
histopatología entre la diabetes tipo 1 y la tipo 2. (Consulte "Enfermedad renal diabética:
manifestaciones, evaluación y diagnóstico", sección sobre "Manifestaciones y diagnóstico" y
"Enfermedad renal diabética: manifestaciones, evaluación y diagnóstico", sección sobre "Historia
natural" ).
https://www.uptodate.com/contents/diabetic-kidney-disease-pathogenesis-and-epidemiology/print?search=nefropatia diabetic&source=search_r… 1/20
En última instancia, las alteraciones de la hemodinámica glomerular, la inflamación y la fibrosis son los
principales mediadores del daño del tejido renal, aunque la contribución relativa de estos mecanismos
probablemente varía entre individuos y durante el curso de la evolución natural de la nefropatía
diabética.
Hemodinámica glomerular : el medio diabético activa el sistema renina-angiotensina-aldosterona

(RAAS) y muchos otros mediadores posteriores, lo que desencadena la hipertrofia renal, el aumento del
flujo plasmático renal (FPR) y el aumento de la fracción de filtración (FF), que en conjunto dan como
resultado una elevación anormal tasa de filtración glomerular (TFG) ( Figura 2) [ 4 ]. En las primeras
etapas de la diabetes, aumentan la "TFG de todo el riñón" y la "TFG de nefrona única (SNGFR)". Estos
estados a menudo se denominan "hiperfiltración glomerular [ 5 , 6 ]". (Ver 'Hiperfiltración glomerular' a
continuación).
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 renal 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]. Although this small,
initial decrease in eGFR after SGLT2 inhibition is not observed among those with an eGFR <45
mL/min/1.73 m2, these drugs nevertheless slow CKD progression in this population [13,14].
Further exacerbation of glomerular hyperfiltration also occurs in diabetes due to impaired

autoregulatory responses of the afferent arterioles to fluctuations in blood pressure [15]. 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 [5,6,16]. 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 [17,18], but also variability in glomerular endowment, which can differ by nearly 10-fold [18,19].
Moreover, there is also significant intraindividual variability in GFR [20], which can be affected by
transient physiologic states including hyperglycemia [21].
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) [22].
● 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 [23]. 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 [24].
Similar physiologic effects of SGLT2 inhibitors may explain why this newer class of antihyperglycemic
agents is protective for diabetic kidney disease [25]. (See "Treatment of diabetic kidney disease".)

Oxidative stress and inflammation — Oxidative stress and inflammation are tightly intertwined,
creating a vicious cycle wherein one process begets the other [3,26]. 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 via
activation of nuclear transcription factors, such as NF-kappaB ( figure 1) [27]. 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 [28,29]. 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 [28]. 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 [30].
Vascular proliferation and endothelial permeability are increased in diabetic kidney disease and are
thought to be mediated by VEGF [31], particularly when accompanied by diabetes-induced
downregulation of endothelial nitric oxide production [32]. Angiopoietins (ANGPT) are also important
regulators of endothelial function, necessitating a balance between ANGPT1, which stabilizes the
endothelium, and ANGPT2, which promotes endothelial proliferation [33]. The ratio of ANGPT2 to
ANGPT1 is consistently elevated in both animal models of diabetic kidney disease as well as from tissue
specimens from human diabetic glomerulopathy.
Diabetic kidney disease is accompanied by glomerular and interstitial infiltration of macrophages, the
magnitude of which correlates with worsening disease [34,35]. Macrophages can be activated by
hyperglycemic stress, angiotensin II, oxidized low-density lipoproteins, and AGE. The result is increased
oxidative stress and production of several injurious cytokines including TGF-beta and platelet derived
growth factor. Macrophages are also a rich source of tumor necrosis factor-alpha (TNF-alpha), a
pleiotropic cytokine resulting in renal hypertrophy, podocyte and tubular epithelial cell injury, and the
triggering of a cascade of other cytokines [35,36].
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
[37]. Hyperglycemia results in shunting of glucose through the hexosamine pathway and subsequently
increased production of TGF-beta and plasminogen activator inhibitor 1 (PAI-1) [38]. 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, infiltration of macrophages, and an excess of
collagen and fibronectin deposition ( figure 1) [1,39].
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 [40] and worldwide [41].
Although the prevalence of diabetes in the United States has increased 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) [42]. However, the distribution of clinical manifestations of diabetic
kidney disease has changed (see "Diabetic kidney disease: Manifestations, evaluation, and diagnosis")
[42]:
● 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 21 percent during the
period from 1988 to 1994 to 16 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 9 to 14 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
[40,43].
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 renal replacement therapy [44,45]. In the United States, more than 58,000 people have ESKD
attributed to diabetes, accounting for nearly 50 percent of all patients with ESKD [40]. Worldwide, annual
incidence rates of ESKD due to diabetic kidney disease are rising and vary from as low as 10 per 1 million
in Romania to as high as 67 per 1 million in Malaysia; the United States ranks 10th with 47 cases per 1
million [40]. However, the true incidence and prevalence of ESKD from diabetes is impossible to know
because kidney biopsies (the gold standard for diagnosis of diabetic kidney disease) are infrequently
performed in diabetic patients with diabetic kidney disease.
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 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.
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) [46]. 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 [47]. 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 [48-50].
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 [49]. 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) [50]. 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 [51]. Youth-onset type 2 diabetes
appears to result in renal complications earlier and with a more rapid rate of progression than in type 1
diabetes [52-54]. 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) [55]. 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 [53].
The more aggressive diabetic kidney disease course in youth-onset type 2 diabetes may be related to
risk factors such as race and ethnicity. African Americans, Latinos, and American Indians are
disproportionately affected with youth-onset type 2 diabetes [51] and are at higher risk for diabetic
kidney disease [40,56,57]. However, other factors may also be important; in the SEARCH study
mentioned above, for example, race and ethnicity did not completely explain the difference in
albuminuria between youth-onset type 2 and youth-onset type 1 diabetes [52]. (See 'Race/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 [58]. 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 [59]. This is likely due in
part to age-related senescence of the kidney, which can contribute to CKD of any cause [60], and which
may explain a rise in the prevalence of normoalbuminuric (rather than albuminuric) diabetic kidney
disease starting in the 5th decade [61]. (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.
Race/ethnicity — Compared with their white counterparts, African American, Latino, and American
Indian populations have higher rates of albuminuria, decreased eGFR, and ESKD [40,62,63]. The highest
rates of ESKD were historically among American Indians; however, with public health interventions, rates
have declined significantly in this population [64]. Incidence rates of diabetic ESKD among African
American, Latino, 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 minority populations and may actually be rising among the Mexican-American population
[42,59].
Sex/gender — Both CKD in general and diabetic kidney disease in particular are more common in
women [40]. However, compared with women, men have a significantly higher risk of progression from
late-stage CKD to ESKD (hazard ratio [HR] 1.37, 95% CI 1.17-1.62) [65]. The reasons for greater CKD
prevalence in women, but higher risk of progression in men, 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 minority 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 [66]. After
controlling for 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 [67]. 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 [68].
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 [69,70]. 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 rural areas.

