Journal of the Formosan Medical Association (2018) 117, 662e675

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journal homepage: www.jfma-online.com

Review Article

Update of pathophysiology and management

of diabetic kidney disease
Yi-Chih Lin a, Yu-Hsing Chang b, Shao-Yu Yang b,*,
Kwan-Dun Wu b, Tzong-Shinn Chu b

a
Department of Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City,
Taiwan
b
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Received 5 November 2017; received in revised form 5 February 2018; accepted 8 February 2018

KEYWORDS Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with dia-
Diabetic kidney betes mellitus and the leading cause of end-stage renal disease in the world. The most char-
disease (DKD); acteristic marker of DKD is albuminuria, which is associated with renal disease progression and
Diabetic nephropathy cardiovascular events. Renal hemodynamics changes, oxidative stress, inflammation, hypoxia
(DN); and overactive renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis
Diabetes mellitus; of DKD, and renal fibrosis plays the key role. Intensified multifactorial interventions, including
Albuminuria RAAS blockades, blood pressure and glucose control, and quitting smoking, help to prevent DKD
development and progression. In recent years, novel agents are applied for preventing DKD
development and progression, including new types of glucose-lowering agents, pentoxifylline,
vitamin D analog paricalcitol, pyridoxamine, ruboxistaurin, soludexide, Janus kinase inhibitors
and nonsteroidal minerocorticoid receptor antagonists. In this review, recent large studies
about DKD are also summarized.
Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction adequate glycemic control, and is one of the main causes of

death in these patients.1 DKD is defined according to the
Diabetic kidney disease (DKD), also known as diabetic ne- changes in renal structure and function. Major renal
phropathy (DN) in the past, usually occurs in patients with structural changes in DKD include mesangial expansion,
type 1 and type 2 diabetes mellitus (DM) without long-term glomerular and tubular basement membrane thickening,

* Corresponding author. Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100,
Taiwan. Fax: þ886 2 23934176.
E-mail address: yangsy@ntuh.gov.tw (S.-Y. Yang).

