Clinical Practice: Mini-Review

Nephron 2019;143:12–16 Received: June 29, 2018

Accepted after revision: August 10, 2018
DOI: 10.1159/000493278 Published online: October 1, 2018

Inflammation in Diabetic Kidney Disease

Rosa E. Pérez-Morales a María Dolores del Pino b José Manuel Valdivielso c, d
     

Alberto Ortiz d–f Carmen Mora-Fernández d, f, g Juan F. Navarro-González a, d, f, g

     

a Servicio
de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain;
b Servicio
de Nefrología, Hospital Torrecárdenas, Almería, Spain; c Grupo de Investigación Traslacional Vascular y
 

Renal, Instituto de Investigación Biomédica IRBLLEIDA, Lleida, Spain; d Red de Investigación Renal (REDINREN),
 

Instituto de Salud Carlos III, Madrid, Spain; e Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-
 

Universidad Autónoma de Madrid y Fundación Renal Iñigo Álvarez de Toledo-Instituto Reina Sofía de Investigación
Nefrológica, Madrid, Spain; f GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad
 

Española de Nefrología, Spain; g Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa
 

Cruz de Tenerife, Spain

Keywords
Diabetes · Diabetic kidney disease · Inflammation ·
Therapies targeting inflammation
Abstract
Background: Diabetes is a growing public health problem.
Diabetic kidney disease (DKD) is the most prevalent chronic
renal disease and the major cause of end-stage renal failure
worldwide, predominantly due to the increase of Type 2 dia-
betes associated with obesity. The intimate mechanisms
leading to the development and progression of renal injury
in DKD are not well understood, but current knowledge in-
dicates that its pathogenesis is multifactorial, where the im-
mune response and inflammation appear to be relevant fac-
tors. Summary: This review summarizes the role of relevant
inflammatory molecules and pathways that participate in
the development of DKD. Likewise, we focused on the new
therapeutic approaches based on anti-inflammatory effects
of different drugs. Key Messages: This new pathogenic per-
spective of DKD as an inflammatory condition leads to novel
horizons, such as the potential role of inflammatory signal-
ing pathways and their downstream products as emerging
biomarkers and promising therapeutic targets.
© 2018 S. Karger AG, Basel
Introduction
Diabetic kidney disease (DKD) is the most prevalent
chronic renal disease and the major cause of end-stage
renal failure worldwide, predominantly due to the grow-
ing incidence of Type 2 diabetes associated with obesity
[1]. DKD has been classically considered the consequence
from the interaction between hemodynamic and meta-
bolic factors, but current knowledge indicates that its
pathogenesis is multifactorial, where the immune re-
sponse and inflammation play a major role [2, 3]. In ad-
dition, pro-inflammatory signaling pathways and their
downstream products are emerging as new biomarkers
and promising therapeutic targets [4].
Inflammation in DKD
Diabetes mellitus (DM) is associated with hemody-
namic and metabolic alterations that produce the activa-
tion of diverse transduction pathways in virtually all types
Contribution from the CME Course of the DIABESITY Working Group
of the ERA-EDTA, Lisbon, November 24–25, 2017.