Obesity — Even in the absence of diabetes, obesity leads to a form of secondary focal segmental
glomerulosclerosis (FSGS), termed "obesity-related glomerulopathy (ORG)" [71]. 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 [72].
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 [73]. 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 [74]. 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 [75], 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 [76]. There is also
increased production of tumor necrosis factor-alpha (TNF-alpha), interleukin 6, and leptin in obese
individuals, which results in greater transforming growth factor-beta (TGF-beta) production [77,78].
Smoking — Even in the absence of diabetes, smoking can result in nodular sclerosis of the kidney
that is indistinguishable from 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 [79]. (See '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 [80-82]. 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) [80].
Hyperglycemia — There is overwhelming evidence that glycemic control impacts the risk for incident
and progressive diabetic kidney disease [83,84]. In addition, restoration of normal glycemic control with
pancreatic transplantation in patients with type 1 diabetes can improve kidney disease in the long term
[85,86]. (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 [87,88], increased albuminuria regression [89,90], reductions
in worsening albuminuria [55,91,92], rapid eGFR decline [93,94], and the development of stage 3 CKD
[95]. 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) [95] and eGFR <60
mL/min/1.73 m2 [95].
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 [96,97]. 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 [96]. 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 explain part, but not all, of the disparity in diabetic kidney
disease among African Americans, Latinos, and American Indians [98]. Familial clustering of diabetic
kidney disease and diabetic ESKD has long been recognized [99], with heritability estimates ranging
from 0.30 to 0.75 depending upon the population (eg, race, ethnicity, diabetes type) and trait under
study (eg, albuminuria, eGFR, ESKD) [100].
Despite the strong 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 [101]. 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 [102-105]; 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 racial disparity in nondiabetic
ESKD but has not born out as a causative factor for diabetic kidney disease among African Americans
[106]. However, APOL1 variants are associated with an increased risk for progression of diabetic kidney
disease in African Americans. (See "Epidemiology of chronic kidney disease", section on 'APOL1 in African
Americans'.)
Acute kidney injury — Diabetes, particularly if accompanied by diabetic kidney disease, is a risk

factor for various types of acute kidney injury (AKI) [107,108]. 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 ( figure 1). 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 2), 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 '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 renal complications
earlier and with a more rapid rate of progression than with youth-onset type 1 diabetes. (See 'Youth-
onset type 2 diabetes' above.)
https://www.uptodate.com/contents/diabetic-kidney-disease-pathogenesis-and-epidemiology/print?search=nefropatia diabetic&source=search_… 10/20

● Among patients with diabetes, risk factors for diabetic kidney disease include older age, non-white
race, Hispanic ethnicity, low socioeconomic status, obesity, smoking, poor glycemic and blood
pressure control, and genetic factors. (See 'Risk factors for diabetic kidney disease' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 3103 Version 34.0

