NRDP 201518

PRIMER
Diabetic kidney disease

Merlin C. Thomas1, Michael Brownlee2, Katalin Susztak3, Kumar Sharma4,
Karin A. M. Jandeleit-Dahm1, Sophia Zoungas5, Peter Rossing6, Per-Henrik Groop7
and Mark E. Cooper1
Abstract | The kidney is arguably the most important target of microvascular damage in diabetes.
A substantial proportion of individuals with diabetes will develop kidney disease owing to their disease
and/or other co-morbidity, including hypertension and ageing-related nephron loss. The presence and
severity of chronic kidney disease (CKD) identify individuals who are at increased risk of adverse health
outcomes and premature mortality. Consequently, preventing and managing CKD in patients with diabetes
is now a key aim of their overall management. Intensive management of patients with diabetes includes
controlling blood glucose levels and blood pressure as well as blockade of the renin–angiotensin–
aldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its
progression. Indeed, the major decline in the incidence of diabetic kidney disease (DKD) over the past
30 years and improved patient prognosis are largely attributable to improved diabetes care. However, there
remains an unmet need for innovative treatment strategies to prevent, arrest, treat and reverse DKD. In this
Primer, we summarize what is now known about the molecular pathogenesis of CKD in patients with
diabetes and the key pathways and targets implicated in its progression. In addition, we discuss the current
evidence for the prevention and management of DKD as well as the many controversies. Finally, we explore
the opportunities to develop new interventions through urgently needed investment in dedicated and
focused research. For an illustrated summary of this Primer, visit: http://go.nature.com/NKHDzg
Of the long-term complications of diabetes, chronic or clinical practice, particularly in patients with type 2
kidney disease (CKD) imposes the highest burden diabetes. Consequently, it is more appropriate to iden-
both in terms of financial cost and the effects on daily tify patients with diabetes and CKD, and to under-
life. The presence and severity of CKD identify indivi take strategies for holistic renoprotection in patients
duals who are at increased risk of adverse health out- with diabetes.
comes — including frailty, reduced quality of life, DKD was originally described by Mogensen7 in the
end-stage renal disease (ESRD) and progressive end- 1980s as a progressive disease that began with the loss
organ damage at other sites — and premature mortal of small amounts of albumin into the urine (30–300 mg
ity. Indeed, excess mortality associated with type 1 per day), known as microalbuminuria or occult or
diabetes and type 2 diabetes is largely confined to those incipient nephropathy. As progressively larger amounts
with CKD1–4. Consequently, preventing and manag- of albumin were lost in the urine, and albuminuria
ing CKD in patients with diabetes is a key aim of their became detectable by the then standard dipstick urin
overall management. alysis (>300 mg per day), the terms macroalbuminuria
Approximately half of all patients with type 2 diabetes or overt nephropathy were used. This presentation was
and one-third with type 1 diabetes will develop CKD, then classically followed by a relentless decline in kid-
Correspondence to M.E.C.
which is clinically defined by the presence of impaired ney function, renal impairment and ultimately ESRD.
e-mail: mark.cooper@
bakeridi.edu.au
renal function or elevated urinary albumin excretion, This paradigm has proved useful in clinical studies,
Baker IDI Heart & Diabetes or both5,6 (BOX 1). The percentage of these patients who especially in type 1 diabetes, for identifying cohorts
Institute, 75 Commercial can be considered to have CKD as a result of their dia- who are at increased risk of adverse health outcomes.
Road, Melbourne, betes is unclear. Invariably, other contributors to renal However, any boundary between stages is artificial, and
Victoria 3004, Australia.
dysfunction are also present, including hypertension, the relationship between urinary albumin excretion
Article number: 15018 dyslipidaemia, obesity, intrarenal vascular disease, acute and adverse health outcomes is log-linear in clinical
doi:10.1038/nrdp.2015.18 kidney injury, glomerular atherosclerosis, renal ischae- practice8. Moreover, many patients with type 1 diabe-
Published online
30 July 2015;
mia and ageing-related nephron loss. Accordingly, it is tes, and most with type 2 diabetes, do not follow this
corrected online seldom possible to precisely define ‘diabetic kidney dis- classic course in modern clinical practice. For example,
29 October 2015 ease’ (DKD) or ‘diabetic nephropathy’ in epidemiology many patients with diabetes and renal impairment do
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 1
© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER
Author addresses
healthier at diagnosis and carry fewer co‑morbid condi-
tions than those with type 2 diabetes. Consequently, the
1
Baker IDI Heart & Diabetes Institute, 75 Commercial Road, renal presentation in type 1 diabetes potentially better
Melbourne, Victoria 3004, Australia. reflects DKD, rather than the mixed picture of CKD in
2
Albert Einstein College of Medicine, Bronx, New York, type 2 diabetes that is confounded by omnipresent other
New York, USA.
contributors, such as ageing, vascular disease, insulin
3
Perelman School of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania, USA.
resistance and obesity.
4
Center for Renal Translational Medicine, University of The incidence, presentation and course of CKD in
California, San Diego, California, USA. patients with diabetes vary considerably across countries
5
Department of Epidemiology and Preventative Medicine, and settings21 (FIG. 1). For example, African American,
Faculty of Medicine, Nursing & Health Sciences, Middle Eastern, Hispanic, Asian and Polynesian patients
Monash University, Melbourne, Victoria, Australia. with diabetes have a higher prevalence of elevated uri-
6
Steno Diabetes Center, Gentofte, Denmark. nary albumin/creatinine ratio (ACR) than European
7
Department of Nephrology, University of Helsinki, populations25. Disadvantaged and minority populations
Helsinki, Finland. also have a high prevalence of CKD and its subsequent
progression. For example, the prevalence of albuminuria
not show excessive urinary albumin loss9,10. Indeed, of is nearly twice as common in Indigenous Australians in
the 28% of the United Kingdom Prospective Diabetes primary care compared with non-Indigenous Australian
Study (UKPDS) cohort who developed an estimated patients presenting to the same clinical practice26. The
glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2, reasons for ethnic differences in CKD are complex 27 and
half did not have preceding albuminuria11. Even in the include economic, social or educational disadvantage,
Diabetes Control and Complications Trial (DCCT), of access to and uptake of care, lower achievement of treat-
the 11% of patients with type 1 diabetes who developed ment goals, lower screening rates, suboptimal early
an eGFR of <60 ml/min/1.73 m2 40% had never experi treatment of complications, diet and lifestyle factors,
enced overt nephropathy 12. Similarly, most patients with smoking, obesity, genetic factors and developmental
microalbuminuria do not develop a progressive increase programming. Another important feature is the younger
in their urinary albumin excretion as in the classic age of onset of type 2 diabetes in these at‑risk groups,
paradigm, and treatment-induced and spontaneous which might be associated with a more malignant
remission of albuminuria are commonly observed10,13. course, including accelerated β‑cell loss in the pancreas,
as well as renal and cardiovascular complications28.
Epidemiology The cumulative risk of ESRD as a result of diabe-
Although improvements in diabetes management have tes also differs considerably between populations both
reduced the proportion of individuals with diabetes between and within countries, from <1% to as high as
who develop CKD over any given time period14–16, their 13%25. This variability partly relates to the competing
improved prognoses17,18 combined with the rising inci- risk of premature mortality, chiefly owing to cardio
dence of both type 1 and type 2 diabetes19 have seen the vascular disease. Many (and probably most) patients
prevalence of CKD continue to grow 20. Of the approxi- with CKD will die before they develop ESRD13,17,29.
mately 400 million people with type 2 diabetes world- Moreover, as most patients with diabetes now reside
wide19, approximately half will have evidence of CKD21. in developing countries19, the few that develop ESRD
Approximately one in five adults with type 2 diabetes will will seldom be able to access renal replacement therapy
have an eGFR of <60 ml/min/1.73 m2 and between 30% (RRT) programmes. However, the unparalleled number
and 50% will have elevated urinary albumin excretion. of patients with diabetes makes this disease the leading
In the UKPDS, for example, after a median 15 years of single cause of ESRD. In many countries, such as the
follow‑up study, albuminuria was observed in 52% United States, diabetes is present in more than half of all
of participants and an eGFR of ≤60 ml/min/1.73m2 in patients entering RRT programmes30.
28% of participants11.
The incidence of CKD in type 1 diabetes differs Mechanisms/pathophysiology
from that observed in type 2 diabetes. It is estimated DKD has been traditionally viewed as a microvascular
that approximately one-third of all people with type 1 disorder, clustered along with retinopathy and neuro
diabetes will develop CKD over the course of their pathy, and separate from macrovascular disease that
lifetime15,22–24. This difference is mostly because sub- contributes to coronary heart disease, peripheral vascu-
jects with type 1 diabetes are generally younger and lar disease and cerebrovascular disease. However, each
disorder can be considered to be a tissue-specific mani-
festation of the same pathogenetic process, and DKD
Box 1 | Clinical criteria for the diagnosis of CKD
is the renal manifestation of the same glucose-driven
One ore more of the following criteria must be present for more than 3 months and process that occurs at susceptible sites elsewhere in the
validated by repeat testing before a clinical diagnosis of chronic kidney disease (CKD) body 31–34. Although all cells are chronically exposed
can be made: to high plasma glucose levels in patients with diabe-
• Estimated glomerular filtration rate of <60 ml/min/1.73 m2 tes, only some show progressive dysfunction, of which
• Urinary albumin/creatinine ratio of ≥30 mg g−1 the endothelial cells lining the vasculature are a prime
• Urinary albumin excretion rate of ≥30 mg per day example. Specifically, the inability of endothelial cells to
2 | 2015 | VOLUME 1 www.nature.com/nrdp

