Diabetic Kidney Disease: From Physiology To Therapeutics

J Physiol 592.
18 (2014) pp 3997–4012 3997
Diabetic kidney disease: from physiology to therapeutics

Carmen Mora-Fernández1,2 , Virginia Domı́nguez-Pimentel3 , Mercedes Muros de Fuentes2,4 ,
José L. Górriz2,5 , Alberto Martı́nez-Castelao2,6 and Juan F. Navarro-González1,2,3
1
Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
2
Sociedad Española de Nefrologı́a & Red de Investigación Renal (RETIC/REDinREN/RD12/0021/0019, ISCIII), Spain
3
Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
4
Clinical Analysis Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
5
University Hospital Dr. Peset, Valencia, Spain
6
University Hospital of Bellvitge, Barcelona, Spain
Abstract Diabetic kidney disease (DKD) defines the functional, structural and clinical
abnormalities of the kidneys that are caused by diabetes. This complication has become the
single most frequent cause of end-stage renal disease. The pathophysiology of DKD comprises
The Journal of Physiology
the interaction of both genetic and environmental determinants that trigger a complex network
of pathophysiological events, which leads to the damage of the glomerular filtration barrier, a
highly specialized structure formed by the fenestrated endothelium, the glomerular basement
membrane and the epithelial podocytes, that permits a highly selective ultrafiltration of the
blood plasma. DKD evolves gradually over years through five progressive stages. Briefly they
are: reversible glomerular hyperfiltration, normal glomerular filtration and normoalbuminuria,
normal glomerular filtration and microalbuminuria, macroalbuminuria, and renal failure.
Approximately 20–40% of diabetic patients develop microalbuminuria within 10–15 years of
the diagnosis of diabetes, and about 80–90% of those with microalbuminuria progress to more
advanced stages. Thus, after 15–20 years, macroalbuminuria occurs approximately in 20–40% of
patients, and around half of them will present renal insufficiency within 5 years. The screening
and early diagnosis of DKD is based on the measurement of urinary albumin excretion and the
detection of microalbuminuria, the first clinical sign of DKD. The management of DKD is based
on the general recommendations in the treatment of patients with diabetes, including optimal
glycaemic and blood pressure control, adequate lipid management and abolishing smoking, in
addition to the lowering of albuminuria.
(Received 3 February 2014; accepted after revision 30 May 2014; first published online 6 June 2014)
Corresponding author J. F. Navarro-González, University Hospital Nuestra Señora de Candelaria, Nephrology and
Research Unit. Carretera del Rosario, 145 Santa Cruz de Tenerife 38010, Spain. Email: jnavgon@gobiernodecanarias.org
Abbreviations ACE, angiotensin-converting enzyme; ACEI, ACE inhibitor; AGEs, advanced glycation end-products;
AI, angiotensin I; AII, angiotensin II; ARB, angiotensin receptor blocker; BP, arterial blood pressure; DKD, diabetic
kidney disease; ESRD, end-stage renal disease; GBM, glomerular basement membrane; GFB, glomerular filtration barrier;
GFR, glomerular filtration rate; PTF, pentoxifylline; PKC, protein kinase C; RAAS, renin–angiotensin–aldosterone
system; UAE, urinary albumin excretion.
Carmen Mora-Fernández is responsible for the Scientific Management of the Research Unit at the
University Hospital Nuestra Señora de Candelaria (RU-HUNSC). She obtained her Bachelor of Medicine
and Surgery in 1991 from the University of Alcalá de Henares (Madrid, Spain). She is principal associate
researcher within the Nephrobiology and Cardiovascular Risk Section at the RU-HUNSC. She is a member
of the Clinical Research Ethics Committee of the HUNSC. Dr. Navarro-González is Chair of the Research
Division with a joint appointment as Staff Nephrologist at the HUNSC, Assistant Professor of Nephrology
at the University of La Laguna (Santa Cruz de Tenerife, Spain), Teaching and Research Coordinator of the
Spanish Society of Nephrology, and National Coordinator of the GEENDIAB (Spanish Study Group for
the study of Diabetic Nephropathy).

C 2014 The Authors. The Journal of Physiology
C 2014 The Physiological Society DOI: 10.1113/jphysiol.2014.272328
3998 C. Mora-Fernández and others J Physiol 592.18
Introduction sence of fenestrations that appear as transcytoplasmic

holes, a structural feature characterized by the absence
New terminology to describe kidney disease attributable
of the diaphragm and the lack of ‘plasmalemmal
to diabetes is being introduced in recent guidelines
vesicle-associated protein-1’ (a type II transmembrane
(National Kidney Foundation, 2007). Thus, the term
glycoprotein that is an integral part of the diaphragm),
‘diabetic nephropathy’ should be replaced by diabetic
retention of the basal lamina, and the presence of surface
kidney disease (DKD), a long-term highly prevalent
glycocalyx that extends over the fenestrations.
major microvascular complication defined as functional,
The fenestrations are transcellular holes of 60–80 nm
structural and clinical abnormalities of the kidneys that
in diameter that occupy 30–40% of the cell surface.
are caused by diabetes. This complication has become
They are mainly concentrated toward the peripheral cyto-
the single most frequent cause of end-stage renal disease
plasm, and arranged in a cluster of sieves separated by
(ESRD), and it is considered ‘a medical catastrophe of
the ridges of cytoplasm. They are thus localized in the
worldwide dimensions’ (Ritz et al. 1999). Additionally, it
region of cytoplasm that is opposite to the podocyte
is strongly associated with cardiovascular morbidity and
foot processes and filtration slit across the basement
mortality. Of the complications of diabetes, DKD may be
membrane (Satchell & Braet, 2009). Fenestrations are an
the most detrimental regarding patients’ quality of life and
adaptation that facilitates the high water permeability
survival.
of the glomerular endothelium which is essential for
This review presents a brief update of DKD, including
filtration function. The size of the fenestrations is much
the physiological aspects of the glomerular filtration
too large to easily exclude large protein, including albumin,
barrier, the pathogenic mechanisms and natural history
from the glomerular filtrate. Therefore, the glomerular
of this complication, and aspects related to screening,
capillary wall is not a perfect barrier for macromolecules
diagnosis and management.
and it allows the albumin to move across. However,
glomerular filtration of albumin is followed by tubular
Glomerular filtration barrier: a physiological update reabsorption, allowing urine to remain virtually albumin
free (Obeidat & Ballermann, 2012).
The kidneys produce a virtually protein-free primary urine The glycocalyx is a polyanionic hydrated mesh
through an apparently simple process: the blood enters composed principally of proteoglycans, glycoproteins
the glomerular tuft via the afferent arteriole and perfuses and sialoproteins, with particular molecular and charge
the glomerular capillaries, where filtration across the characteristics, on the luminal surface of glomerular
glomerular filtration barrier into Bowman’s space occurs. endothelial cells. This structure covers the fenestrations
The primary urine is drained into the renal tubules, and the and participates in regulating permeability as well as
blood exits the tuft via the efferent arteriole. However, the ligand/receptor and cellular interactions (Weinbaum et al.
success of this filtration process is based on the presence of 2007). The biophysical models indicate that glycocalyx
a highly specialized structure: the glomerular filtration contributes to about 50% of the overall hydraulic
barrier (GFB). This filtration barrier permits a highly resistance of the glomerular filtration barrier, and the
selective ultrafiltration of the blood plasma: it is freely specific composition of the glycocalyx in the fenestrations
permeable to water, small- and mid-sized solutes, and is important for maintaining the permeability properties
low-molecular-weight proteins up to the mass of albumin, and the glomerular filtration rate (Singh et al. 2007).
but largely precludes the filtration of plasma proteins with
a mass of more than 60–70 kDa, especially if they are
negatively charged. As an example, the estimated sieving
coefficient of albumin is lower than 0.0005, meaning The glomerular basement membrane. The GBM is a thin
that normally less than 0.05% of plasma albumin passes layer (250–400 nm) of extracellular matrix proteins that
through the GFB to the urinary space. separates the vasculature from the urinary space. Most
This filtration apparatus is formed by three layers: of this membrane is located between two cellular beds:
the fenestrated endothelium, the glomerular basement the endothelial cells that line the glomerular capillaries,
membrane (GBM), and the epithelial podocytes with their and the podocytes that sit on the opposite side within
‘slit diaphragms’ (Fig. 1). The GFB functions as a whole, the urinary space. The remaining portions of the GBM
with each layer making an important contribution to lie between mesangial cells and podocytes at the bases
selective permeability, and its integrity and functionality of the capillary loops. Podocytes and glomerular end-
is maintained by an interplay of the cell types and othelial cells synthesize the components of the GMB
constituents (Pavenstädt et al. 2003) (Table 1). (with mesangial cells participating in the turnover),
which contains specific protein isoforms, some of them
The glomerular endothelium. Glomerular endothelial being crucial for glomerular development, structure and
cells have special characteristics, such as the pre- function (Miner, 2011, 2012).