https://doi.org/10.1016/j.jfma.2018.02.007
0929-6646/Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Update of pathophysiology and management of diabetic kidney disease
and glomerular sclerosis. DKD usually manifests a clinical
syndrome including persistent albuminuria (Table 1),
increased blood pressure, sustained reduction in glomerular
filtration rate (GFR), increased cardiovascular events and
cardiovascular event-associated mortality.
According to the data from the International Diabetes
Foundation in 2014, there were approximate 380 million
people with diabetes who accounted for 8.3% of the world
population. Among the causes of ESRD in the world, DM
accounted for 30e47%. In the United States, about 54.4% of
patients with type 1 diabetes mellitus will eventually
receive renal replacement treatment (RRT).2 According to
the data from the Bureau of Health Promotion Annual
Report in Taiwan in 2011, the prevalence of hyperglycemia
was 9.5% and the prevalence of kidney disease in patients
with DM was 15.42%.3 Annual Report on Kidney Disease in
Taiwan in 2014 showed that the annual patient number of
incident dialysis was 10,486 in 2012, and the ratio of pa-
tients with DM in incident dialytic patients gradually
increased from 36.9% in 2000 to 45.2% in 2012. Besides, the
prevalent number of dialytic patients with DM in Taiwan
also increased from 3778 persons (11.9% of prevalent dia-
lytic patients) in 2000 to 23,139 persons (34.2% of prevalent
dialytic patients) in 2012.4 The most importance of all, the
dialytic patients with diabetes have higher mortality than
those without diabetes.
Albuminuria is one of the most characteristic clinical
signs in DKD. In the past, especially from the observations in
patients with type 1 DM, the clinical stages of DKD were
considered to begin from early glomerular hyperfiltration,
followed by the development of microalbuminuria, mac-
roalbuminuria, and then declined GFR (Fig. 1).5 However, in
recent studies of type 2 DM, many patients with DKD do not
manifest above classic step-by-step changes. Therefore,
the concept of natural history of DKD is changing and
continuing to be evolved. Albuminuria is now considered an
active and deteriorating condition rather than a sequent
process in DKD.6 Development of macroalbuminuria often
accompanies with the decline of GFR and may progress to
end-stage renal disease (ESRD).2 This review summarizes
the recent evolution of pathophysiology and novel treat-
ment of DKD and expects providing help for clinical man-
agement of DKD.
Pathophysiology
Conventional pathogenesis
Renal fibrosis, the final common pathway in the patho-
physiology of DKD, is caused by at least renal hemodynamic
changes, ischemia and glucose metabolism abnormalities-
associated oxidative stress increases, inflammatory
Table 1 Definition of the albuminuria in diabetic kidney disease.
Normoalbuminuria
Moderately increased albuminuria (Microalbuminuria)
Severely increased albuminuria (Macroalbuminuria)
663
processes and overactive renin-angiotensin-aldosterone
system (RAAS)7 (Fig. 2).
Renal hemodynamic changes
Glomerular hyperfiltration leads to the occurrence of DKD.
Hyperglycemia causes afferent arteriolar dilatation by
release of vasoactive mediators, such as insulin-like growth
factor 1 (IGF-1), glucagon, nitric oxide (NO), vascular
endothelial growth factor (VEGF) and prostaglandin. On the
other hand, alterations in renal tubular function also occur
in the early stage of DM, and are related to the degree of
glycemic control. Due to high filtrated load of glucose,
reabsorption of both glucose and sodium chloride is
increased because of upregulation of sodium glucose
cotransporter 2 (SGLT2) in the proximal tubules. Thus, the
delivery of sodium chloride to the macula densa of distal
tubules is decreased, and then causes dilatation of afferent
arteriole because of tubuloglomerular feedback. At the
same time, constriction of efferent arteriole occurs due to
high local level of angiotensin II, and then causes changes
of autoregulation and glomerular hypertension.8
On the other hand, hyperglycemia, insulin resistance
and compensatory hyperinsulinemia independently cause
endothelial dysfunction by promoting some intracellular
mechanisms, such as increased reactive oxygen species
(ROS) production, activation of protein kinase C (PKCs) and
advanced glycation end-products (AGE)-induced pro-
inflammatory signaling. The interactions of mediators pro-
duced by endothelial cells are disrupted and tend to
imbalance. Within these mediators, endothelin-1 (ET-1) is
the most potent vasoactive peptide produced by endothe-
lial cells in regulation of vascular homeostasis. In the
endothelium, compensatory hyperinsulinemia increases ET-
1 secretion, thus results in vasoconstriction and vascular
dysfunction.9 In the kidney, activation of endothelin-
receptor A is not only associated with vasoconstriction,
but also podocyte injury, oxidative stress, inflammation,
and fibrosis.10
Ischemia and inflammation
Glomerular and vascular lesions in DKD reduce the oxygen
supply, cause renal medulla hypoxia and renal tubular
dysfunction. In advanced DKD, multiple mechanisms reduce
the intrarenal vasodilative NO production.11 For compen-
sation, the oxygen demand of the residual nephrons is
increased. Without adequate oxygen supply, more free
radicals would be produced and thus destruct renal tissues.
Hypoxia-inducible factor (HIF) is increased to deal with
hypoxic states. However, hyperglycemia may interfere the
stability of HIF and facilitate tissue fibrosis. The higher is
the blood sugar level, the stronger response is the tissue
damage.12
Daily urine albumin amount: <30 mg
Daily urine albumin amount: 30 mge300 mg or
Ratio of urine albumin over urine creatinine: 30e300
Daily urine albumin amount: >300 mg or
Ratio of urine albumin over urine creatinine: >300
664 Y.-C. Lin et al.

Figure 1 Nature history and renal changes in type 1 diabetes mellitus. Type 2 diabetes mellitus may not follow this time
course. DN, diabetic nephropathy; ESRD, end-stage renal disease; GBM, glomerular basement membrane; GFR, glomerular
filtration rate; BP, blood pressure.

Figure 2 Conventional pathophysiology and novel medical treatment of diabetes kidney disease. IGF-1, insulin-like growth
factor 1; TGF-b1, transforming growth factor b1; VEGF, vascular endothelial growth factor; NO, Nitric oxide; PG, prostaglandin; AT
II, angiotensin II; ET-1, endothelin-1; SGLT2, sodium glucose co-transporters 2; ROS, reactive oxygen species; AGEs, advanced
glycation end products; TNF, tumor necrosis factor; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; HIF,
hypoxia-inducible factor; RAAS, renin-angiotensin-aldosterone system; ECM, extracellular matrix; PTF, pentoxifylline; VitD,
vitamin D.