PRIMER
NHANES III NEFRON RIACE

(USA) (Indigenous Australian) (Italy)
n = 1,430 n = 143 n = 15,773
4% eGFR <60 ml/min/1.73 m2
10% Patients with albuminuria

9% 17%
10% 8%
27% 42% 19%
No CKD = 54% No CKD = 38% No CKD = 62%
DEMAND DEMAND DEMAND DEMAND

(global) (Asia) (Central/South America) (Europe)
n = 11,473 n = 2,862 n = 483 n = 4,497
6%
9% 7% 10%
13% 17% 13%

14%
34% 41%
45% 32%
No CKD = 43% No CKD = 32% No CKD = 39% No CKD = 43%
Figure 1 | The prevalence of CKD in different populations with type 2 diabetes. Data Nature | Disease
Reviews with
from patients type 2Primers
diabetes surveyed in the US NHANES III4, the Australian NEFRON study5, the Italian RIACE study86,240 and the DEMAND
study21. Yellow circles denote the percentage with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2.
Blue circles denote patients with albuminuria. The percentage not included in either circle denotes patients without
chronic kidney disease (CKD).
downregulate their glucose transport in response to high the receptor for advanced glycation end-products and
glucose levels35 leads to an overwhelming flux of intra- its activating ligand S100A8/9, and activation of vari-
cellular glucose, which triggers the generation of patho- ous protein kinase C (PKC) isoforms. Together, these
genetic mediators that contribute to the development of diversions lead to cellular dysfunction, inflammation,
diabetic complications, including DKD. apoptosis and fibrosis in cells exposed to excessive glu-
cose flux. The central importance of ROS in initiating
Reactive oxygen species each of these processes is illustrated by the fact that each
Excessive glucose flux leads to the generation of toxic can be prevented when hyperglycaemia-mediated ROS
intermediates, the most important of which are thought generation is curtailed38.
to be reactive oxygen species (ROS). Excessive glu-
cose flux can generate ROS in several different ways. Nutrient-sensing pathways
Enhanced mitochondrial substrate oxidation with con- Each cell has pathways that recognize and specifically
sequent enhanced mitochondrial membrane potential respond to nutrient abundance to ensure efficient sub-
leads to the overproduction of superoxide. At the same strate use. The best known of these nutrient sensors
time, increased glucose flux leads to the activation of include mammalian target of rapamycin (mTOR), 5′
NADPH oxidase and uncoupling of nitric oxide syn- AMP-activated protein kinase (AMPK) and the sir-
thase36. ROS-mediated DNA strand breaks in the nucleus tuins. From the renal perspective, diabetes is sensed as
activate DNA repair mechanisms, including the enzyme a ‘bonanza state’ of nutrient surfeit that directly leads
poly(ADP ribose) polymerase 1 (PARP1), which inhibits to changes in the expression and activity of AMPK, sir-
the key glycolytic enzyme glyceraldehyde-3-phosphate tuins and mTOR37 and downstream signalling effects
dehydrogenase (GAPDH) by polyADP-ribosylation. on cellular homeostasis, including the downregulation
Inhibition of GAPDH activity causes a bottleneck in of autophagy, regeneration, mitochondrial biogenesis
glycolysis, resulting in the upstream accumulation and other cytoprotective responses that contribute
of early glycolytic intermediates that are increasingly to DKD39.
diverted into activating pathogenetic signalling path- In addition, podocyte-specific activation of mTOR
ways37,38 (FIG. 2). These diversions include increased recapitulates many features of DKD, including mesangial
polyol pathway flux, increased hexosamine pathway expansion and proteinuria40,41. These findings have led to
activity, increased formation of the highly re active the concept of directed interventions to simulate energy
α‑dicarbonyl methylglyoxal, increased expression of depletion (associated with increased activity of AMPK

PRIMER
and sirtuins and reduced mTOR activity) and promote and oxidative stress, as well as haemodynamic factors,
efficient cellular function. Experimental data seem to including shear stress induced by transmitted systemic
support this strategy for renoprotection39–42, and agents hypertension, impaired autoregulation, hyperperfu-
such as metformin, peroxisome proliferator-activated sion and hypoperfusion, and activation of the renin–
receptor (PPAR) agonists 37,38, ph osphodiesterase angiotensin–aldosterone system (RAAS)43. On their
inhibitors and resveratrol act on these pathways. own, these factors do not cause DKD but rather, in the
presence of diabetes, feed into and enhance common
The multifactorial pathogenesis of DKD pathogenetic mechanisms that include increased lev-
Only one-third of patients with type 1 diabetes will els of growth factors, vasoactive hormones, cytokines
develop overt nephropathy 15,22–24, whereas almost all and chemokines in the kidney. For example, glucose-
patients with type 1 diabetes eventually develop some induced endothelial dysfunction increases vascular
degree of retinopathy. This suggests that additional risk susceptibility to shear stress, oxidative stress and other
factors beyond hyperglycaemia must also be involved in stressors. Endothelial dysfunction and subsequent
DKD. Indeed, although hyperglycaemia is an essential microvascular rarefaction induced by hyperglycaemia
requirement for DKD, it is seldom the only contribu- also reduce blood flow while oxygen consumption is
tor. Pathogenetic pathways initiated and sustained in increased, leading to hypoxia. In turn, renal hypoxia
the kidney by elevated glucose levels can be enhanced induces compensatory — but ultimately maladaptive —
by several different factors. These include a range of changes in blood flow, metabolism and polar vasculosis
metabolic factors, including excess fatty acids, carbonyl (glomerular neoangiogenesis)44–46.
Diabetes
eNOS
Mitochondria eNOS eNOS
Nucleus
Glucose ROS NADPH
oxidases ROS
DNA damage
PARP
NADPH NADP+ NAD+ NADH Polyol

Sorbitol Fructose pathway
Glucose-6-P
Gln Glu
Hexosamine
Fructose-6-P Glucosamine-6-P UDP-GLcNAc pathway
GFAT
NADH NAD+ PKC

DHAP α-Glycerol-P DAG PKC pathway
Glyceraldehyde-3-P NF-κB
Methylglyoxal AGEs AGE
RAGE and RAGE ligands pathway
GAPDH
1,3-Diphosphoglycerate
Glycolysis
Figure 2 | The central role of ROS in diabetic complications. Mitochondrial production Nature | Disease
Reviewsoxygen
of reactive Primers
species
(ROS) accelerates in response to an increase in intracellular glucose. In addition, pathogenetic ROS are also generated
through the ROS-induced uncoupling of nitric oxide synthase (eNOS) and inactivation of NADPH oxidases. ROS can
mediate DNA damage, which in turn activates poly(ADP ribose) polymerase (PARP). PolyADP-ribosylation of
glyceraldehyde‑3‑dehydrogenase (GAPDH) by PARP leads to the inhibition of this key glycolytic enzyme and a subsequent
bottleneck in glycolysis. As a result, early glycolytic intermediates accumulate and are then diverted into pathogenetic
signalling pathways. AGE, advanced glycation end-product; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate;
GFAT, glutamine fructose‑6‑phosphate amidotransferase; NF-κB, nuclear factor-κB; PKC, protein kinase C; RAGE, receptor
for AGE; UDP-GLcNAc, uridine diphosphate N-acetylglucosamine.

PRIMER
Podocytopathy
• Podocyte loss through
detachment and apoptosis
• Hypertrophy
• Foot-process effacement
• Reduction in slit diaphragms
• Basement membrane thickening
Mesangial cell
Mesangial hypertrophy
matrix and proliferation
Afferent deposition
arteriole Epithelial Tubule epithelial
cell cell atrophy
Granular
cells
Albuminuria
Diabetic
Healthy
Distal
convoluted
tubule
Proximal tubule
Efferent Bowman’s space
arteriole Basement membrane
Pedicel
Podocyte
Renal corpuscle Mesangial cell