© 2018 S. Karger AG, Basel Dr. Juan F. Navarro-González

Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria
Carretera del Rosario 145
E-Mail karger@karger.com
ES–38010 Santa Cruz de Tenerife (Spain)
www.karger.com/nef E-Mail jnavgon @ gobiernodecanarias.org
of kidney cells [2, 3]. DKD is associated with both sys-
temic and local renal inflammation with the participation
of crucial inflammatory cells, molecules, and pathways,
such as macrophages, the nuclear transcription factor-
kappa B (NFκB), the janus kinase/signal transducers and
activators of transcription (JAK/STAT) pathway, and in-
flammatory cytokines [2, 3].
The mononuclear phagocyte system is activated in
DM. Macrophages infiltrate the kidney, and the cycle of
cytokine release and monocyte and macrophage recruit-
ment culminates in inflammatory-related structural
changes. Other cells such as mast cells also infiltrate the
tubule-interstitium and releases inflammatory mediators
and proteolytic enzymes. The magnitude of macrophage
infiltration and the extent of mast cell degranulation is
associated with the rate of loss of estimated glomerular
filtration (eGFR) [4].
NFκB, a transcription factor that is activated by cyto-
kines and oxygen radicals, controls the expression of
genes involved in different processes, such as the immune
response and inflammation. In addition, NFκB is central
in the interplay among the different factors, molecules,
and pathways resulting in structural alterations and func-
tional abnormalities observed in DKD, such as activation
of the renin-angiotensin system, advanced glycation end-
products accumulation, and nicotinamide adenine dinu-
cleotide phosphate hydrogen (NADPH)-dependent oxi-
dative stress [2, 3].
Inflammatory Cytokines
Cytokines are a group of polypeptide signaling mole-
cules that promote autocrine, paracrine, and juxtacrine
signaling as a part of the innate immune response. Pro-
duction of cytokines is induced by numerous stimuli in
DM [4]. In the kidney, both blood-borne cells as well as
diverse intrinsic renal cells (glomerular, endothelial, tu-
bular, and mesangial cells) are able to synthesize inflam-
matory cytokines. The levels of these substances increase
as nephropathy progresses, with an independent rela-
tionship between these inflammatory parameters and
urinary albumin excretion, suggesting a role in the patho-
genesis of DKD [2, 3].
Different actions from diverse cytokines, such as inter-
leukin (IL)-1, IL-6, IL-18, and tumor necrosis factor-al-
pha (TNFα) have been involved in the pathogenesis of
DKD [5, 6]. IL-1 stimulates the production of prostaglan-
din E and the release of phospholipase A2, participating
in the development of intraglomerular hemodynamic ab-
normalities. IL-1 activity is also linked to increased per-
meability of vascular endothelial cells. IL-6 plays a role in
Inflammation in DKD
facilitating neutrophil infiltration of the tubule-intersti-
tium, influences extracellular matrix dynamics, and pro-
motes overall kidney hypertrophy, thickening of the glo-
merular basement membrane, podocyte hypertrophy,
and cell cycle arrest, which is correlated with albumin-
uria. IL-18 stimulates the release of interferon gamma
and other cytokines, increases the expression of adhesion
molecules, and induces endothelial cell apoptosis. High
serum levels of IL-18 have been noted in patients with
macroalbuminuria, suggesting a role in the development
of microvascular kidney complications. Early in the
course of diabetes, both glomerular and tubular cells
show increased TNFα mRNA expression levels. TNF-α
has multiple actions: induction and differentiation of in-
flammatory cells, cytotoxicity to kidney cells, activation
of apoptosis, altered glomerular hemodynamics, in-
creased vascular endothelial permeability, and increased
oxidative stress. TNFα exerts its biological actions via the
interaction with 2 cell surface receptors, TNFα receptor 1
(TNFR1) and 2 (TNFR2), which have shown a promise
value as new prognostic DKD biomarkers [7].
Chemokines
Chemokines are a subgroup of cytokines that function
as “chemoattractant” molecules, playing a key role in in-
flammatory cell recruitment, migration, and interaction, as
well as in cellular adhesion, differentiation, and tissue dam-
age in the setting of DKD [8]. Several inflammatory chemo-
kines, which are upregulated in response to metabolic and
hemodynamic features of the diabetic milieu, participate in
the pathogenesis of renal damage in diabetes, particularly
monocyte chemotactic protein-1 (MCP-1)/chemokine
C-C motifligand 2 (CCL2), C-X3-C motif chemokine (CX-
3CL1), and CCL5/RANTES (C-C motif ligand 5/regulated
on activation, normal T cell expressed and secreted).
Elevated levels of MCP-1/CCL2 have been reported in
biopsied kidneys and urine from patients with DKD, and
they play a role in macrophage infiltration of the tubule-
interstitium. Angiotensin II directly induces MCP-1/
CCL2 expression, and blockade of the renin-angiotensin
system (RAS) leads to the reduction of MCP-1/CCL2 in
urine. Other biological roles for MCP-1/CCL2 include ef-
facement of podocyte foot processes, podocytopenia with
glomerular basement membrane denudement, and dam-
age to the slit diaphragm, all of which explain the correla-
tion between urine levels of MCP-1/CCL2 and albumin-
uria. The receptor for this chemokine (MCP-1/CCL2C-C