Recent researches reveal that the prevalence of
obstructive sleep apnea (OSA) among the patients with dia-
betes mellitus is relatively high.13 OSA has been indicated to
influence the control of blood sugar and blood pressure.14,15
Besides, OSA and accompanying intermittent hypoxia cause
the similar pathogenesis associated with diabetic vascular
abnormalities, including activation of inflammatory
response and ROS reaction and production of AGEs. Treat-
ment and control of OSA have potential benefit to prevent
from vascular complications of diabetes mellitus.16e18
Toxic metabolites are also related to renal tissue dam-
age. Hyperglycemia causes mitochondrial overload and
then leads to produce ROS, which further destruct
glomerular podocytes and promote their apoptosis. AGEs
also result in the protein dysfunction, and impair the
metabolism of extracellular matrix.19 Moreover, smoking is
also considered to cause renal damage and progression of
DKD in both type 1 and type 2 diabetes via some patho-
genesis, including elevated oxidative stress, upregulation
of growth factors, and endothelial dysfunction.20
Update of pathophysiology and management of diabetic kidney disease
Cellular and molecular experiments show that inflam-
mation is an important key to the pathophysiology of DKD.
Nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-kB), a transcription factor, is also a major regu-
lator of inflammatory factors. In DKD, increased tumor
necrosis factor (TNF) and ROS activate NF-kB by phos-
phorylation. Moreover, NF-kB is associated with proteinuria
and renal interstitial inflammatory cells infiltration.21
The response of immune system is also related the
development of DKD. The predominant immune response in
the development of DKD is innate immune response.22 Hy-
perglycemia causes cellular stress and dysfunction due to
disturbed function of mitochondria and endoplasmic retic-
ulum, ROS production, and abnormal activation of intra-
cellular signals pathways. As a result of these diabetic
stress, kidney cells produce proinflammatory responses and
then facilitate innate immune response via release of
chemokines, cell adhesion molecules (CAMs) and danger
associated molecular patterns (DAMPs).23 The initiation of
innate immune response is recruitment of macrophage.24
As hyperglycemia persists, AGEs and oxidized lipoproteins
are increased and then cause formation of immune com-
plexes. These immune complexes deposit in the kidney and
then further amplify the innate immune response by acti-
vation of complement and immunoglobulin Fcg receptors.
Activated complement facilitates the recruitment of leu-
kocytes and mast cells in the kidney.25 As DKD continues
developing, the susceptibility of renal ischemia becomes
more apparent, which enhances renal inflammation
through increasing infiltration of neutrophils and macro-
phages in the kidney. These immune responses accelerate
renal damage and decline of renal function in DKD. Hence,
the inflammation in DKD is involved with a complex inte-
gration of innate immune responses.22
Janus kinaseesignal transducer and activator of tran-
scription (JAKeSTAT) pathway has found to be integrally
associated with DKD progression. JAKeSTAT proteins can
assist innate immune responses in kidney cells through
chemokine, cytokine and angiotensin receptors. Animal
diabetic model shows that selectively enhanced expression
of JAK2 in glomerular podocytes increases functional and
pathological features of DKD. Whether early or progressive
DKD, the expressions of JAKeSTAT genes are increased in
glomerular podocytes and tubulointerstitium.26
Recent researches have focused on the roles of gut
microbiome, which is associated with chronic inflammation
status in type 2 DM and CKD. Gut dysbiosis, or pathogen
overgrowth, may promote loss of gut barrier integrity
(leaky gut syndrome), facilitate translocation of gastroin-
testinal bacteria and its products into blood, and trigger the
activation of innate immune responses and a persistent
systemic inflammation, which is possibly associated with
the development and progression of DKD.27
Overactive renin-angiotensin-aldosterone system
Hyperglycemia and AGEs induce expression of renin and
angiotensinogen in renal cells via ROS and kidney specific G
protein-coupled metabolic receptor GPR91.28,29 Besides,
high-sodium intake can blunt the antihypertensive and
antiproteinuric effects of ACEi and ARB due to activation of
the renal renin-angiotensin system.30 Activation of intra-
renal RAAS aggravates the deterioration of DKD. Evidences
665
from studies in animal models and randomized clinical trials