Endothelial T cell
cells
GBM Macrophage
Slit Inflammatory mediators
diaphragm
Albumin
Nature
Figure 3 | Glomerulopathy in diabetes. Morphological and functional alterations to renal Reviews
glomeruli Disease
are| one Primers
of the
hallmarks of diabetic kidney disease. GBM, glomerular basement membrane.
Key changes in the diabetic glomerulus demonstrate that podocyte-specific injury can recapitu
Despite the importance of the vascular endothelium in late a diabetes-like phenotype of glomerulosclerosis and
microvascular complications, many investigators propose tubulointerstitial fibrosis, even in the absence of hyper-
that the early changes in renal glomeruli are critical for glycaemia 51. Moreover, protecting podocytes from
the subsequent development of glomerulosclerosis and hyperglycaemia with a podocyte-specific deletion of
nephron dropout (FIG. 3). Among these changes, the most the glucose transporter solute carrier family 2, facilitated
important might be dysfunction of glomerular podocytes, glucose transporter member 4 (SLC2A4; also known as
which are highly specialized terminally differentiated GLUT4)51 or from the resulting oxidative stress52 can
cells that cover the urinary side of the glomerular base- prevent diabetes-associated albuminuria without restor-
ment membrane (GBM)47. Together with glomerular ing normal levels of glucose. Such data place podocytes,
endothelial cells, podocytes are responsible for the main- and more particularly the dysregulation of their growth
tenance of the GBM, its charge barrier and the shape and differentiation, at the very centre of the pathogenesis
and integrity of the glomerular capillary loop; all func- of DKD. Some studies suggest that a reduction in podo-
tions that are compromised in the diabetic glomerulus. cyte density might be a useful predictor for DKD and
The diabetic milieu induces ‘patho-adaptive’ changes its progression53,54.
in podocytes, including cytoskeletal rearrangement, One of the earliest and most characteristic of all glo-
de‑differentiation, apoptosis and autophagy manifested merular changes in diabetes is a homogenous thicken-
by morphological widening, retraction and flattening ing of the GBM53,55. Thickening of the GBM is present
(known as effacement), reduced motility, increased in almost all patients with diabetes within a few years
formation of intercellular tight junctions, a decrease in of diagnosis, although more pronounced changes
slit diaphragm length, glomerular hypertrophy, detach- are observed in DKD56. Whether GBM thickening is
ment and dropout 48–50 (FIG. 3). Experimental models a marker of podocyte or endothelial dysfunction or

PRIMER
Bone marrow-derived Local resident deposition and progressive decline in the GFR47,63. The
fibrocytes fibroblasts influx of inflammatory cells into the diabetic kidney
is partly in response to tissue injury but can also act
as a mediator of DKD64,65, as inflammatory cells and
their products (for example, cytokines, chemokines,
Tubulointerstitial activated complement and ROS) transform the renal
fibrosis microenvironment. In experimental models, inhibition of
Endothelial to Tubuloepithelial to leukocyte recruitment and accumulation in the diabetic
mesenchymal mesenchymal kidney protects against the development of albuminuria
transition transition and progressive renal damage66,67. Indeed, Rag1‑knockout
Mesenchymal
stem cells mice, which are deficient in both T and B cells, fail to
develop albuminuria associated with diabetes, although
renal fibrosis and hyperfiltration still occur 65.
Nature Reviews | Disease Primers

Renal tubular dysfunction and fibrogenesis
Figure 4 | Cellular contributors to myofibroblast recruitment and subsequent The renal tubule is also adversely affected by diabetes.
tubulointerstitial fibrosis in DKD. The myofibroblasts responsible for the matrix Early in diabetes, the increased glucose load delivered
deposition that leads to tubulointerstitial fibrosis in diabetic kidney disease (DKD) to the proximal tubule triggers maladaptive hyper
are derived from various sources. Transformation of local resident fibroblasts, trophy and hyperplasia of the cortical tubuli68 together
mesenchymal stem cells and bone marrow-derived fibrocytes and the induction of
with upregulation of glucose transport 69, possibly to
endothelial to mesenchymal and tubuloepithelial to mesenchymal transitions are
the main contributors241. facilitate glucose reabsorption and reduce glucose wast-
ing. However, as a consequence, sodium delivery to the
macula densa is reduced and tubulo-glomerular feedback
a mediator of progressive DKD is unclear. Certainly, is activated, leading to increased intraglomerular pres-
changes in the composition, charge or architecture of sure and hyperfiltration70–72. Chronic hyperglycaemia and
the GBM associated with thickening could contribute to other metabolic disturbances associated with diabetes
albuminuria. Stiffening of the GBM might also reduce also lead to progressive and cumulative atrophy of tubu-
distensibility of the pericapillary wall and compromise lar epithelial cells. In DKD, up to half of the glomeruli
the subpodocyte space, facilitating glomerular injury are attached to dilated and atrophic tubules, and up to
through haemodynamic mechanisms57. 17% of glomeruli may be atubular 73. Such tubular dys-
Mesangial cells are also substantially altered by dia- function results in defective uptake, transcytosis and/or
betes, undergoing proliferation and hypertrophy while lysosomal processing of filtered protein, alterations that
increasing their production of matrix proteins. These also contribute to albuminuria74.
changes lead to some of the unique structural features of Tubulointerstitial fibrosis is widely considered to
diabetic glomerulopathy (FIG. 3), including an increase in be the final common pathway for loss of renal func-
the fractional volume of the glomerulus occupied by the tion in DKD75. Indeed, renal function and prognosis in
mesangium (mesangial expansion), focal degeneration DKD might ultimately correlate better with tubuloint-
of mesangial cells and the mesangial matrix (mesangio erstitial fibrosis than with classic and early glomerular
lysis)58, and ultimately glomerulosclerosis59. There is a changes75. It is generally thought that the accumulation
strong link between mesangial matrix expansion and of activated myofibroblasts is the major contributor to
progression of DKD53,55,60. However, unlike podocytes, progressive renal scarring in diabetes. These fibrogenic
upregulation of glucose transport into mesangial cells cells might be derived from several different sources,
does not recapitulate a diabetic phenotype61, suggesting including transformation of resident fibroblasts and
that crosstalk among podocytes, endothelial and inflam- mesenchymal stem cells, recruitment of fibroblasts from
matory cells mediates mesangial matrix expansion rather the bone marrow, and tubuloepithelial to mesenchymal
than it being a direct effect of glucose exposure on mesan- trans‑differentiation76 (FIG. 4).
gial cells. Although the molecular details of how diabetes
alters mesangial cells are not completely understood, the Complex histopathology of DKD
importance of mesangial matrix expansion in the develop The same clinical presentation of DKD can be associ-
ment and progression of diabetes-associated glomerulo ated with a heterogeneous range of pathological features,
sclerosis is clear. For example, the resulting reduction including nodular or diffuse glomerulosclerosis, tubulo
in capillary surface area as a result of the expansion of interstitial fibrosis, tubular atrophy and renal arterio
the mesangium contributes to glomerular hypertension, lar hyalinosis, alone or in combination. The presence
proteinuria and reduced glomerular filtration62. and severity of each of these features are independently
associated with the risk of progressive renal disease, but
Inflammatory cell recruitment not always with each other 77. A histopathological sta
Diabetes is also associated with the recruitment of acti- ging system for glomerular lesions has been proposed77
vated leukocytes, particularly T cells and macrophages, (BOX 2). However, its predictive utility remains to be estab-
into the glomerulus and tubulointerstitium, even in lished. Routine renal biopsy is not feasible or clinically
the early stages of DKD. Markers of renal and sys- appropriate beyond a research setting, and DKD remains
temic inflammation correlate with albuminuria, matrix a clinical diagnosis in most patients with diabetes.