GRAPHICS
Consequences of accelerated formation of advanced glycation end products (AGEs) in the

diabetic kidney
The schematic shows major mechanisms whereby AGEs exert their harmful effects in the diabetic kidney. AGEs typically crosslink
and alter protein structure and function in extracellular compartment, modify cytosolic molecules, and exert receptor-mediated
effects that lead to activation of multiple signaling pathways and genes implicated in a variety of pathophysiological mechanisms
in the diabetic kidney.
RAGE: receptor for AGEs; rac: renin-angiotensin system-related C3 botulinum toxin substrate 1; Src: homeotic protein sex combs reduced;
ROS: reactive oxygen species; MAPK: mitogen-activated protein kinases; ROCK: Rho kinase; NAD(P)H: nicotinamide adenine dinucleotide
phosphate; NO: nitric oxide; BM: basement membrane; ECM: extracellular matrix; NF-kappaB: nuclear factor kappa B.
From: Vallon V, Komers R. Pathophysiology of the diabetic kidney. Compr Physiol 2011; 1(3):1175-1232.
https://onlinelibrary.wiley.com/doi/10.1002/cphy.c100049. Copyright © 2011 American Physiological Society. All rights reserved. Reproduced with
permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be
downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or
use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library
(https://onlinelibrary.wiley.com/).
Graphic 122592 Version 1.0

Mechanisms of hyperfiltration in diabetic kidney disease
Schematic (net) effect of factors implicated in the pathogenesis of glomerular hyperfiltration in diabetes. Several vascular and tubular factors are
suggested to result in a net reduction in afferent arteriolar resistance, thereby increasing (single-nephron) GFR. Effects of insulin per se seem to
depend on insulin sensitivity. A net increase in efferent arteriolar resistance—leading to increased GFR—is proposed for other vascular factors.
Growth hormone and insulin-like growth factor-1 likely increase filtration by augmenting total renal blood flow, without specific arteriolar
preference. Glucagon and vasopressin seem to principally) act through TGF. Intrinsic defects of electromechanical coupling or alterations in
signal transduction in afferent arterioles may impair vasoactive responses to renal hemodynamic (auto)regulation. Augmented filtration by
increases in the ultrafiltration coefficient and net filtration pressure via reduction in intratubular volume and subsequent hydraulic pressure in
Bowman's space are not depicted. Several vascular factors may be released or activated after a (high-protein) meal (eg, nitric oxide, COX-2
prostanoids, angiotensin II), whereas TGF becomes (further) inhibited, through increased amino acid (and glucose)-coupled sodium reabsorption
in the proximal tubule and/or increased glucagon/vasopressin-dependent sodium reabsorption in the thick ascending limb. These changes may
collectively play a part in postprandial hyperfiltration.
GFR: glomerular filtration rate; TGF: tubuloglomerular feedback; COX-2: cyclooxygenase 2; ETA: endothelin A receptor.
Republished with permission of the American Society of Nephrology, from: Tonneijck L, Muskiet MH, Smits MM, et al. Glomerular hyperﬁltration in diabetes:
Mechanisms, clinical signiﬁcance, and treatment. J Am Soc Nephrol 2017; 28:1023; permission conveyed through Copyright Clearance Center, Inc. Copyright ©
2017.
Graphic 122590 Version 1.0

Contributor Disclosures
Amy K Mottl, MD Grant/Research/Clinical Trial Support: Aurinia [FSGS clinical trial]; Boehringer Ingelheim [Chronic
kidney disease, with and without diabetes, clinical trial]; Calliditas [IgA nephropathy clinical trial]; Pfizer [FSGS clinical
trial]. Consultant/Advisory Boards: AstraZeneca [Use of SGLT2i in diabetes]; Bayer [CKD in Diabetes]. Katherine R
Tuttle, MD, FASN, FACP, FNKF Grant/Research/Clinical Trial Support: Goldfinch Bio. Consultant/Advisory Boards: Eli
Lilly and Company; Boehringer Ingelheim; Astra Zeneca; Gilead; Goldfinch Bio; Novo Nordisk; Bayer [Diabetes,
chronic kidney disease, diabetic kidney disease]. Speaker’s Bureau: Eli Lilly and Company [Diabetic kidney
disease]. George L Bakris, MD Grant/Research/Clinical Trial Support: Bayer [Diabetic nephropathy clinical trial];
Janssen [Diabetic nephropathy clinical trials]; Vascular Dynamics [Resistant hypertension trial]. Consultant/Advisory
Boards: AstraZeneca [Diabetic nephropathy]; Vifor [Hyperkalemia]; Merck [Diabetes]; Ionis [Resistant hypertension];
Alnylam [Resistant hypertension]; KBP BioSciences [Resistant hypertension]. John P Forman, MD, MSc Nothing to
disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be provided
to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate
standards of evidence.
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Acute kidney injury — Diabetes, particularly if accompanied by diabetic kidney disease, is a risk

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34. Nguyen D, Ping F, Mu W, et al. Macrophage accumulation in human progressive diabetic

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Consequences of accelerated formation of advanced glycation end products (AGEs) in the

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Mechanisms of hyperfiltration in diabetic kidney disease

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