show efficacy of RAAS inhibition to slow the progression of
DKD.31 Both transforming growth factor-b1 (TGF-b1) and
angiotensin II are involved in the processes of renal tissue
fibrosis, including renal tubules dysfunction and atrophy,
reduction of the number of small vessels, and chronic
hypoxia.32 Aldosterone is also thought to play important
roles in the pathophysiology of DKD, through regulating
gene expression and other mechanisms, including upregu-
lation of pro-sclerotic growth factors, such as plasminogen
activator inhibitor 1 (PAI-1) and TGF-b, and promotion of
macrophage infiltration and consequent renal fibrosis.33
Novel molecular pathogenesis
Recent molecular and cellular researches explore novel
fields of pathophysiology of diabetes and DKD, including
genetic and epigenetic regulation, mitochondria dysfunc-
tion and podocyte autophagy. By these mechanisms, the
targets of DKD treatment can be more specified (Fig. 3).
Genetic and epigenetic regulations
Growing evidences support the important roles of genetic
and epigenetic mechanisms of pathophysiology of DKD.
Epigenetic modifications consist of DNA methylation, non-
coding RNAs and histone posttranslational modifications
(PTMs).34 Hyperglycemia, hypoxia, inflammation, and cy-
tokines are proved to be able to modify the epigenetic
profiles.35
Several genes have different degrees of DNA methylation
between type 2 DM patients with DKD and without DKD. The
gene UNC13B has been shown to involve the initial patho-
genesis of DKD and apoptosis of glomerular cells due to
hyperglycemia.36 Moreover, hypermethylation of RASALI
gene increases Ras activation in fibroblasts and then leads
tissue proliferation and fibrosis.37 These studies prove the
importance of DNA methylation in regulating genes related
to DKD, and provide possible therapeutic genetic targets of
DKD management.
MicroRNAs (miRNAs) are small noncoding RNA, which
promote translation repression or mRNA degradation.38
Several miRNAs are considered to have effects on kidneys
because they are abundant in the kidneys. Among DKD-
related miRNAs, miRNA-192 is the best studied one. The
level of miRNA-192 increases in the early stage of DKD, and
miRNA-192 causes upregulation of the key genes associated
with the pathogenesis of DKD, including Cola2 and Col4a1,
in mesangial cells.39 Besides, miRNA-192 can promote the
autoregulation of TGF-b1 in mesangial cells by regulating
other miRNAs and amplify the response of p53 to TGF-
b1.40,41
Histone PTMs regulate gene expression via lysine acet-
ylation, lysine methylation and phosphorylation. Histone
acetylation is involved in the induction of miRNA-192 in
DKD. The regulation of miRNAs is mediated changes in
epigenetic histone acetylation under normal and diabetic
states.42 Histone methylation is associated with gene
expression of TGF-b1-mediated extracellular matrix (ECM)
expansion under normal and high glucose conditions.43
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a
transcription factor of the basic region leucine zipper
666
Figure 3 Novel molecular and cellular pathophysiology of diabetes kidney disease. Nrf2, nuclear factor (erythroid-derived 2)-
like 2; TGF-b1, transforming growth factor b1; PTMs, posttranslational modifications; Atg, autophagy-related protein; mTOR,
mammalian target of rapamycin; AMPK, adenosine monophosphate activated protein kinase; PI3K-I/PKB, phosphatidylinositol
3-kinase I/protein kinase B; eNOS, endothelial nitric oxide synthase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated
B cells.
family.44 Nrf2 has important functions for regulating and
activating the intracellular antioxidation to neutralize ROS,
and maintaining redox homeostasis. Several investigations
revealed protective effects of Nrf2 in diabetes through in-
hibition of TGF- b1, decreased ECM production and down-
regulating cyclin-dependent kinase inhibitor 1A.45e48
Podocyte autophagy
Recent studies show that autophagy is involved in the
pathogenesis of diabetes-related podocyte injury and
renoprotective in diabetic nephropathy.49 Autophagy con-
trols the quality of the cytoplasm by degrading proteins,
peroxidases, and maintaining the homeostasis of intracel-
lular environment.50 Activated podocyte autophagy has a
protective effect on DKD through autophagy-related (Atg)
protein conjugation system and mammalian target of
rapamycin (mTOR) regulation.
Atg12 is a ubiquitin-like protein involving in the auto-
phagosome formation, and autophagy activation needs the
conjugation of Atg12 to Atg5.51 b-arrestins is a negative
adaptor of G protein-coupled receptors (GPCRs) and ag-
gravates podocyte injury through autophagy inhibition via