C 2014 The Physiological Society
J Physiol 592.18 Diabetic kidney disease: from physiology to therapeutics 3999
Table 1. Key molecules in the glomerular filtration barrier most abundant protein in basement membranes: There
are six genetically distinct collagen IV α chains (α1 to
Glomerular endothelial cells α6), and these chains assemble to form three different
Glycocalyx
heterotrimers. In the mature GBM, the composition of
Proteoglycans
collagen IV chains is α3α4α5, although there is a switch of
Glycosaminoglycans: heparan sulphate
Plasma proteins: albumin
these chains during glomerulogenesis. Regarding laminin,
Glomerular basement membrane this is a ubiquitous basement membrane component
Laminin (laminin-521 (α5β2γ1)) that possesses several isoforms. They are all composed
Type IV collagen (α3α4α5) of three different homologous chains (α, β and γ), and
Heparan sulphate proteoglycans (agrin) secreted as αβγ heterotrimers. Laminin-521 (α5β2γ1)
Nidogen-1 and -2 is the major isoform in the normal GBM. However,
during the processes of GBM formation and maturation,
Podocytes and slit diaphragm
Nephrin Neph1/Neph3 Podocin
there is a developmental transition in laminin trimer
CASK JAM-A Zona occludens-1 deposition, which occurs coincidentally with the trans-
Catenins ition of type IV collagen chains. Concerning the third
TrpC6 CLIC5 CD2-associated protein constituent of the GBM, nidogen-1 and nidogen-2, these
are two virtually ubiquitous basement membrane homo-
CASK, calcium–calmodulin-dependent serine protein kinase;
JAM-A, junctional adhesion molecule A; TrpC6, transient receptor
logous glycoproteins encoded by two different genes.
potential-6 channel; CLIC5, chloride intracellular channel 5; CD2, Since nidogen-1 binds to both laminin and type IV
cluster of differentiation 2. collagen, it has been suggested that nidogen functions
to connect the separate laminin and type IV collagen
networks in basement membranes, providing extra
Nine major proteins have been found in the GBM, stability under situations of unusual stress. Finally, the
although like other basement membranes, the main four last main component is agrin, the major heparan sulphate
types of extracellular matrix macromolecules are type IV proteoglycan of the GBM. Agrin is highly negatively
collagen, laminin, heparan sulphate proteoglycan and charged due to the presence of sulfated glycosaminoglycan
nidogen (Miner, 2011, 2012). Type IV collagen is the with anionic sites that ultimately provide a net negative
Actin Actin
Cadherin
Podocin
Podocin Nephrin
CD2-associated
protein
Podocyte Neph1
URINARY
SPACE
Foot Slit
Podocyte process diaphragm
Main components:
Glomerular basement membrane
Type IV collagen, Laminin
Nidogen, Heparan sulphate proteoglycan
Endothelial cell Endothelial CAPILLARY

fenestrations SPACE
Figure 1. Schematic representation of the kidney filtration apparatus and main protein components of
the podocyte slit diaphragm