PRIMER
Diagnosis, screening and prevention memory’ (REF. 88), ‘metabolic karma’ (REF. 89) or the ‘leg-
Risk factors for DKD acy effect’ (REF. 83) and has been used to explain many
Several different factors contribute to the develop- clinical observations relating to diabetes and its manage-
ment of CKD in patients with diabetes (BOX 3). Some of ment, including the persistent renal benefits observed
these factors, including hyperglycaemia, hypertension, as a result of intensive control during the DCCT80 and
weight gain and dyslipidaemia, are potentially modifi- UKPDS trials81,90 as well as the apparent lack of benefits
able through optimized diabetes care. Moreover, robust observed in many short-term and intermediate-term
clinical data show that intensive diabetes manage trials (as patient outcomes may be significantly deter-
ment significantly reduces the cumulative incidence mined by glucose exposure before the commencement
of albuminuria, renal impairment and ESRD. Indeed, of the trials91). The physiological mechanism or mech
the major decline in the incidence of CKD over the anisms responsible for metabolic karma remain poorly
past 30 years is considered to be largely attributable to defined but might include epigenetic programming,
improved diabetes care14,15. remodelling and persistent post-translational modifi
cations, such as advanced glycation end-products89.
Elevated blood glucose Further understanding the molecular basis of a meta-
The most important risk factor for CKD is hyperglycae- bolic legacy in diabetes will certainly provide new targets
mia. Although there are some structural similarities to for intervention to reduce the burden of CKD in patients
other renal diseases, fundamentally, the phenotype of with diabetes.
DKD is only observed in the context of elevated glu-
cose levels. Elliot Joslin first hypothesized a relationship High blood pressure
between glucose and diabetic complications78. However, Elevated blood pressure is an important risk factor for
the defining prospective clinical study by Jean Pirart the development CKD in both type 1 and type 2 dia-
and his Belgian colleagues unequivocally demonstrated betes92–94. In individuals with type 1 diabetes, blood
that the degree and duration of hyperglycaemia were pressure levels are usually normal at diagnosis, but
associated with microvascular complications, including become elevated proximate to the onset of micro
CKD79. Subsequently, randomized controlled trials have albuminuria95. In type 2 diabetes, other factors contrib-
validated this causal link in both type 1 diabetes80 and ute to the presence and severity of hypertension, which
type 2 diabetes81,82. Nevertheless, although conventional may precede CKD by many years or follow in its wake.
markers of glucose levels, such as glycated haemoglobin This importance of hypertension to the pathogenesis
(HbA1c), are associated with the incidence of micro of renal damage can be partly explained by the loss of
albuminuria, it is also clear that many patients with poor renal autoregulation in diabetes, whereby systemic pres-
glycaemic control do not develop renal complications, sure is directly transmitted to vulnerable glomerular
whereas others do despite intensive interventions and capillaries96,97. Consequently, there is no specific cut-off
dedicated compliance (FIG. 5). This discordance might above which the specific risk for CKD can be denoted
be because markers such as HbA1c fail to capture the or below which the therapeutic impact of blood pres-
dynamic dysglycaemia associated with diabetes. Indeed, sure control on the development of albuminuria can be
even in the absence of chronic hyperglycaemia, transient ignored in patients with diabetes.
hyperglycaemia, transient hypoglycaemia or increased
glycaemic variability around a normal mean might have Blood lipid abnormalities
long-lasting and long-term effects on the development Dyslipidaemia is another important risk factor for the
and progression of complications related to diabetes, development of CKD in diabetes. In particular, elevated
including renal disease83–87. triglycerides, non-low-density lipoprotein cholesterol,
Alternatively, past periods of poor glucose control, apolipoprotein-B-100 or low high-density lipoprotein
even before diagnosis, could also have a long-lasting leg- (HDL) cholesterol levels are independently associated
acy in the kidney, and therefore the risk for DKD might with the development of CKD in both type 1 and type 2
not be represented by current or recent HbA1c levels. diabetes98,99. However, conventional lipids and lipoprotein
This phenomenon has become known as ‘metabolic measurements do not fully account for the complex lipid
and lipoprotein changes associated with diabetes and/or
CKD. For example, HDL might not only lose its vaso-
Box 2 | Proposed histological staging of diabetic glomerulopathy* protective, antioxidant and anti-inflammatory prop-
Class I: glomerular basement membrane thickening alone erties in CKD, but dysfunctional HDL can be directly
Glomerular basement membrane thickness of >430 nm in men and >395 nm in women pathogenetic100. Detailed analyses of lipid sub-fractions
Class II: mesangial expansion‡ have suggested that HDL3‑cholesterol, sphingomyelin,
Defined by expansion present in >25% of the mesangium apolipoprotein(a), apolipoprotein A-I and apolipo
Class III: nodular sclerosis protein A-II, apolipoprotein C-I and triglyceride
Defined by the presence of Kimmelstiel–Wilson lesions but <50% diffuse global enrichment might all be independently associated with
glomerulosclerosis progressive DKD101,102. Attempts have been made using
Class IV: advanced diabetic glomerulosclerosis lipidomics to establish a ‘lipid fingerprint’ associated
Defined as >50% diffuse global glomerulosclerosis with or without nodules with complications in diabetes103,104. However, exactly
which lipids or lipoproteins are the most important in
*See REF. 77 for more details. ‡Previously known as diffuse diabetic glomerulosclerosis.
the pathogenesis of CKD in diabetes remains unclear.

PRIMER
Insulin resistance including lipid, blood pressure and glucose control, as

Insulin resistance is also independently associated with well as promoting insulin resistance. Obesity also has
CKD beyond its indirect links with glucose, blood direct effects on the kidney, including changes in intra
pressure, body weight and lipid control105–107. Insulin- glomerular haemodynamics, increased sympathetic
sensitizing interventions (for example, thiazolidinedione activity, hypertension, systemic inflammation, endo
therapy, exercise and weight loss) all reduce albuminuria thelial dysfunction, altered expression of growth factors
beyond their actions on metabolic control. In podocytes, and renal compression associated with visceral adiposity.
resistance to insulin signalling, arising from deletion of Indeed, even in the absence of diabetes, obesity may be
the insulin receptor or its downstream effectors mTOR or associated with an increased frequency and severity of
RAC-beta serine/threonine protein kinase (also known albuminuria111, and obesity-related glomerulopathy has
as protein kinase AKT2), leads to progressive glomerular been extensively described112.
damage similar to that observed in diabetes51. Impaired
insulin sensitivity also results in altered renal cell glu- Programming for DKD
cose metabolism105. At the same time, increased insulin The majority of the variability in incident CKD remains
signalling as a result of compensatory hyperinsulinae- unaccounted for by conventional risk factors. Indeed, the
mia in the setting of pathway-selective insulin resistance long-term survival of some of the very first patients to
might also contribute to abnormal vasoreactivity, angio- be treated with insulin without the advantages or inten-
genesis, fibrogenesis and other pathways implicated in sity of modern treatment regimens suggest that some
progressive renal disease108 as well as atherogenesis109. individuals are ‘protected’. This cannot be explained as
simply having the ‘right’ genes. Although an inherited
Obesity predisposition for DKD is evident 113 and several poten-
CKD is more prevalent and develops more rapidly in tial loci have been reproducibly associated with CKD
people with diabetes who are obese than their normal- (TABLE 1), most genetic variants associated with CKD lie
weight counterparts28. This is one major reason why in non-coding regions. Overall, current evidence sug-
the cumulative incidence of CKD is greater in type 2 gests that the genetic code explains only a small amount
diabetes than type 1 diabetes110. Obesity negatively of why some individuals develop CKD and some do
influences the major risk factors associated with CKD, not 114. Furthermore, any role for these genes, alone or
in combination, in the molecular pathobiology of CKD
remains to be established114.
Although the genetic programming for CKD
Box 3 | Risk factors for diabetic kidney disease
remains elusive, risk can be imprinted through other
Non-modifiable means. In particular, epigenetics has emerged as an
• Increasing age increasingly powerful paradigm to understand complex
• Young age at onset of diabetes28 non-Mendelian diseases, including CKD. Persistent epi-
• Prolonged duration of diabetes genetic changes can be acquired during development or
• Genetic factors114 in adaptations following environmental exposure (the
so‑called environmental footprint), including metabolic
• Ethnicity
fluctuations associated with diabetes83,115–117. These epi-
• Family history of diabetic kidney disease, type 2
genetic modifications — including changes in DNA
diabetes, non-diabetic chronic kidney disease,
hypertension or insulin resistance
methylation, histone modification and chromatin struc-
ture — store, retain and recall past experiences in a way
• Intrauterine growth retardation
that can shape the transcription of specific genes and,
• Maternal gestational diabetes or developmental
therefore, cellular functions118. Technological advances
glucose exposure
now make it possible to initiate epigenome-wide associ
Modifiable ation studies119 to identify epigenetic marks associated
• Poor glycaemic control (mean, variability and maximal) with disease across the whole genome119,120, with compa-
• Hypertension (mean, variability and maximal)92–94 rable resolution and throughput to genome-wide studies.
• Dyslipidaemia98–104 For example, some studies have identified differentially
• Socioeconomic disadvantage124–127 methylated regions in individuals with diabetes with
• Sedentary lifestyle or low intensity of physical activity CKD compared to those without CKD121,122. Many of
• Obesity28,196,197
the genes identified were also differentially expressed,
including some that had been previously linked to CKD
• Smoking228
in genome-association studies. However, the broader
• Insulin resistance or metabolic syndrome51,105–107
utility of epigenetic markers to identify imprinted risk
• Recurrent or chronic infections229,230 in individual patients beyond conventional risk factors
• Episodes of acute kidney injury231 remains to be established.
• Advanced glycation end-products232 Some ‘risk’ programming also occurs during gestation
• Oral contraceptive use233 and early development and is determined by the intra
• Hyperuricaemia234 uterine environment, as well as the pre-conception nutri-
• Vitamin D deficiency235 tion and health of both the mother and father 123. Cells are
more sensitive to this epigenetic programming during