chemokine receptor type 2 [CCR2]) is distributed in the
kidney mononuclear phagocyte system and possibly in
differentiated podocytes. CX3CL1 and CCL5/RANTES
Nephron 2019;143:12–16 13
DOI: 10.1159/000493278
are upregulated in diabetes, both within the glomerular
and tubular cells, and in peritubular capillaries, acting as
chemoattractants for immune cells and for cellular adhe-
sion.
Adhesion Molecules
Intercellular adhesion molecule 1 (ICAM-1), vascular
cell adhesion protein 1, endothelial cell-selective adhe-
sión molecule, and E-selectin are cell surface-localized
factors that facilitate intercellular binding, adhesion, and
intercellular communication, participating in the patho-
genesis of DKD [9]. The expression of adhesion mole-
cules in DKD is increased in response to TNFα, NFκB,
and hemodynamic shear stress. ICAM-1 exhibits high ex-
pression in resident kidney cells, and elevated urine levels
of ICAM-1 have been related to DKD progression. High
circulating levels of soluble forms of vascular cell adhe-
sion protein 1 and ICAM-1 are also related to the progres-
sion of DKD from microalbuminuria to macroalbumin-
uria. Endothelial cell-selective adhesion molecule reduces
glomerular permeability, and its downregulation in early
DKD may promote albuminuria, whereas soluble levels
of E-selectin are positively correlated with albuminuria
and with cardiovascular disease.
Inflammatory Signal Transduction
JAK/STAT is an intracellular cytokine-associated sig-
naling pathway that serves as a key mediator between
paracrine stimuli and nuclear receptors. Cytokines and
diabetic factors activate this essential mechanism that reg-
ulates cell activation, proliferation, recruitment, migra-
tion, and differentiation [10]. The upregulation of JAK/
STAT has been reported in the glomerular cells of patients
with early DKD, and tubule-interstitial expression of var-
ious JAK and STAT isoforms increases with disease pro-
gression and correlates inversely with the eGFR.
NF-kB, a key transcription factor for inflammatory
processes in the diabetic kidney, is activated via JAK/
STAT. In resident kidney cells, NF-kB is rapidly activated
by diverse stimuli, including hyperglycemia, advanced
glycation end-products, mechanical stress, reactive oxy-
gen species (ROS), inflammatory cytokines, angiotensin
II, and albuminuria/proteinuria. Upon activation, NF-kB
stimulates the transcription of proinflammatory cyto-
kines, chemokines, and adhesion molecules [6].
JAK/STAT members are controlled in a classical neg-
ative-feedback loop by the suppressors of cytokine signal-
ing (SOCS) family (SOCS1–7 and CIS). The dysregulated
JAK/STAT/SOCS pathway contributes to the pathogen-
esis of cancer, autoimmune and inflammatory disorders
14 Nephron 2019;143:12–16
DOI: 10.1159/000493278
including diabetes. Moreover, the activation of JAK/
STAT is an important mechanism by which hyperglyce-
mia contributes to renal damage [11].
NADH Oxidase and Suppressors of Cytokine Signaling
Chronic hyperglycemia in combination with growth
factors and cytokines act on cells to impair redox balance
due to either increased generation of ROS or insufficient
antioxidant defense systems, thus resulting in oxidative
damage of biological macromolecules (lipids, proteins,
and DNA) and tissue injury. Potential sources of ROS in-
clude NADPH oxidase (Nox), a multi-subunit enzyme
that catalyzes the generation of the reactive-free radical
superoxide by reduction of O2 using either NADPH or
NADH as a substrate. Collectively known as the Nox fam-
ily, 7 isoforms are expressed in mammals, Nox1 and Nox4
being the main isoforms involved in DKD [12].
Therapies Targeting Inflammation: Future
Perspectives
New therapeutic strategies in DKD have moved to-
ward anti-inflammatory agents as potential new treat-
ments [13] (Table 1).
Pentoxifylline (PTF) is a methylxanthine-derived phos-
phodiesterase inhibitor with beneficial effects on microcir-
culatory blood flow. A meta-analysis published in 2008 re-
ported a substantial antiproteinuric effect of PTF in patients
with diabetic nephropathy, and pointed to the reduction of
proinflammatory cytokines as the most likely explanation
for this action [14]. The Pentoxifylline for Renoprotection
in Diabetic Nephropathy study [15] was a clinical trial that
evaluated the effect of PTF in DKD patients with residual
albuminuria despite RAS inhibitor treatment. After 24
months, the eGFR decreased by 2.1 ± 0.4 mL/min/1.73 m2
in the treatment group, a significant difference (p < 0.001)
compared with 6.5 ± 0.4 mL/min/1.73 m2 decline in the
control group. The between-group difference in the change
in albuminuria between the groups was also significant (5.7
vs. –14.9%; p = 0.001). Interestingly, a recent post hoc anal-
ysis of the Pentoxifylline for Renoprotection in Diabetic
Nephropathy trial has shown that treatment with PTF leads
to a significant increase in serum and urinary Klotho con-
centrations, clinical findings supported by experimental
data that show that PTF prevents the downregulation of
Klotho protein and mRNA expression induced by albumin
and inflammatory cytokines in renal tubular cells [16].
Emapticap pegol is an MCP-1/CC2 antagonist evalu-
ated in a phase 2, placebo-controlled trial of DKD pa-
Pérez-Morales et al.
Table 1. Potential therapies for diabetic kidney disease targeting inflammatory pathways