charge on the GBM. Agrin is important due to its effects as P-cadherin or catenins, and proteins typically found in
on different aspects. Such as the charge selectivity within tight junctions, such as zona occludens-1 and junctional
the glomerular filtration barrier and the linking of the adhesion molecule A. In addition, several integral
GBM to the adjacent cells. membrane proteins, including nephrin, podocin and
The GBM participates importantly in the normal Neph1, not found in other junctions, have been identified
homeostasis and function of the GFB through different as slit diaphragm components. During development,
functions: it provides structural support for the podocytes are initially connected via tight-junction and
glomerular capillaries, harbours ligands for receptors on gap-junction components, which are gradually replaced
the surface of the adjacent endothelial cells, podocytes by nephrin, podocin and Neph1, although tight-junction
and mesangial cells, and contributes to glomerular and adherens-junction molecules remain in the vicinity of
permselectivity. In support of this idea, mutations in the slit diaphragm. Nephrin, podocin and Neph1 form a
genes encoding the four major proteins of the GBM zipper-like structure that is the hallmark of the mature slit
are known to cause human kidney diseases. In addition, diaphragm (Grahammer et al. 2013).
environmental conditions can also produce alterations in Nephrin, a type 1 transmembrane protein, is considered
the composition and structure of the GBM, with DKD the central molecule to bridge the gap between adjacent
as an example in which the GBM is adversely affected by podocyte foot processes through interactions with
the microenvironment. Finally, primary changes in the other nephrin molecules (homologous) or with Neph1
GBM may result in structural and functional alterations molecules (heterologous), and therefore, is hypothesized
in the neighbouring cells (podocytes, endothelial cells to be the ‘pore’ of the slit diaphragm (Wartiovaara et al.
and mesangial cells), thereby affecting glomerular 2004). In biopsy-controlled clinical studies, it has been
filtration. demonstrated that nephrin expression is reduced by more
than 60% in type 2 diabetic patients. Finally, podocin
seems to recruit other slit diaphragm proteins and to
The podocytes and the slit diaphragm. The podocytes increase the signalling properties of the nephrin–Neph1
are the glomerular visceral epithelial cells, terminally complex.
differentiated and highly specialized cells of mesenchymal Whenever podocytes undergo stress or injury,
origin that cover the urinary aspect of the GBM. They have irrespective of the causative stimulus, they undergo a
a cell body, long primary processes and a complex network response that ultimately leads to foot process effacement
of interdigitating cellular extensions called secondary and loss of slit diaphragms, resulting in proteinuria.
processes or foot processes. The foot processes of different
podocytes interact at specialized intercellular junctions
called filtering slit or slit diaphragms (Pavenstädt et al.
Epidemiology of diabetic kidney disease
2003; Grahammer et al. 2013).
The complex cellular architecture of podocytes, Diabetes mellitus is one of the most common chronic
essential to maintain its unique structure and function, diseases. The frequency of diabetes, especially type 2,
is preserved by the presence of an actin cytoskeleton, is continuing to be an increasing international health
a particular organization of microtubules and actin burden. This is related to several factors such as the ageing
microfilaments in the cellular cytoplasm. Actinin-4 of the population and the burden of obesity. Importantly,
and synaptopodin are actin-associated proteins with an similar trends are also found for type 1 diabetes, with
important role in the regulation of actin cytoskeleton the predictions showing that the number of new cases
(Mathieson, 2012). In addition to this architectural aspect of type 1 diabetes in European children younger than
of podocytes, increasing interest has been paid to the 5 years is predicted to double between 2005 and 2020,
composition of the slit diaphragm, a dynamic structure and the prevalent cases younger than 15 years will rise
with an essential role in the function of GFB (Huber & by 70% (Patterson et al. 2012). Therefore, the data from
Benzing, 2005). the International Diabetes Federation estimate that the
The protein components of the slit diaphragm number of people with diabetes will rise from 366 million
have to fulfil several tasks, including their role as a in 2011 to more than 550 million in 2030, which represents
macromolecular filter: anchor the filter to the GBM, a 50% increase in less than 20 years (Whiting et al.
connect the slit diaphragm to the actin cytoskeleton, 2011). Thus, ever more subjects are exposed to the risk
and be part of a signalling complex that integrates and of ultimately developing diabetic complications which
mediates extracellular and intracellular signals regulating impose a tremendous burden on patients, their families,
the plasticity of foot processes (Grahammer et al. health-care systems and society.
2013). A number of proteins that are associated with The frequency of nephropathy in type 1 diabetes has a
junctions in other locations are also found at the slit rather predictable prevalence (around 30–40%), whereas
diaphragms, including adherens junction proteins, such in type 2 diabetes it depends on several factors, such as race

and ethnicity, which have a major impact on the risk for the factors, renal damage in diabetes is not solely explained
development of kidney disease as well as for progression by these elements. Current knowledge indicates that
to renal damage. In the last 10 years, rates of ESRD due this represents only a partial view of a much more
to diabetes in the African American, Native American and complex scenario with the interaction of both genetic
Hispanic populations are increasing, whereas rates have and environmental determinants that trigger a complex
been unchanged in the white and Asian populations in network of pathophysiological events (Fig. 2 and
the United States (Stanton, 2014). Irrespective of these Table 2).
considerations, diabetes mellitus is the most common
cause of ESRD, and DKD is the leading specific primary Genetic factors. During the last decades, growing
renal diagnosis for patients initiating renal replacement evidence supports the participation of genetic factors
therapy. in the development and progression of DKD. Both
However, in the last few years an interesting paradox candidate gene approaches and genome-wide linkage
has been noted: a declining trend in the incidence of analyses have suggested several candidate genes with
ESRD due to diabetes at the same time as diabetes pre- potential impact on this complication. However, many
valence is increasing in the general population (Burrows of these findings have not been robustly replicated, and
et al. 2010). Several factors have been considered to many genes responsible for susceptibility to diabetic
explain this situation, including the success of current nephropathy remain to be identified. In recent years,
efforts in prevention, early detection and management several meta-analyses have strongly pointed to some
of DKD, the improvement of general treatment and care, polymorphisms as potential genetic factors for DKD
the better control of additional ESRD risk factors (i.e. (Table 3), although definitive studies are required to firmly
hypertension), or the effectiveness of pharmacological establish the role of these polymorphisms on the risk of
agents as renoprotective instruments. However, it might DKD.
be premature to state a real decline in ESRD in diabetes,
and these initial data must be confirmed by adequate
Metabolic factors. The cellular elements of the kidney
epidemiological studies.
respond to hyperglycaemia by prompting diverse intra-
cellular processes, including: alteration in cellular energy
Pathogenic mechanisms of diabetic kidney disease
production; activation of different enzymes, such as aldose
Although DKD was classically considered the result of reductase and protein kinase C (PKC); enhanced flux
the interaction between metabolic and haemodynamic of polyols and hexosamines; generation of advanced
Genetic factors Environmental factors
DIABETES
Pathogenic mechanisms for renal injury

Hyperglycaemia
Renin-Angiotensin-Aldosterone System
Metabolic Haemodynamic Inflammatory

Advanced glycation Systemic hypertension Inflammatory cells
Polyol Impaired renal vascular regulation Adhesion molecules
Protein kinase C Intraglomerular hypertension Chemokines
Oxidative stress Altered sodium/fluid balance Inflammatory cytokines
Activation of cell signalling pathways and transcription factors
Cellular and extracellular matrix-related effects

Differentiation ↑Collagen & fibronectin
Proliferation ↑Connective tissue
Hypertrophy ↑Inhibition metalloproteinases
Apoptosis ↓Matrix degradation
Renal functional and structural changes

Figure 2. Schematic overview of the
pathogenic mechanisms of diabetic kidney Diabetic Kidney Disease
disease