PRIMER
18 6 The best formula to accurately estimate GFR remains

contentious129, although all widely used formulae will
16
5 identify the majority of patients who have eGFR values
of <60 ml/min/1.73 m2. Newer methods for estimating
Proportion of patients (%)
14
Microalbuminuria (hazard)
the GFR, including cystatin C‑based formulae, have
12 4
some advantages130, especially in the high to normal
10 range of GFR for which serial monitoring using cysta-
3
8 tin C can be used to accurately identify individuals with
rapidly declining renal function (so-called progressors)
6 2 well before the eGFR declines to <60 ml/min/1.73 m2
4 (REF. 131). There is no place for the formal measurement
1 of GFR using inulin, iothalamate or other substrates
2
in the routine clinical assessment of renal function in
0 0 patients with DKD132,133.
0 5 6 7 8 9 10 11 12 13
HbA1c (%) Estimating urinary albumin excretion
Nature
Figure 5 | The relationship between glycaemic control Reviews
and the | Disease
incidence Primers
of CKD. The second element used to identify individuals with
The risk of development of an albumin excretion rate of >30 mg per day in adults from diabetes and CKD is to detect those with persistently
the FinnDiane study of individuals with type 1 diabetes and no chronic kidney disease elevated urinary albumin excretion5,6 (BOX 1). When the
(CKD) (orange), and the distribution of glycaemic control (histogram) in those patients kidneys are healthy, little or no intact albumin enters
with type 1 diabetes who develop microalbuminuria (bars) (P.-H.G. and M.C.T., the urine, meaning that the presence of albumin in the
unpublished observations). urine can be used to denote abnormal kidney function.
Urinary albumin excretion can also be estimated in sev-
development and differentiation, when gene regulatory eral different ways. The preferred method measures the
regions are established. However, programming can also concentration of albumin in a urine sample using a sensi-
include constitutional or structural endowment. For tive assay, adjusting the result for the urinary creatinine
example, reduction in nephron mass and filtration area concentration. This metric is known as the ACR and is
associated with intrauterine growth retardation, mater- considered the most practical way to adjust for the void
nal diabetes or vitamin A deficiency can increase the risk volume and urine concentration5,6. The ACR is best deter-
of CKD124–127. At present, intrauterine growth retardation mined in urine collected at the first void in the morn-
affects one-quarter of live births in developing countries, ing, but can also be performed in a random manner; for
the same countries in which the risk of diabetes and example, at the time of a medical visit. Timed urine col-
CKD are also the greatest 128. lections (for example, 4‑hourly, overnight or 24‑hourly
urine collections) are also used but are time-consuming
Estimating the GFR and seldom adequately performed outside hospital set-
CKD is a clinical diagnosis made in a patient with a tings. Spot tests of urinary albumin concentration are not
reduction in their eGFR to <60 ml/min/1.73 m2, a per- recommended as the concentration of urine varies con-
sistently elevated urinary albumin excretion or both5,6 siderably from void to void. A positive urinary dipstick
(BOX 1). The eGFR is a measure of the flux of plasma test or elevated urine albumin concentration is almost
fluid filtered from the glomerular capillaries into the always associated with an abnormal ACR134. However,
Bowman’s capsule per unit time (FIG. 3) . An eGFR fewer than half of adults with both type 2 diabetes and
<60 ml/min/1.73 m2 is used to denote a moderate to an abnormal ACR have an elevated urinary albumin
severe renal impairment, and approximates an eGFR concentration or a positive dipstick test134.
more than two standard deviations below the mean Owing to substantial day‑to‑day variability in urinary
eGFR of healthy individuals aged 20–35 years. The albumin excretion in any one individual (approximately
eGFR can be inexpensively estimated using an appro- 40%), any abnormal results should always be confirmed
priate mathematical formula from the serum creatinine in at least one out of two additional samples collected
levels, and patient age, gender and ethnicity. This cal- over a 3–6‑month period. If albumin excretion is within
culation is often performed automatically by clinical the normal range in all three initial tests, further screen-
pathology services. The importance of this initiative is ing is repeated on an annual basis. Any negative result, in
illustrated by the fact that at least half of all individ an individual with previously negative tests, can simply
uals who currently have a reported eGFR of <60 ml/ be repeated annually as part of routine assessment for
min/1.73 m2 still have a serum creatinine concentra- complications, as it is unlikely that significant CKD has
tion in the normal range, meaning that until recently, been missed. However, any de novo abnormal results
renal impairment was frequently undetected in patients should be confirmed with an additional two tests during
with diabetes until late in the course of their disease. the 3–6 months5,6.
However, serum creatinine is notably variable within Cut-off values for defining what constitutes elevated
individuals and is modified by several different factors urinary albumin excretion vary from guideline to
(such as hydration status, physical activity and muscle guideline. The American Diabetes Association and the
mass), meaning that repeat testing is important to verify National Kidney Foundation Kidney Disease Outcomes
any abnormal results. Quality Initiative (NKF KDOQI) guidelines recommend

PRIMER
that in patients with diabetes, the presence of albumin Other biomarkers of the risk for CKD
uria is defined by a persistent ACR of ≥30 mg g−1 in Although screening for albuminuria and renal impair-
either men or women135,136. Other guidelines adjust for ment will identify most patients who are at risk of CKD,
gender differences in urinary creatinine arising from advanced and irreparable structural damage might
differences in muscle mass between men and women already be present by the time CKD is diagnosed.
(for example, defining albuminuria as persistent ACR Indeed, an eGFR of <60 ml/min/1.73 m 2 denotes a
of >22 mg g−1 in men and >31 mg g−1 in women), which loss of renal function of >50%. At the same time, an
might more accurately approximate clinical risk in adverse prognosis is not inevitable in patients with overt
patients with diabetes137. Formulae to estimate urinary nephropathy and/or a reduced eGFR131. Developing
albumin excretion using a single sample are also avail practical ways to identify patients with good prognoses
able, and as for GFR estimation, these might better from those with poor prognoses remain important for
adjust for demographic confounders138. the management of patients with diabetes and CKD,
especially in the primary care setting. Some research-
Screening for CKD in diabetes ers have developed models incorporating additional
All patients with type 2 diabetes should have their renal clinical variables such as age, ethnicity and retinopathy
function screened at least annually post diagnosis, using status for risk stratification141,142, although most of the
both ACR and eGFR136, as both criteria are indepen- variability in these models can be predicted on the basis
dently as well as synergistically associated with mortal- of eGFR and albumin excretion alone143. Nevertheless,
ity and progression to ESRD139. In adults with type 1 incorporating some of these additional patient variables
diabetes, annual screening should begin at most 5 years adds to their predictive utility. An unmet clinical need
after diagnosis. More frequent monitoring is appropriate is to identify novel biomarkers that have the potential
for individuals with established renal impairment and to both diagnose and risk stratify CKD in patients with
those at increased risk of progressive kidney disease diabetes earlier than current techniques. Indeed, a
(for example, those with proteinuria of >1 g per day). number of individual biomarkers have been proposed
Critically, such screening enables the identification of (BOX 4). Other studies have attempted to more broadly
susceptible individuals so that appropriate preven- identify at-risk profiles using urine proteom ics 144,
tive actions can be taken. Indeed, identification of risk metabolomics 145 and analysis of urinary exosomes
through screening must be followed by intensification of (for microRNA)146. However, none of these techniques
and/or changes in management, such as those detailed is currently applicable to the hundreds of millions of
in the next section140. people with diabetes worldwide.
Table 1 | Genes potentially linked to diabetic kidney disease*

Gene Locus Alteration Putative functions
Angiotensin I converting enzyme (ACE) rs179975 Insertion/deletion of a 287-base-pair Renin–angiotensin system
Alu repetitive element in intron 16
Apolipoprotein E (APOE) rs429358 T>C Lipid metabolism, haematopoietic
rs7412 T>C progenitor stem cell proliferation
Aldo-keto reductase family 1, member B1 rs759853 A>G>T Metabolism, polyol pathway
(AKR1B1) [AC]n microsatellite Z-2 allele at an [AC]n microsatellite
4.1 protein ezrin, radixin, moesin (FERM) rs10868025 G>C Cytoskeletal integrity
domain containing 3 (FRMD3) rs1888747 A>G
Cysteinyl-tRNA synthetase (CARS) rs739401 C>T Protein translation
rs451041 A>G
Acetyl-CoA carboxylase-β (ACACB) rs2268388 C>T Lipid metabolism
Myosin, heavy chain 9, non-muscle (MYH9) rs4821480 G>T Renal development
rs2032487 C>T
rs4281481 T>C
rs3752462 C>T
Sp3 transcription factor (SP3) rs4972593 T>A Fibrogenesis
rs174162256 G>C
AF4/FMR2 family, member 3 (AFF3) rs7583877 C>T Transcriptional activation, DNA binding,
RNA binding
Erb‑b2 receptor tyrosine kinase 4 (ERBB4) rs7588550 A>G Renal development, fibrogenesis
Locus between RGMA (repulsive guidance rs12437854 G>T Unknown
molecule family member a) and MCTP2
(multiple C2 domains, trans-membrane 2)
Peroxisome proliferator-activated rs1801282 C>G Metabolism
receptor-γ (PPARG)
*See REF. 114 for more details.