Drug Target Identifier Study population Outcomes

Pentoxifylline Inflammatory EudraCT number Type 2 diabetes Mean difference in UAE of 21%
Cytokines 2007-005985-10 eGFR 15–60 (p < 0.001) and eGFR decline
UAE >30 mg/24 h 4.3 mL/min/1.73 m2 lower than in
the placebo group (p < 0.001)
Baricitinib JAK1/JAK2 NCT01683409 Type 2 diabetes Albuminuria reduction by 40%
Macroalbuminuria No effect on eGFR
eGFR 20–75 mL/min/1.73 m2
Emanticap Pegol CCL2 NCT01547897 Type 2 diabetes Albuminuria reduction by 29%
(NOX-E36) eGFR >25 mL/min/1.73 m2 compared with baseline ( p < 0.05),
UACR >100 mg/g but no significant difference with
­placebo
CCX 140-B CCR2 NCT01447147 Type 2 diabetes 18% reduction of albuminuria
eGFR ≥25 mL/min/1.73 m2 compared with placebo (p < 0.0004)
UACR 100–3,000 mg/g in the 5 mg group. No reduction
of albuminuria in the 10 mg group
CTP-499 PDE NCT01487109 Type 2 diabetes 16% UACR reduction
eGFR no limit
UACR 300–5,000 mg/g
LY3016859 TGF-α/epiregulin NCT01774981 eGFR <90 mL/min/1.73 m2 Study ongoing.
UACR >400 mg/g No results available

eGFR, estimated glomerular filtration rate; TGF-α, transforming growth factor alpha; UACR, urinary albumin-to-creatinine ratio.

tients with residual macroalbuminuria while on RAS in-
hibitor therapy. After 12 weeks, urinary albumin-to-cre-
atinine ratio (UACR) was lower by 29% compared with
baseline, without differences from the placebo group. The
maximum difference, that is, 26% (p = 0.06) between
emapticap and placebo, was seen 8 weeks after discon-
tinuation of treatment [17].
CCX140-B is a selective inhibitor of CCR2 that was
tested in a double-blind, placebo controlled trial also en-
rolling DKD patients with proteinuria, eGFR of 25 mL/
min/1.72 m2 or higher, and managed on RAS inhibitors,
who were treated with 5- or 10-mg doses of CCX140-B.
Only participants who had uninterrupted treatment for
52 weeks were included in the intention-to-treat analysis.
Treatment with the 5-mg dose resulted in a significant
decrease in albuminuria of 18% as compared to the pla-
cebo group. The albuminuria-lowering treatment effect
persisted throughout the 52 weeks of study [18].
Baricitinib, a JAK 1/2 inhibitor, reduced UACR in a
dose-dependent manner after 3 and 6 months of treat-
ment in a phase 2 clinical trial in DKD patients with re-
sidual macroalbuminuria on RAS inhibitor treatment. A
daily dose of 4 mg Baricitinib decreased morning UACR
by 41% at week 24 compared with placebo; there was no
change in eGFR but decreased serum levels of inflamma-
tory biomarkers including urine C-X-C motif chemo-
kine-10 and urine C-C motif ligand-2, plasma soluble
TNFR 1 and 2, ICAM-1 and serum amyloid A [19].
Studies have shown that the overexpression of SOCS
in the kidney can relieve the progression of DN by inhib-
iting the JAK/STAT pathway. Moreover, SOCS can also
suppress renal tubular epithelial-mesenchymal transition
that is induced by oncostatin-M, a multifunctional mem-
ber of the IL-6 cytokine family. Finally, renal delivery of
SOCS1 and SOCS3 ameliorates proteinuria and leads to
reduced oncostatin expression and extracellular matrix
deposition [11, 20].
Conclusions
DM is a major global health problem and DKD is one
of its most important complications. Conventional treat-
ments provide incomplete kidney protection and new
therapeutic approaches are needed. Nowadays, inflam-
mation is acknowledged as a key factor in the develop-

Inflammation in DKD Nephron 2019;143:12–16 15

DOI: 10.1159/000493278
ment and progression of DKD, and therefore, anti-in-
flammatory targets directed at specific molecular signa-
tures can be promising therapeutic strategies for DKD.
to JFNG, and FIS PI15/00298, CP14/00133 and PI16/02057;
ISCIII-RETIC REDinREN RD16/0009; Sociedad Española de Ne-
frología (S.E.N.) and ACINEF. We acknowledge cofounding by
Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea
(“Una forma de hacer Europa”).

Acknowledgments

Research activity of the authors have been supported by Insti- Disclosure Statement
tuto de Salud Carlos III (ISCIII; Spanish Ministry of Economy,
Industry and Competitiveness): EC07/90021 and FIS PI16/00024 The authors have no conflicts of interest to declare.

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