Table 2. Key factors and pathways in the pathogenesis of diabetic kidney disease
Haemodynamic
Prostanoids Nitric oxide
Renin–angiotensin–aldosterone system
Vascular endothelial growth factor (VEGF)
Transforming growth factor (TGF)-β1
Metabolic
Glucose transporters: GLUT-1, GLUT-4, glucokinase/hexokinase.
Advanced glycation end products and their receptors
Aldose reductase Protein kinase C
Diacylglyerol UDP-N-acetylglucosamine
NADPH oxido-reductase Oxidative stress
TGF-β–Smad–mitogen-activated protein kinase (TGF-β–Smad–MAPK)
Janus kinase–signal transducer and activator of transcription (JAK-STAT)
Growth factors
VEGF Connective tissue
TGF-β1 growth factor
Inflammation
Chemokines: monocyte chemoattractant protein-1
Adhesion molecules: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1).
Inflammatory cytokines: interleukin-1, -6, -18, and tumour necrosis factor-α
Transcription factors: nuclear transcription factor κ-B (NF-κB)
Table 3. Association between genetic polymorphisms and diabetic kidney disease in recent meta-analysis
Gene Polymorphism Effect References
Angiotensin-converting Insertion/deletion (I/D) D or DD associated Yu et al. 2012

enzyme ESRD susceptibility
Glucose transporter 1 Xbal, Enh2, HaeIII Susceptibility to DKD Cui et al. 2012
Carnosinase D18S880 Susceptibility to DKD Zhu et al. 2013
microsatellite
MTHF reductase C677T Increased risk of DKD Yang et al. 2013;
Chang et al. 2013
Tumour necrosis factor-α -308 G/A A allele protective Zhao et al. 2013
against DKD
Adiponectin rs17300539/rs2241766 Increased risk of DKD Lin et al. 2014
Transforming growth T869C Reduced risk of DKD Zhou et al. 2014
factor-β1
Endothelial nitric oxide 4b/4a, T786C, G894T Increased risk of DKD Dellamea et al. 2014
synthase
Apolipoprotein E ε2 and ε4 Increased risk of DKD Yin et al. 2014
D or DD, heterozygous and homozygous for the deletion (D) allele; DKD, diabetic kidney disease; ESRD, end-stage renal disease;
MTHF, methylenetetrahydrofolate.
glycation end-products (AGEs) and reactive oxygen Increased expression of the glucose transporter-1 has
species; activation of transducer signalling pathways; been related to the pathobiology of diabetic complications.
abnormal expression of cyclin kinases and their inhibitors; In addition, the expression of glucokinase/hexokinase, an
and dysregulation of factors controlling the extracellular important enzyme involved in the transport of glucose into
matrix homeostasis (Kanwar et al. 2011; Forbes & Cooper, cells, is regulated by glucose-6-phosphate dehydrogenase,
2013). which presents significant changes at sites of diabetes
Cells within tissues that are prone to diabetic complications.
complications are not able to modulate glucose trans- Hence, the highly regulated energy production process
port rates to prevent excessive intracellular glucose in the cells is uncontrolled in the context of diabetes as a
accumulation. result of excess substrate availability, in particular glucose.

Abnormalities in energy production are common signs of AGEs. Under normal conditons, AGEs are produced
seen in micro- and macrovascular diabetic complications, in small amounts but their concentrations markedly
playing an important role in their development. These increase under hyperglycaemia, in both the cellular and
include alteration in release of substrates, switching the extracellular compartments. Intracellularly, the AGEs
proportions of cell-specific fuel sources among glucose can modulate various events, such as the activation
intermediates, fatty acids and amino acids, changes in of PKC, mitogen-activated protein kinase (MAPK) and
respiratory chain protein function, and uncoupling of the transcription factors such as NF-κB, which, in turn,
respiratory chain. regulate the expression of diverse cytokines and growth
Once glucose is transported inside the cell, most factors, with special relevance for TGF-β1, which is a key
of this molecule is metabolized via glycolysis, with contributor to glomerular sclerosis and tubulointerstitial
the conversion of glucose-6-phosphate to fructose-6 fibrosis.
phosphate (F6-P), and then to glyceraldehyde 3-phosphate Regarding extracellular AGEs, these molecules are
(G3-P). G3-P forms glycerol phosphate, a precursor of formed based on a key characteristic of certain reactive
diacylglycerol (DAG), a signalling molecule responsible or precursor AGEs, their ability for covalent crosslink
for the recruitment and activation of PKC. This formation between proteins, which alters their structure
enzyme occupies a central position among signalling and function, as in cellular matrix, basement membranes,
kinases in the pathogenesis of DKD. A number of and vessel wall components. These modified proteins may
PKC isoforms are expressed in the kidney and are have decreased susceptibility to enzymatic hydrolysis by
activated in diabetic conditions, with special relevance for matrix metalloproteinases, which would allow them to
PKC-β2. PKC is activated by multiple routes, including accumulate. Thus, the characteristic structural changes
DAG, the polyol pathway and AGEs. PKC activation of DKD, thickened glomerular basement membrane and
influences a number of downstream pathways (end- mesangial expansion, are accompanied by accumulation
othelial nitric oxide synthase, endothelin-1, vascular end- of AGEs, leading to glomerulosclerosis and interstitial
othelial growth factor, transforming growth factor-β1 fibrosis. In addition, glycation of sulfated proteoglycans
(TGF-β1), NADPH oxido-reductase, nuclear factor-κB reduces their electronegativity and thus modifies the
(NF-κB)), with pathophysiological modifications that charge-selective filtration properties of the basement
result in altered blood flow and capillary permeability, membrane. Finally, the other major feature of AGEs is
and increased production of extracellular matrix proteins. related to their interaction with a variety of cell-surface
Under conditions of elevated intracellular glucose AGE-binding receptors, leading to the modulation of
concentrations, glycolysis diverts F6-P stepwise to cellular functions, and the activation of pro-oxidant,
UDP-N-acetylglucosamine, which is a precursor of pro-inflammatory events.
extracellular matrix proteins such as the proteoglycans. In
addition, UDP-N-acetylglucosamine produces the post-
translational modification of proteins within the cyto- Haemodynamic factors. Haemodynamic dysfunctions in
sol and nucleus. Therefore, these modified sugar residues patients with diabetes are represented by intraglomerular
compete with phosphate groups altering gene expression hypertension, hyperfiltration and systemic increase in
in diabetic tissues. arterial blood pressure (BP).
It is relevant that the excess glucose is also channelled Early studies demonstrated that the hyperglycaemic
into the polyol pathway, where it is reduced to sorbitol state impairs the physiological autoregulatory mechanism
by aldose reductase, a NADPH-dependent enzyme with a that maintains normal glomerular capillary pressure,
physiological role in detoxification of aldehydes into inert protecting the intraglomerular structures from changes
alcohols. Under basal conditions, the polyol pathway has in systemic BP. The final result is the ready transmission
a very low activity, but in a high-glucose environment, of systemic pressure to the glomerular capillary, with
around 30% of the glucose is derived to this pathway. the subsequent elevation of the transcapillary hydraulic
This increased activity results in the relative depletion pressure and the development of hyperfiltration, which is
of NADPH and reduced glutathione and glutathione associated with more serious structural changes (Hostetter
peroxidase activity, an increase in the NADH/NAD+ ratio, et al. 1982). Interestingly, it has been postulated that
and decreased levels of nitric oxide, leading to oxidant and there is a bidirectional interplay between metabolic and
osmotic stress. mechanical stimuli at the cellular level. Therefore, the
Finally, through the non-enzymatic reaction of mechanical forces on glomerular cells are able to induce
reducing sugars with free amino groups of proteins, the overexpression of GLUT-1, resulting in greater glucose
lipids and nucleic acids, AGEs are formed. The initial uptake and activation of intracellular signalling pathways
product of this reaction is called a Schiff base, which (Gnudi et al. 2007).
spontaneously rearranges itself into an Amadori product. One of the most important elements participating in the
A series of subsequent reactions lead to the formation haemodynamic dysfunction in diabetes and DKD is the