PRIMER
Management Box 4 | Potential biomarkers for progressive DKD*

Diabetes control in patients with established CKD
Intensive management of diabetes, including concurrent Circulating biomarkers
control of glucose, lipids and blood pressure as well as • Soluble tumour necrosis factor-α receptors
diet and lifestyle modifications, can slow the progression • Tumour necrosis factor‑α
of established DKD17,18,147–149. Indeed, some data suggest • Soluble Fas ligand
such approaches can even reverse early glomerulopathy. • Fibroblast growth factor 23
For example, pancreatic transplantation, which restores • Transforming growth factor‑β
normal glucose levels in patients with type 1 diabetes, is
• Bone morphogenic protein 7
able to ameliorate the renal histological changes associ-
• Inflammatory markers (for example, C‑reactive protein,
ated with diabetes150. However, it takes at least 10 years
fibrinogen, serum amyloid A protein, interleukin‑6,
to observe any regression150, and metabolic control with interleukin‑10 and intercellular adhesion molecule 1)
standard therapy can seldom achieve that observed
• Uric acid
following pancreatic transplantation. Even with inten-
• Endothelial cell-selective adhesion molecule
sive management in the robust setting of clinical trials
detailed below, many patients with diabetes still experi- Urinary biomarkers
ence a progressive decline in renal function. This finding • Collagen IV
has led to the suggestion that, at best, current therapy • Connective tissue growth factor
simply delays the inevitable. Nonetheless, in the clinical • Angiotensin converting enzyme 2
setting, any delay in CKD has potentially profound effects • Angiotensinogen
on patient health. • Filtered urinary proteins (for example, transferrin
and ceruloplasmin)
Intensive glucose control • Neutrophil gelatinase-associated lipocalin
Whether preventing hyperglycaemia is sufficient on
• Hepatitis A virus cellular receptor 1 (also known as
its own to treat progressive CKD once it is established kidney injury molecule 1)
is uncertain. Significant reductions in albuminuria and
• Protein O‑GlcNAcase
its progression are certainly observed following intensi-
• Immunoglobulin G2
fication of glucose control using standard therapies in
both type 1 and type 2 diabetes151,152. However, within • Immunoglobulin A
the limited confines of clinical trials, no significant effect *See REFS 236–239 for more details.
has been observed on other renal outcomes, including
doubling of the serum creatinine level, ESRD or death
from renal disease151. Nonetheless, 6.5 years of inten- patients to an increased risk of adverse drug reactions.
sive diabetes therapy in the DCCT study was ultimately Each class of glucose-lowering agent has some limitations
associated with a 50% reduction in the risk of renal (BOX 5). In particular, the risk of severe hypoglycaemia
impairment in its follow‑up Epidemiology of Diabetes is independently associated with a reduced eGFR and
Interventions and Complications (EDIC) study and elevated urinary albumin excretion156. The increased risk
a modestly lower rate of decline in renal function153. of hypoglycaemia in patients with CKD can be explained
Moreover, this effect seemed to be entirely attributable by several different factors that include prescribing prac-
to improved glucose control153. In addition, over the tices in this setting, altered insulin and drug pharma-
course of the EDIC study, RRT (haemodialysis, perito- cology (including drug and metabolite accumulation,
neal dialysis or renal transplantation) was needed in only inadequate compensatory gluconeogenesis in CKD and
8 participants in the intensive-therapy group, whereas flattening of the relationship between mean glucose con-
16 patients in the conventional-therapy group required trol and HbA1c). Thus, careful individualized targeting,
RRT. Furthermore, the Action in Diabetes and Vascular prescribing, patient education, planning and vigilance
Disease: Preterax and Diamicron MR Controlled for hypoglycaemia are all important components in the
Evaluation (ADVANCE) study of 11,140 patients with management of CKD. Where possible, glucose-lowering
type 2 diabetes also reported that fewer patients required agents not associated with hypoglycaemia are preferred,
RRT following intensification of glucose control154 com- especially those not limited by renal impairment or associ-
pared with a control group. Moreover, as with the EDIC ated co‑morbid conditions such as heart failure. In some
study, a recent 5‑year follow‑up of the ADVANCE study patients with CKD, less-intensive glycaemic control might
confirmed this renal benefit 155. However, total ESRD be appropriate. Indeed, there may be a U‑shape relation-
events (RRT plus deaths from renal disease) (FIG. 6) and ship between HbA1c and adverse outcomes, including
doubling in serum creatinine were not significantly hospitalization and mortality in patients with diabetes
changed. Whether intensive glycaemic control has any who have an eGFR of <60 ml/min/1.73 m2 (REF. 157).
influence on cardiovascular or mortality outcomes when Several glucose-lowering agents are purported to have
initiated late, that is, after patients have established DKD pleiotropic renoprotective actions in patients with diabe-
or cardiovascular disease, also remains controversial91. tes and CKD beyond glucose lowering 158. These drugs
Similarly, intensification of glucose control in patients include metformin, dipeptidyl peptidase 4 (DPP4) inhibi-
with diabetes and CKD can be problematic as the multi- tors159, glucagon-like peptide 1 (GLP1) analogues160, thia-
ple agents and high doses that are often required exposes zolidinediones161 and sodium/glucose co-transporter 2

PRIMER
100 improve ESRD, cardiovascular disease or other hard out-

Active comes with the exception of stroke165. Overall, treatment
Placebo
of hypertension in patients with CKD at best only mod-
80
estly reduces the risk of ESRD170, but exposes patients to
increased drug costs, orthostatic symptomatology and
Total events (n)
60 potentially hypoperfusion in the setting of impaired

autoregulation. Indeed, an increased risk of declining
renal function and incident acute kidney injury has
40 also been reported in some studies, which may itself
contribute to a progressive decline in renal function in
20
diabetes171. Moreover, the cost and challenges of achiev-
ing this level of blood pressure control in many patients
has contributed to the 2014 Joint National Council 8
0 guidelines recommending a relaxed unified target of
ESRD RRT Renal death ESRD RRT Renal death <140/90 mmHg 172. However, stroke risk is also greatest
BP lowering Glucose lowering in patients with CKD, and the most appropriate blood
Figure 6 | The incidence of ESRD in patients with type 2 diabetes
Nature Reviewsfrom the Primers
| Disease pressure target continues to be the subject of avid debate.
ADVANCE‑ON trial. Incidence of end-stage renal disease (ESRD) stratified according Although results from large observational studies
to intervention group, whereby patients were subjected to either blood pressure (BP) suggest that the risk of albuminuria can be reduced by
lowering or glucose lowering treatments. Data are presented for sites (n = 144) that were blood pressure reduction, regardless of modality 173,
able to follow the majority (≥85%) of patients surviving to participate in post-trial the renoprotective efficacy of blockade of the RAAS
follow‑ups, outlining the number of patients who progressed to ESRD and, of these, using angiotensin converting enzyme (ACE) inhibitors
the number who were receiving renal replacement therapy (RRT) and the number
or angiotensin receptor blockers (ARBs) seems to be
who had died as a result of kidney disease (renal death). Neither BP-lowering nor
greater than that achieved by other agents with a similar
glucose-lowering treatment significantly reduced the incidence of ESRD155.
degree of blood pressure reduction167,174. For example, in
the Irbesartan in Diabetic Nephropathy Trial (IDNT),
(SGLT2) inhibitors162. These putative renal benefits are fewer patients receiving irbesartan (an ARB) required
suggested from studies in which these agents reduced RRT compared with those receiving amlodipine
or prevented albuminuria in experimental models or in (a calcium channel blocker)175. However, despite these
which renal benefits (such as reduced albuminuria) were data, RAAS blockade (any and/or in adequate doses) in
observed in patients with DKD. Although plausible mech- patients with diabetes and CKD continues to be under-
anisms can explain why such agents are renoprotective, used in routine clinical care176. No differences in the clini-
these actions remain to be established by comprehen- cal efficacy of ACE inhibitors versus ARBs with respect
sive clinical trials with a renal focus, although some are to reduction in blood pressure are evident, although
currently in progress163,164. tolerability and compliance might be greater with ARBs.
The combination of ACE inhibitors and ARBs is not
Blood pressure control recommended in DKD, partly because of the increased
Lowering blood pressure is widely regarded the most effi- risk of acute‑on‑chronic renal impairment and hyper-
cacious treatment for CKD in diabetes, with many clinical kalaemia177. The addition of the direct renin inhibitor
trials demonstrating significant reductions in the risk of aliskiren to conventional RAAS blockade in patients
progression and increased rate of regression of albumin with diabetes was also associated with adverse outcomes
uria following interventions to lower systolic blood pres- and had no effect on ESRD, although albuminuria was
sure165. For example, in the UKPDS trial, a reduction in modestly reduced along with blood pressure levels178.
systolic blood pressure from 154 mmHg to 144 mmHg Mineralocorticoid receptor antagonists also significantly
was associated with a 30% reduction in microalbumin reduce albuminuria when added to conventional RAAS
uria166. This benefit seems to occur regardless of whether blockade179, but are limited by anti-androgenic adverse
patients had an elevated blood pressure to begin with167, effects and hyperkalaemia, especially in patients with
and no evidence of a threshold for loss of efficacy or renal impairment. Newer mineralocorticoid receptor
J-curve168 has been noted; the risk for albuminuria con- antagonists that reduce these adverse effects are being
tinues to decrease as the achieved blood pressure falls. actively explored for the management of DKD180.
Although this relationship might not be the same for Ultimately, any decision as to which blood-pressure-
mortality in patients with diabetes169, such data provide lowering agent is best is largely academic. Even in a
a renoprotective rationale for aggressively treating all trial setting, most patients require three to four differ-
patients with diabetes and CKD with antihypertensive ent antihypertensive agents to achieve acceptable blood
agents, regardless of blood pressure. pressure targets181. Establishing the optimal combina-
Although a target blood pressure of <130/80 mmHg tion is perhaps a more appropriate clinical question.
has been previously recommended for patients with dia- For example, in the Avoiding Cardiovascular Events
betes and CKD, when achievable and tolerated, data from through Combination Therapy in Patients Living with
the ADVANCE and Action to Control Cardiovascular Systolic Hypertension (ACCOMPLISH) trial, better renal
Risk in Diabetes (ACCORD) trials showed that intensi- outcomes (with respect to doubling of serum creatinine,
fication of blood pressure control failed to consistently starting dialysis or death) were observed in patients