renin–angiotensin–aldosterone system (RAAS), which is kines (monocyte chemoattractant protein-1, also known
directly involved in the regulation of BP and fluid volume, as CCL2), adhesion molecules (intracellular adhesion
and participates in vascular injury and inflammation. molecule-1 and vascular adhesion molecule-1), and
Although aldosterone, renin, and several breakdown proinflammatory cytokines (interleukin-1, -6, -18, and
products of angiotensin I (AI) are also involved, most tumour necrosis factor-α).
of the effects of the RAAS on target tissues are mediated
by angiotensin II (AII), which is generated both in the
circulation and in the tissues. Hyperglycaemia induces New pathogenic factors from transgenic experimental
the activation of the local renal RAAS (e.g. in the models. Recent studies with the use of genetically
tubular epithelial cells, mesangial cells and podocytes) modified animals as experimental models of DKD
and increases the production of AII, which exerts a pre- have reported novel factors with interest from a
ferential constrictor effect on the efferent glomerular pathogenic and therapeutic perspective, including tissue
arteriole, resulting in a higher intraglomerular capillary inhibitor of metalloproteinase-3 (TIMP-3), matrix
pressure. In addition, the locally produced Ang II activates metalloproteinase-2 (MMP-2), and CCL2/C-C chemo-
multiple intracellular signalling pathways and induces kine receptor 2 (CCR2).
inflammation, renal cell growth, mitogenesis, apoptosis, TIMP-3, an endogenous inhibitor of matrix
migration and differentiation (Macı́a-Heras et al. 2012). metalloproteinases, is the most highly expressed
In the classic pathway of the RAAS, renin is secreted TIMP in the kidney. It influences the extracellular matrix
from the juxtaglomerular apparatus of the kidney and acts integrity and the tissue microenvironment. Loss of
on the circulating precursor angiotensinogen to generate TIMP-3 in mice has been reported to increase renal
AI. Angiotensin-converting enzyme (ACE) present in the damage (Kassiri et al. 2009). A recent study using double
endothelium and tissues converts AI to the octapeptide mutant mice in which the TIMP-3 gene was deleted in the
AII. In the heart, kidneys and brain, AII is also produced genetic diabetic Akita mouse (Basu et al. 2012) showed
by non-ACE pathways involving chymases, cathepsin G, that loss of TIMP-3 leads to the aggravation of diabetic
kallikrein-like enzymes and endopeptidases, and seems to renal injury as exemplified by significantly increased
exert effects on target tissues that are even greater than the kidney mass, glomerular mesangial matrix score, and
effects of centrally generated AII. AII acts on the heart and urinary albumin excretion, which are all early features of
the kidneys by binding to the G protein-coupled receptors DKD. These changes occurred in the absence of worsening
type 1 (ATR1) and type 2 (ATR2). The ATR1 mediates the of hypertension or glycaemic control, demonstrating that
more deleterious effects of AII, whereas the ATR2 regulates TIMP-3 plays a key and organ-specific role in diabetic
opposing effects. renal injury and is consistent with observations made in
Recently, a new component of the RAAS has been human DKD (Ewens et al. 2005).
described, ACE2, a homologue of ACE that act as a MMP-2, an endopeptidase responsible for the
negative regulator of the system, counterbalancing the degradation of type IV collagen and laminin, major
actions of ACE. ACE2 cleaves AI and AII into the inactive components of extracellular matrix proteins, has been
angiotensin 1–9, and the vasodilator and anti-proliferative showed to have a reduced expression and activity
angiotensin 1–7, respectively. ACE2 within the kidneys is in advanced human DKD. To further elucidate the
largely expressed in tubular epithelial cells and glomerular pathophysiological role of MMP-2, renal injury was
epithelial cells. In DKD, reduced expression of ACE2 assessed in a model of streptozotocin-induced DKD in
coupled with increased expression of ACE has been the context of genetic deletion of MMP-2 (Takamiya
described. In addition, both ACE2 genetic ablation and et al. 2013). This study showed that the renal expression
pharmacological ACE2 inhibition have been shown to and activity of MMP-2 are increased as a compensatory
increase albuminuria and promote glomerular injury mechanism in the early phase of DKD, and that MMP-2
(Soler et al. 2008). could play a protective role against the progression of renal
injury in diabetes.
Inflammation. Significant advances have been made Finally, a recent study investigated the effect of the
in relation to the pathogenesis of DKD that have blockade of CCL2/CCR2 signalling on the development
recognized the involvement of inflammatory molecules of experimental DKD (Seok et al. 2013). Administration
and pathways in the development and progression of the CCR2 antagonist RS102895 to type 2 diabetic
of DKD (Navarro-González & Mora-Fernández, 2008; db/db mice improved the pathological (e.g. mesangial
Rivero et al. 2009). The relationships between this matrix expansion, GBM thickening and podocyte foot
inflammatory state and the initiation and evolution process effacement) and the functional (e.g. increased
of DKD involve very complex network processes. albuminuria) impairments of DKD. This therapy
Diverse inflammatory molecules play significant roles ameliorated DKD not only by improving blood glucose
in this scenario, including toll-like receptors, chemo- levels but also by preventing CCL2/CCR2 signalling