PRIMER
receiving benazepril (an ACE inhibitor) plus amlodi- a history of cardiovascular disease (which is often typical
pine (a calcium channel blocker) than in those receiving in DKD). Certainly, significant weight loss is associated
benazepril and hydrochlorothiazide (a diuretic), despite with reduced incidence of progressive CKD in diabetes,
equivalent blood pressure control182. and regression of albuminuria has been observed follow-
ing bariatric surgery 196,197. Avoiding high levels of protein
Blood lipid lowering intake (that is, less than 1.3 g of protein per kilogram body
Lipid-lowering treatment is widely recommended in all weight per day or more than 20% of food energy from
patients with CKD183 to reduce the risk of cardiovascular protein) is also appropriate for individuals with CKD198.
disease and associated mortality 183. Whether lipid lower However, formal protein restriction (<0.8 g per kg body
ing also protects the kidneys remains controversial. No weight per day) is not generally recommended as it is
clear renoprotective effect of statins in patients with difficult to apply and enjoy and might be associated with
diabetes is evident 184,185, and some potential risks have clinically important risks, including malnutrition and
been recently identified186. By contrast, fibrate drugs bone remodelling 199. Some studies have suggested that a
reduce albuminuria187; whether this effect is mediated dietary intake of omega‑3 polyunsaturated fatty acids200
by lipid lowering, pleiotropic effects mediated by the or omega‑3 supplementation201 might also have beneficial
activation of PPARα or trans-repression of other tar- effects on albuminuria in CKD.
gets is unclear 188–190. Fenofibrate is also associated with
a rapid increase in serum creatinine (~10–15%), leading Managing co‑morbidity in patients with CKD
to a fall in the eGFR, although the true GFR might be Patients with diabetes and CKD experience an increased
unaffected191. Nonetheless, an agent that increases serum risk and severity of other diabetic complications, includ-
creatinine makes its use in patients with established renal ing retinopathy, neuropathy, gastroparesis, sexual dys-
impairment challenging. function, cognitive decline, sleep and mood disorders,
heart failure, atrial fibrillation, cardiovascular disease
Diet and lifestyle interventions and foot disease. The presence of CKD in a patient with
Intensive diet and lifestyle interventions that are fre- diabetes can be considered a risk marker for each of these
quently recommended to patients with diabetes and CKD conditions33 but it is also often an aggravating factor.
include weight loss, increased physical activity, smoking The more severe the renal impairment, or the greater
cessation, Mediterranean diet and sodium restriction. the albuminuria, the greater the risk of cardiovascular
Limited research supports the ability of such interven- as well as other complications. For example, myocardial
tions to reduce risk factors for progressive renal disease infarction and stroke are approximately twice as com-
and albuminuria192–195. Indeed, the LOOK-AHEAD study mon in those with diabetes and CKD than in those with
reported a significant reduction in incident albuminuria diabetes but without renal disease202,203, and patients
following a multifactorial diet and lifestyle intervention196. with ESRD carry a cardiovascular risk that is at least ten
However, the ability to truly modify renal progression times greater again.
or co‑morbid vascular outcomes remains controver- Such is the complexity of the management in CKD, it
sial, and the restrictions imposed by adherence might is common for other diabetic complications (for example,
be associated with a reduced quality of life in precisely eye or foot disease) to go undiagnosed or to be relatively
those patients who have the shortest life expectancy. neglected, even though the risk of non-renal calamity can
Moreover, the beneficial impacts of multifactorial lifestyle be very high. The presence of CKD in diabetes necessi-
intervention on hospitalizations and cost in the LOOK- tates intensive prevention, monitoring and screening and
AHEAD study were not evident among individuals with early aggressive treatment of co‑morbid disease. Indeed,
aggressive multifactorial intervention specifically in
patients with CKD has sustained beneficial effects with
Box 5 | Key limitations of glucose-lowering strategies in DKD respect to their other vascular complications and reduces
Metformin their mortality 204. Moreover, the application of such treat-
Dose modification required at reduced estimated glomerular filtration rate (eGFR), ments and improved control of risk factors has largely
discontinuation at a low eGFR, increased gastrointestinal side effects, hyperlactaemia been responsible for the halving of age-standardized
Sulfonylureas mortality in patients with CKD over the past 20 years17.
Increased hypoglycaemia, accumulation of parent or active metabolites (with As cardiovascular and cerebrovascular diseases are the
glyburide, glimepiride), require discontinuation at a low eGFR (all) major preventable causes of death in patients with dia-
Thiazolidinediones betes and CKD, particular emphasis should be placed on
Fluid retention, increased risk of congestive heart failure reducing cardiovascular risk, including lowering lipid
Dipeptidyl peptidase 4 inhibitors levels, treatment of hypertension, smoking cessation and
Dose modification (except linagliptin) lifestyle modification. Indeed, the absolute benefit from
aggressive lipid lowering seems to be greatest in patients
Glucagon-like peptide 1 agonists
Discontinuation at a low eGFR (exenatide), increased gastrointestinal adverse effects with CKD205,206. Low-dose aspirin can also be appropriate
for the primary prevention of cardiovascular disease in
Sodium glucose co‑transporter 2 inhibitors
patients with CKD, as most have a 10‑year risk of cardio-
Reduced efficacy at a low eGFR, hypovolaemia, interaction with loop diuretics
vascular events of more than 10%207. However, paradoxi-
Insulin
cally harmful effects from antiplatelet therapy have also
Increased hypoglycaemia, prolonged insulin half-life
been reported for aspirin208 and clopidrogel in patients

PRIMER
with CKD209. Patients at high risk of CKD can also be disturbances, calciphylaxis and bone demineralization.
considered appropriate for screening for asymptomatic In each case, these complications are more common, have
heart disease because early management can improve out- greater severity and are less well tolerated in patients with
comes, although many of these patients are already maxi- diabetes than those without diabetes who have a similar
mally medically treated and the utility of cardiac screening degree of renal impairment210. Patients with CKD are also
beyond risk stratification remains unclear. more vulnerable to episodes of acute kidney injury, includ-
Similarly, the multifactorial interventions needed for ing contrast nephropathy, renal ischaemia, hypovolaemia,
the management of CKD in diabetes and its associated sepsis, surgery and non-steroidal anti-inflammatory
burden of co‑morbid disease frequently exposes patients drug-induced acute kidney injury, all of which can be
to iatrogenic complications. In particular, adverse drug avoided by vigilance, education, close follow‑up monitor-
reactions are more commonly observed in patients with ing and assiduous early management, including stopping
CKD, which reflects the pill burden, altered pharmaco RAAS blockade, diuretic use and metformin treatment
kinetics, interactions with abnormal physiology and when appropriate. Ultimately, progressive renal decline
other medications, as well as frequently inadequate requires timely referral to specialist services and, when
dose-adjustments in this setting. Appropriate targeting, appropriate, advanced care planning for some form of
cautious prescribing, judicious dosing and close monitor- RRT or conservative care before their renal impairment
ing are necessary for all therapies in patients with CKD, becomes symptomatic211,212. The optimal timing for any
especially when multiple practitioners are involved and RRT should be determined by individual circumstances,
renal disease is not the primary focus. Given the sheer but generally dialysis should be considered when there are
complexity of multifactorial management in patients signs or symptoms of uraemia, inability to control hydra-
with CKD, optimal care is best delivered by compre- tion status or blood pressure or a progressive deterioration
hensive multidisciplinary teams focused on individual in nutritional status. Such individuals are usually identi-
patient needs. Such coordinated care is often limited fied when the eGFR falls to between 6–9 ml/min/1.73m2.
and challenging to implement in routine clinical prac- Earlier asymptomatic initiation of dialysis specifically
tice, although if only one subset of patients with diabe- because of diabetes is not warranted, unless uraemic
tes could be targeted for such an intensive approach, it symptoms are difficult to detect and/or close supervision
should be those with CKD. is not feasible.
Managing advanced CKD Quality of life

Advanced-stage CKD is also associated with a range of The presence and severity of CKD in any individual with
complications that require specific additional manage- diabetes is also strongly associated with their health-
ment, including anaemia, fluid retention, itch, electrolyte related quality of life (HRQOL)213,214. The HRQOL in
these patients is partly mediated by the presence and
severity of co‑morbid disease (FIG. 7) and associated risk
Cognitive
impairment factors. In parallel, CKD can also affect HRQOL through
Depression
the burden of multifactorial interventions necessitated
Cerebrovascular
and anxiety disease by the increased risk for or presence of co‑morbid disease,
which often leads to a costly time-consuming round of
clinical appointments with multiple practitioners across
Periodontal Coronary different specialities, contributing to patient confusion,
disease heart disease poly-pharmacy and an increased risk of iatrogenic com-
plications156. Clinically relevant improvements in HRQOL
in patients with diabetes and CKD can be obtained from
Diabetic structured management programmes that incorporate
Eye disease DKD cardiomyopathy different specialties. Specific education and support pro-
grammes targeting at-risk patients with CKD can also
vastly improve diabetes care; such care can be individual-
Erectile Peripheral ized or community-based care215. Formalized education
dysfunction vascular disease of primary care physicians and other health care pro-
viders, as well as systematic management and decision-
support programmes, can also improve outcomes for their
patients, including HRQOL216–218.
Neuropathy Foot disease
Beyond its association with co‑morbid disease, CKD
Bladder can also directly affect HRQOL indices in individuals with
dysfunction diabetes through its negative effects on physical perfor-
mance, fatigability, appetite, nutrition, immune function,
Figure 7 | The strong association between diabetic Nature
kidneyReviews
disease|and increased
Disease Primers
incidence and prevalence of other diabetic complications. The increased risk of bone mineralization, cognitive function, pruritus and
diabetic complications for patients with chronic kidney disease (CKD) means that the fluid retention. Some of these complications are medi-
management of CKD in diabetes is never only focused on the kidney, but must also ated by the retention of so‑called uraemic toxins, which
involve the pro-active prevention, early detection and effective treatment of all are highest when HRQOL is at its lowest. Renal anaemia
diabetic complications. might also play an important part in some patients. By the

PRIMER
steadily increasing burden of ESRD222. Without effective

Box 6 | Strategies currently in clinical development for DKD
prevention and treatment, the current global epidemic
• Endothelin 1 receptor antagonism of diabetes combined with improved survival from heart
• Novel mineralocorticoid receptor blockade disease may well lead to a similar crisis of CKD, with
• Pirfenidone (and other novel antifibrotics) overwhelming requirements for RRT and health care
• C‑C chemokine receptor type 2 antagonists systems, particularly in developing counties that carry
• Macrophage migration inhibitory factor antagonists
the greatest burden of type 2 diabetes19. Even in the past
10 years, the number of people with diabetes in RRT
• Membrane primary amine oxidase (also known as vascular adhesion protein 1 and
programmes has more than doubled30.
semicarbazide sensitive amine oxidase) inhibitors
Intensive management of diabetes, including control
• Vitamin D analogues
of glucose and blood pressure and blockade of the RAAS,
• Xanthine dehydrogenase/oxidase inhibitors will reduce the incidence of CKD and slow its progression.
• Phosphodiesterase inhibitors Indeed, a decline in the incidence of CKD over the past
• Urotensin 2 antagonists 30 years14,15 and recent plateau in the number of patients
• NADPH oxidase inhibitors with diabetes who develop ESRD is considered to be
• Factor erythroid 2‑related factor 2 agonists attributable to improved diabetes care223,224. The prognosis
• Advanced glycation end-product scavengers of patients with DKD has also dramatically improved17,18.
• Peroxisome proliferator-activated receptor agonists However, there remain deficiencies in implementation
that need to be bridged through pragmatic guidelines
• MicroRNA therapeutics
and clinical pathways, Phase IV studies and audits, provi-
sion of adequate resources, and appropriate targeting of
education and support.
time the eGFR declines to <60 ml/min/1.73 m2, up to one An unmet need also remains for innovative treatment
in three individuals with diabetes will have anaemia219. strategies for preventing, arresting, treating and reversing
Palliative correction of anaemia using erythropoietin CKD in diabetes. Despite initially positive findings, clini-
receptor agonists can improve performance and quality cal trials of new agents have frustratingly failed to live up
of life, but not without considerable cost in terms of the to their promise225. Even the failure of early RAAS block-
financial cost of the medications themselves, potential ade to reduce the development of CKD226,227 in patients
for adverse effects220, and the systematic management with diabetes has undermined what was widely viewed to
and follow‑up programme they require. Abnormal cal- be the best means of renoprotection. However, each fail-
cium phosphate homeostasis is also common in patients ure has led to an evolution of our understanding of CKD,
with CKD, as well as those with reduced HRQOL, but and led to newer agents, strategies and designs of clinical
no clear evidence has shown that vitamin D, phosphate trials. Several novel therapies are currently in develop-
binders or calcimimetics improve HRQOL221. Limitations ment 225 (BOX 6). However, at present, even when used in
and restriction of certain foods and fluid in patients with an optimal combination with standard medical care, renal
advanced-stage CKD also places an additional burden. complications seem to be only modestly reduced at best,
However, by far the most important consideration for and treatment often comes at the considerable expense
HRQOL in advanced CKD relates to the initiation of RRT, of additional pill burden, cost and exposure to off-target
its appropriateness, its timing, modality and setting. It is effects. Given the primacy of CKD in clinical outcomes
beyond the scope of this Primer to discuss the enormous for those with diabetes, and the current absence of speci
challenges of RRT in patients with diabetes. Importantly, fic treatment, increased investment in CKD research is
even the finest RRT will at best achieve much less than urgently required.
a naturally functioning kidney, reinforcing the primary To provide evidence of efficacy in CKD it is necessary
importance of renoprotection in the management of dia- to target robust clinical end points. However, because the
betes. In addition, RRT will not be appropriate for some progression of renal disease is usually a slow process, over
patients with diabetes and CKD, because of co-morbidity, many years or even decades, clinical trials with defined
frailty, symptomatology and the anticipated excessive end points such as ESRD are impractical. Although sur-
burden of therapy. rogate end points such as change in albuminuria and/or
change in eGFR are useful indicators, individually or in
Outlook combination they might not reflect the true renoprotective
The health implications of the diabetes epidemic are of potential of interventions. Robust surrogate end points for
unparalleled proportions, both in terms of morbidity progressive renal injury in diabetes are urgently needed
and mortality as well as the vast health resources that to facilitate the testing of different strategies. Given the
they currently demand and will need in the future. The heterogeneous nature of CKD, a systematic panel of bio-
majority of these resources will be directed towards the markers and molecular phenotypes rather than a one-
prevention and management of diabetic complications, size-fits-all surrogate approach will probably be essential
including CKD. A portent of the coming storm can be for the development of new treatments. Improving the
demonstrated by the Pima Indian population, among design of clinical trials will also be important, including
whom an ‘outbreak’ of type 2 diabetes began in the late larger risk-enriched cohorts, early selection of respond-
1950s. Inevitably, in the 1970s, an epidemic of DKD ers and early exclusion of those intolerant to therapy, and
followed that has continued into this century, with a appropriate surrogate and end point definition.

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quality improvement using electronic health records. are associated with a higher prevalence of Novartis, Novo Nordisk, Merck Sharp & Dohme, Eli Lilly and
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with diabetes and CKD: a pilot study for a cluster- (2015). Ingelheim, Eli Lilly and Company, Merck Sharpe and Dohme,
randomized trial. Am. J. Kidney Dis. 51, 777–788 236. Forsblom, C. et al. Added value of soluble tumor Servier, Takeda, Novo Nordisk and AstraZeneca, as well as
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CORRECTION
Diabetic kidney disease

Merlin C. Thomas, Michael Brownlee, Katalin Susztak, Kumar Sharma, Karin A. M. Jandeleit-Dahm,
Sophia Zoungas, Peter Rossing, Per-Henrik Groop and Mark E. Cooper
Nat. Rev. Dis. Primers article number: 15018; doi:10.1038/nrdp.2015.18; published online 30 July 2015
In the version of the article originally published, Figure 1 incorrectly stated that the DEMAND study with 2,862 participants
was conducted in an Indigenous Australian population. This analysis was conducted using participants from Asia. The
article has now been corrected.

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PRIMER

Diabetic kidney disease

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 1

© 2015 Macmillan Publishers Limited. All rights reserved

2 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

NHANES III NEFRON RIACE

10% Patients with albuminuria

27% 42% 19%

No CKD = 54% No CKD = 38% No CKD = 62%

DEMAND DEMAND DEMAND DEMAND

13% 17% 13%

No CKD = 43% No CKD = 32% No CKD = 39% No CKD = 43%

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 3

© 2015 Macmillan Publishers Limited. All rights reserved

NADPH NADP+ NAD+ NADH Polyol

NADH NAD+ PKC

4 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

Renal corpuscle Mesangial cell

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 5

© 2015 Macmillan Publishers Limited. All rights reserved

Nature Reviews | Disease Primers

6 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7

© 2015 Macmillan Publishers Limited. All rights reserved

Insulin resistance including lipid, blood pressure and glucose control, as

8 | 2015 | VOLUME 1 www.nature.com/nrdp

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18 6 The best formula to accurately estimate GFR remains

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9

© 2015 Macmillan Publishers Limited. All rights reserved

Table 1 | Genes potentially linked to diabetic kidney disease*

10 | 2015 | VOLUME 1 www.nature.com/nrdp

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Management Box 4 | Potential biomarkers for progressive DKD*

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11

© 2015 Macmillan Publishers Limited. All rights reserved

100 improve ESRD, cardiovascular disease or other hard out-

60 potentially hypoperfusion in the setting of impaired

12 | 2015 | VOLUME 1 www.nature.com/nrdp

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NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13

© 2015 Macmillan Publishers Limited. All rights reserved

Managing advanced CKD Quality of life

14 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

steadily increasing burden of ESRD222. Without effective

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15

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16 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 17

© 2015 Macmillan Publishers Limited. All rights reserved

18 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 19

© 2015 Macmillan Publishers Limited. All rights reserved