from altering renal nephrin and vascular endothelial Although the largest proportion of patients develop
growth factor expression through blocking macrophage the ‘classical’ natural history of DKD, suffering from
infiltration, inflammation and oxidative stress. proteinuria and diabetic glomerulosclerosis as the under-
lying pathology, DKD is more heterogeneous than pre-
viously thought. Thus, an increasing number of studies
Natural history of diabetic kidney disease
have indicated other possibilities regarding the evolution
The natural history of DKD, a process that advances of DKD: a significant initial deterioration of GFR, a
gradually over years, was defined in the eighties based on spontaneous reduction of microalbuminuria, the pre-
longitudinal studies of patients with type 1 and type 2 sence of reduced renal function accompanied, rather
diabetes, being reported that the general evolution of than preceded, by macroalbuminuria, or even present
DKD was comparable in both major types of diabetes. in patients with microalbuminuria, or in those with
Approximately 20–40% of diabetic patients develop albuminuria levels that revert to normal, or in subjects
microalbuminuria within 10–15 years of the diagnosis whose albuminuria levels remain normal. At the pre-
of diabetes, and about 80–90% of those with micro- sent moment, it is not clear what factors determine this
albuminuria progress to more advanced stages. Thus, after different presentation and natural history (Halimi, 2012).
15–20 years, macroalbuminuria occurs in approximately In addition, intervention strategies for the management
20–40% of patients, and around half of them will present of DKD have changed the natural history of the disease.
renal insufficiency within 5 years (Hasslacher et al. 1989; As an example, in the seventies, the median time to ESRD
Remuzzi et al. 2002). from the appearance of proteinuria in type 1 diabetes was
Five stages of DKD were defined. (1) Early less than 7 years, whereas now this time is higher than
functional phase with reversible glomerular hyper- 14 years.
filtration. (2) Normal glomerular filtration and An important consideration is that the presence of trace
normoalbuminuria (urinary albumin excretion (UAE) amounts of albumin in the urine is not only a predictor
< 30 mg day–1 ). (3) Incipient nephropathy, defined by of high renal risk, but is also an independent predictor of
normal glomerular filtration and microalbuminuria (UAE increased cardiovascular risk, especially in type 2 diabetes.
of 30–300 mg day–1 ), which develops between 5 and The cardiovascular risk increases progressively even when
10 years after the diagnosis of diabetes, and it is the first the UAE rate is within the normal range. Remarkably, the
clinical sign of DKD. (4) Macroalbuminuria (UAE higher annual death rate increases from less than 1% in the stage
than 300 mg day–1 ), after 10–20 years of diabetes evolution. of normoalbuminuria to more than 12% in the stage of
Once macroalbuminuria is present, there is a progressive renal failure. Subjects who present macroalbuminuria are
reduction in glomerular filtration rate (GFR), the rate more likely to die than to develop renal failure during
varying widely from patient to patient, with an average the evolution of the disease, highlighting that in these
decline of approximately 10 ml min–1 year–1 in untreated patients, the death rate exceeds the rate of progression to
subjects. (5) Renal failure, which leads ultimately to worse nephropathy (Adler et al. 2003).
ESRD. More precise knowledge about the progression of
nephropathy in type 2 diabetes was provided by the United
Kingdom Prospective Diabetes Study (UKPDS). Thus, Detection and management of diabetic
using observed and modelled data, from the diagnosis
kidney disease
of diabetes, development of microalbuminuria occurred
at 2.0% per year, progression from microalbuminuria to Diagnosis and screening. Kidney biopsy is the definitive
macroalbuminuria at 2.8% per year, and progression from method to establish the diagnosis of DKD, although in
macroalbuminuria to elevated plasma creatinine or renal most cases, careful evaluation of patients can identify
replacement therapy at 2.3% per year (Adler et al. 2003). subjects most likely to have DKD without the need for
The main pathophysiological changes in DKD include kidney biopsy.
the thickening of the GBM, mesangial expansion, The screening and early diagnosis of DKD is based
nodular sclerosis (Kimmelstiel–Wilson change), diffuse on the measurement of UAE. In normal individuals, a
glomerular sclerosis, tubular interstitial fibrosis, and small amount of albumin is filtered in the glomeruli,
arteriosclerosis and hyalinosis of kidney blood vessels. which is almost completely reabsorbed by the tubules.
The severity of glomerular damage is proportional The UAE is considered normal when it is less than
to GFR value, diabetes mellitus duration, and blood 30 mg day–1 , a threshold based on the fact that the UAE
glucose regulation. Recently, the Scientific Committee of 95% of normal subjects falls below this value. A new
of the Society for Pathological Anatomy has established nomenclature intends to emphasize the continuous nature
the pathological classification of DKD, where diabetic of albuminuria as a risk factor, thus the terms micro-
glomerular lesions have been histologically divided into albuminuria (30–299 mg (24 h)–1 ) and macroalbuminuria
four stages (Table 4). (>300 mg (24 h)–1 ) are rather referred to as persistent

Table 4. Classification of glomerular lesions in diabetic kidney disease
Class Description Inclusion criteria
I Mild or non-specific light microscopy Biopsy does not meet any of the criteria for class II,
changes and GBM thickening III or IV GBM >395 nm in female and >430 nm in
proved by electron microscopy male subjects 9 years of age or older
IIa Mild mesangial expansion Mild mesangial expansion in 25% of the observed
mesangium. Biopsy does not meet criteria for
class III or IV
IIb Severe mesangial expansion Severe mesangial expansion in 25% of the
observed mesangia. Biopsy does not meet criteria
for class III or IV
III Nodular sclerosis (Kimmelstiel–Wilson At least one convincing Kimmesteil–Wilson lesion.
lesion) Biopsy does not meet criteria for class IV
IV Advanced diabetic glomerulosclerosis Global glomerular sclerosis in >50% of glomeruli.
Lesions from class I–III
GBM, glomerular basement membrane. Adapted from Tervaert et al. (2010).
albuminuria at levels 30–299 mg (24 h)–1 and levels to stage DKD (American Diabetes Association, 2014). In
ࣙ300 mg (24 h)–1 , respectively (American Diabetes addition, significant diabetic renal lesions may occur in
Association, 2014). subjects with normoalbuminuria and normal GFR, and
Historically, detection of macroalbuminuria was the furthermore, concomitant conditions may suggest the
basis of the diagnosis of DKD. However, the development presence of non-diabetic kidney disease, such as active
of more sensitive and accurate assays specific for albumin urinary sediment (mainly haematuria), a short time of
has enabled the detection of very small concentrations of diabetes evolution, or the absence of retinopathy (in most
albumin in urine. Clinically, the first sign of DKD is the people with diabetes, chronic kidney disease should be
presence of microalbuminuria, an analysis widely available attributable to DKD in the presence of increased UAE
nowadays. The recommended method for screening is the and retinopathy). Therefore, further evaluation, including
measurement of the albumin-to-creatinine ratio (ACR) in consideration of kidney biopsy, may be required in some
a spot urine sample (preferably the first morning void), cases to establish the diagnosis of DKD.
since timed collections are inconvenient and susceptible
to inaccuracy, and changes in urinary concentration
Management of diabetic kidney disease. The general
caused by hydration status may confound the evaluation
suggestions in the treatment of diabetes (glycaemic and
of tests of albumin concentration alone. Patients with
BP control, adequate lipid management, and abolishing
diabetes should be screened annually for DKD. Initial
smoking) must be applied strictly when DKD is
screening should commence 5 years after diagnosis of
present. These recommendations, in addition to the
type 1 diabetes, whereas it must be performed at diagnosis
lowering of UAE, are the primary interventions that pre-
in type 2 diabetes, due to the inability to establish the
vent the development, and slow the progression, of DKD.
onset of the disease with certitude. Since urinary albumin
Hyperglycaemia is the main initial factor in the
excretion rate has a high variability due to diverse factors,
development of DKD, and therefore, adequate glycaemic
including metabolic and haemodynamic perturbations,
control is the principal target for therapy in patients with
physical exercise, fever, protein intake, congestive heart
potential development of DKD, and the best strategy
failure or urinary tract infection, multiple positive test
to reduce the risk of vascular complications (DCCT,
results are required. Thus, at least two specimens with
1995; Duckworth et al. 2009). Optimal glycaemic control
elevated ACR collected within a 3–6 months period are
established as soon as possible after diagnosis of diabetes
needed for confirmation (National Kidney Foundation,
will reduce the risk of developing diabetic nephropathy,
2012; American Diabetes Association, 2014).
and delay the progression of renal disease. A number of
Although the current screening recommendations are
interventions with different anti-diabetic drugs have been
effective for the great majority of patients, they are not
demonstrated to reduce the risk and slow the progression
sufficient in all cases, since a proportion of patients with
of renal disease both in type 1 and type 2 diabetes (DCCT,
diabetes may present a decreased GFR in the absence of
1995; UKPDS, 1998a,b; DCCT, 2000; Patel et al. 2008;
increased UAE. Thus, serum creatinine with estimated
Ismail-Beigi et al. 2010). While is evident that insulin is
GFR should be assessed at least annually in all adults
the obligate therapy in type 1 diabetes, metformin is the
with diabetes, regardless of the degree of UAE excretion.
preferred initial pharmacological agent in patients with
Information on UAE and estimated GFR may be used

type 2 diabetes, barring contraindication or intolerance. lack of negative feedback from end-products of the RAAS,
When metformin fails to achieve or maintain glycaemic producing a reactive increase in renin and consequent
goals, another agent should be added. Although there are increases in AI and AII concentrations, which overwhelm
numerous trials comparing dual therapy to metformin the pharmacological blockade. Thus, dual blockade would
alone, few directly compare drugs as add-on therapy. The provide more complete blockade of the system by limiting
effects of oral antidiabetic agents on diabetic nephropathy the compensatory responses of AII, aldosterone, renin or
have been thought to be due to their ability to control blood their effects (Macı́a-Heras et al. 2012).
glucose levels, and few studies have examined whether The use of ACEIs plus ARBs represents the most
these agents may also have direct effects on the kidney. A frequent dual RAAS blockade strategy. A recent
recent systematic review on the ‘Comparative effectiveness meta-analysis evaluated the effect of this combination
and safety of oral diabetes medications for adults with on albuminuria (Kunz et al. 2008). Analysing seven
type 2 diabetes’, sponsored by the Agency for Healthcare clinical trials of ACEI plus ARB versus placebo plus ARB,
Research and Quality (US), concluded that overall, each the addition of an ACEI reduced albuminuria by 24%
new class of non-insulin agents added to the initial therapy (95% confidence interval (CI), 15%, 32% reduction) over
lowers the concentration of glycated haemoglobin around 1–4 months follow-up. Analysing seven clinical trials of
0.9–1.1%, and that there is insufficient and low-quality ARB plus ACEI versus placebo plus ACEI, the addition
evidence on the effectiveness of individual new oral anti- of an ARB reduced albuminuria by 22% (95% CI, 16%,
diabetic drugs on the development and progression of 28% reduction) over 1–4 months follow-up. These data
nephropathy (Bennett et al. 2011). demonstrate that the combination of an ACEI and ARB
In addition to metabolic regulation, optimization of reduces albuminuria compared with monotherapy.
BP control is another key element to reduce the risk or In addition to the effect of this strategy on UAE, the
slow the progression of DKD (UKPDS, 1998). Hyper- recently published VA NEPHRON-D (Veterans Affairs
tension is a common comorbidity of diabetes, affecting the Nephropathy in Diabetes) trial evaluated the efficacy of
majority of patients, especially when renal involvement is combination therapy with an ACEI (lisinopril) and an
present. There is solid evidence demonstrating the benefit ARB (losartan) as compared with ARB monotherapy
(reduction of cardiac events, stroke and nephropathy) in slowing the progression of proteinuric DKD (Fried
of lowering BP lower than 140 mmHg systolic and less et al. 2013). This multicentric, double-blind, randomized,
than 80 mmHg diastolic. Patients with blood pressure controlled study, which is specific to patients with
higher than 120/80 mmHg should be advised on lifestyle DKD, included 1448 patients with type 2 diabetes and
changes to reduce BP, consisting, among others, of weight macroalbuminuria, with a median follow-up of 2.2 years.
loss, if overweight; reducing sodium intake; moderation The primary end point was the first occurrence of a
of alcohol intake; and increased physical activity. Patients decline in the estimated GFR (an absolute decrease
with confirmed BP higher than 140/80 mmHg should, in of ࣙ30 ml min–1 (1.73 m2 )–1 if the estimated GFR
addition to lifestyle modifications, have prompt initiation was ࣙ60 ml min–1 (1.73 m2 )–1 at randomization or a
and timely subsequent titration of pharmacological relative decrease of ࣙ50% if the estimated GFR was
therapy to achieve blood pressure goals. Pharmacological <60 ml min–1 (1.73 m2 )–1 ), ESRD (defined by the
therapy should comprise a regimen that includes a initiation of maintenance dialysis or an estimated GFR
blocker of the RAAS, either an ACE inhibitor (ACEI) of <15 ml min–1 (1.73 m2 )–1 ), or death. The study
or an angiotensin receptor blocker (ARB), which is was prematurely interrupted according to the data and
recommended to titrate up to the maximum approved safety monitoring committee, primarily on account of
dose in the absence of side effects or adverse events. safety concerns due to increased rates of serious adverse
Diuretics, calcium channel blockers, and β-blockers events, hyperkalaemia, and acute kidney injury in the
should be used as additional therapy to further lower combination therapy group as compared with the mono-
BP in patients already treated with ACEIs or ARBs or therapy group, along with low conditional power (<5%
as alternative therapy in the individual unable to tolerate for the observed trend) to detect a treatment effect on
these drugs. Multiple-drug therapy is generally required the primary end point. This study demonstrated that
to achieve BP targets, and one or more antihypertensive combination therapy with an ACEI and an ARB in
medications should be administered at bedtime since there patients with type 2 diabetes and proteinuric DKD did
is an association between increase in sleeptime BP and not provide an overall clinical benefit, being associated
incidence of cardiovascular events (American Diabetes with an increased risk of serious adverse events.
Association, 2014). The effects of the addition of aldosterone antagonists
A special multiple-drug strategy is the simultaneous use (spironolactone and eplerenone) to ACEIs or ARBs
of two RAAS inhibitors (i.e. dual RAAS blockade). This for the reduction of albuminuria have been recently
approach is based on the finding that incomplete blockade evaluated. In a systematic review including 14 studies with
of the RAAS with ACEI or ARB monotherapy can cause a spironolactone, and one with eplerenone, most of these

investigations reported that addition of an aldosterone experimental studies, showing potential beneficial effects
antagonist reduced albuminuria by 30–40% (Bomback on DKD (Zheng et al. 2002; Flyvbjerg et al. 2004;
et al. 2008). The antiproteinuric effect of spironolactone Thallas-Bonke et al. 2004; Coughlan et al. 2007). More
was compared with losartan (an ARB) and placebo as importantly, the clinical use of the specific AGE inhibitor
add-on therapy to a high-dose of lisinopril (an ACEI) in aminoguanidine in patients with type 1 diabetes and
patients with diabetes (mostly type 2), hypertension and renal disease showed a significant reduction of proteinuria
macroalbuminuria. Compared with placebo, the addition (Bolton et al. 2004). A similar trial in patients with overt
of spironolactone to lisinopril reduced albuminuria by type 2 diabetic nephropathy was initiated (Freedman et al.
34% at 48 weeks, whereas the addition of losartan to 1999). However, the development of those studies were
lisinopril reduced albuminuria by 17% (Mehdi et al. 2009). discontinued for financial reasons by its pharmaceutical
The newest RAAS inhibitor available for clinical use company sponsors. More recently, a 1 year clinical trial
is the direct renin inhibitor aliskiren. This drug directly with pyridoxamine, a metabolic derivative of pyridoxal
blocks the activity of secreted renin. Effects of the dual phosphate able to inhibit AGEs, failed to significantly alter
RAAS blockade with aliskiren and losartan on albuminuria the progressive loss of renal function in patients with type 2
in the setting of type 2 DKD were investigated in the diabetes mellitus and advanced nephropathy (Lewis et al.
AVOID study. Patients treated with the combination 2012).
experienced a 20% reduction in albuminuria as compared Ruboxistaurin mesylate is a bisindolylmaleimide that
with participants assigned to placebo (Parving et al. specifically inhibits the β isoform of PKC. In a
2008). More recently, a randomized, double-blind, variety of experimental models of DKD, ruboxistaurin
placebo-controlled trial was conducted in more than 8500 normalized glomerular hyperfiltration, decreased urinary
patients with type 2 diabetes already taking an ACEI or an albumin excretion, preserved kidney function, and
ARB as standard practice, to determine the effectiveness reduced mesangial expansion, glomerulosclerosis and
and safety of aliskiren, compared with placebo, with tubulointerstitial fibrosis (Tuttle, 2008). Regarding clinical
respect to fatal and non-fatal renal and cardiovascular studies, a randomized, double-blind, placebo-controlled,
events (Parving et al. 2012). The independent data and multicentre trial showed that in patients with type 2
safety monitoring committee recommended the early diabetes and nephropathy, treatment with ruboxistaurin
termination of the study, on the basis that the excessive reduced albuminuria and maintained the estimated GFR
risk of adverse events in the aliskiren group could over 1 year (Tuttle et al. 2005). In addition, a study in
not be offset by a reduction in major cardiovascular patients with type 1 diabetes showed that PKC-β appears
and renal events. Therefore, the ALTITUDE (‘Aliskiren to play a role in the maintenance of hyperfiltration, and its
trial in type 2 diabetes using cardiorenal endpoints’) inhibition resulted in a decrease in GFR, suggesting that
trial demonstrated that dual RAAS blockade, in this the impact of ruboxistaurin depends on filtration status
case with the direct renin inhibitor aliskiren added to (Cherney et al. 2009).
standard-of-care renin–angiotensin blockade in high-risk Endothelial dysfunction is a key element in
patients with type 2 diabetes, did not reduce cardiovascular the pathogenesis and progression of microvascular
or renal outcomes, and resulted in an increased number complications of diabetes, including DKD. Endothelin-1
of adverse events. (ET-1) is a potent vasoconstrictor with additional
An ACEI or ARB for the primary prevention of diabetic proliferative, profibrotic and proinflammatory properties.
kidney disease is not recommended in diabetic patients Diabetes is associated with increased ET-1 and elevated
with normal BP and UAE lower than 30 mg (24 h)–1 . Either renal expression of the endothelin A receptor. Recent
ACEIs or ARBs are recommended for the treatment of the studies based on the use of the endothelin receptor
patient with modestly elevated (30–299 mg (24 h)–1 ) or blocker atrasentan have shown a significant reduction
higher levels (300 mg (24 h)–1 ) of UAE (American Diabetes of proteinuria and urine neutrophil gelatinase-associated
Association, 2014). lipocalin (NGAL) (Kohan et al. 2011; Andress et al.
Despite the implementation of these strategies, the 2012), suggesting that the addition of endothelin
number of patients with diabetes that ultimately develop receptor blockade to currently established therapies with
DKD and ESRD remains high. Additional studies have RAAS blockers may result in synergistic renoprotection.
focused on the potential of novel therapies that either However, caution is necessary with these kinds of drugs
target various pathways upregulated by hyperglycaemia or based on previous studies. Thus, the ASCEND trial
other targets believed to promote the progression of renal (‘Avosentan on time to doubling of serum creatinine,
disease, such as the inhibition of AGEs and PKC, end- end-stage renal disease or death in patients with type 2
othelin system, vitamin D and inflammation pathways. diabetes mellitus and diabetic nephropathy’) (Mann
Different approaches (dietary and pharmacological) et al. 2010) examined in a prospective, randomized,
have been used to reduce the accumulation of AGEs double-blind fashion the effect of avosentan on time
or to block the interaction with their receptors in to doubling of serum creatinine, ESRD, or death, in

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UK Prospective Diabetes Study Group (1998). Tight blood Additional information
pressure control and risk of macrovascular and Competing interests
microvascular complications in type 2 diabetes: UKPDS 38.
BMJ 317, 703–713. None of the authors have any conflicts of interest.
UKPDS (1998a). Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional Funding
treatment and risk of complications in patients with type 2 Research studies by the authors have been funded by the
diabetes (UKPDS 33). UK Prospective Diabetes Study Spanish Ministry of Health, Instituto de Salud Carlos III
(UKPDS) Group Lancet 352, 837–853. (EC07/90021), Sociedad Española de Nefrologı́a and ACINEF.
UKPDS (1998b). Effect of intensive blood-glucose control with
We also acknowledge cofunding by the European Regional
metformin on complications in overweight patients with
Development Funds (ERDF).
type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study
(UKPDS) Group. Lancet 352, 854–865. Acknowledgements
Wartiovaara J, Ofverstedt LG, Khoshnoodi J, Zhang J, Mäkelä
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Skoglund U & Tryggvason K (2004). Nephrin strands Intensificación de la Actividad Investigadora, Instituto de Salud
contribute to a porous slit diaphragm scaffold as revealed by Carlos III, Ministry of Economy and Competitiveness (Convenio
electron tomography. J Clin Invest 114, 2004. ISCIII-Comunidad Autónoma Canarias).


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J Physiol 592.

18 (2014) pp 3997–4012 3997

Diabetic kidney disease: from physiology to therapeutics

Introduction sence of fenestrations that appear as transcytoplasmic

Endothelial cell Endothelial CAPILLARY

Genetic factors Environmental factors

Pathogenic mechanisms for renal injury

Metabolic Haemodynamic Inflammatory

Activation of cell signalling pathways and transcription factors

Cellular and extracellular matrix-related effects

Renal functional and structural changes

Gene Polymorphism Effect References

Angiotensin-converting Insertion/deletion (I/D) D or DD associated Yu et al. 2012

Table 4. Classification of glomerular lesions in diabetic kidney disease

Class Description Inclusion criteria

people with type 2 diabetes and overt nephropathy. References

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