downregulating Atg12-Atg5 conjugation in DKD. Therefore,
modulation of this pathway may be a novel therapeutic
approach for treating patients with DKD.52
mTOR is essential to regulation of cell growth, and
activation of mTOR can suppress autophagy. In the up-
stream of mTOR, there are two separated protein kinases,
phosphatidylinositol 3-kinase I (PI3K-I)/protein kinase
B(Akt/PKB) and AMP-activated protein kinase (AMPK),
which are regulated by different conditions.53 PI3Ks are
consisted of three isoforms, including PI3K-I, PI3K-II, and
PI3K-III.54 PI3K-I inhibits autophagy while PI3K-III activates
it. The activation of class I PI3K is triggered by interaction
Y.-C. Lin et al.
of insulin or growth factors and interacts with insulin re-
ceptors or tyrosine kinase receptors. Activation of Akt/PKB
and PKD1 (polycystic kidney disease 1), and subsequent
inhibition of tuberous sclerosis complex 1 and 2 (TSC1/2)
promote mTOR activation. Finally, podocyte autophagy is
suppressed.55
AMPK is an essential regulator in energy metabolism and
can be activated by an increase in cellular calcium con-
centration and the stimulation of numerous hormones,
adipokines, and cytokines.56 In the condition of ATP defi-
ciency, including starvation or insulin effect, the down-
stream TSC1/2 is activated by AMPK, and finally enhances
autophagy by suppressing mTOR activation.57
Mitochondria dysfunction
Traditional view on the association with mitochondria
dysfunction and complications of DM involves hyperglyce-
mia-related deleterious effect. Hyperglycemia promotes
overload of the electron transport chain and subsequently
causes DNA damage and reduced GAPDH activity via
increased ROS production. Hence, the course of glycolysis is
disturbed and an accumulation of all upstream glycolytic
intermediates occurs. Metabolic flux is shifted into other
alternative processes, including increased activity in the
polyol pathway, production of AGE precursors, PKC acti-
vation, and hexosamine pathway activity. As a result,
fibrosis, thrombosis, DNA damage, cellular dysfunction,
vascular leakage, angiogenesis and inflammation, and
decreased oxidative stress defense are accompanied to
cause kidney damages.58,59
Alternative mechanism of mitochondria involvement in
diabetic kidney is associated with reduced mitochondrial
superoxide. The view of high degree of ROS related to
harmful to many kinds of cells is well-known before. The
Update of pathophysiology and management of diabetic kidney disease
diabetic kidney was found to have a reduction of mito-
chondrial content and reduced activity of the electron
chain complexes. Normal mitochondrial superoxide level is
able to maintain AMPK activation and eNOS phosphoryla-
tion. Hence, production of mitochondrial superoxide can be
an indicator of healthy mitochondria and physiologic
oxidative phosphorylation. In response to excess glucose
exposure or nutrient stress, there is a reduction of mito-
chondrial superoxide, oxidative phosphorylation, and
mitochondrial ATP generation in the kidney. Decreased
mitochondrial superoxides cause reduced AMPK activity and
eNOS phosphorylation, and then subsequently stimulate
inflammatory processes via NF-kB and vascular dysfunc-
tion.60 Persistent reduction of mitochondrial oxidative
phosphorylation complex activity is associated with the
release of oxidants, proinflammatory and profibrotic cyto-
kines from nonmitochondrial sources. Finally, a manifes-
tation of organ dysfunction occurs.61
According to these theories, higher or lower mitochon-
drial ROS levels, a biphasic response, increase the risks of
tissue damage. This concept is in the term of mitochondrial
hormesis.61 Stimulation of mitochondrial biogenesis and
mitochondrial electron transport chain activity leads to
beneficial outcomes in DKD. Restoration of mitochondrial
function and superoxide production via activation of AMPK
has now been associated with improvement in markers of
renal dysfunction in diabetes. Approaches that stimulating
AMPK via exercise, caloric restriction, or medicines can
result in increasing mitochondrial oxidative phosphoryla-
tion activity, restoring physiologic mitochondrial superox-
ide production, and promoting organ healing.60
Prevention and management
Interventions of DKD mainly consist of correction of hy-
perglycemia, hypertension, and dyslipidemia, and modifi-
cation of lifestyle.62,63 Primary prevention represents
prevention from normoalbuminuria to microalbuminuria,
while secondary prevention represents prevention from
microalbuminuria to macroalbuminuria. Multiple interven-
tional managements with control of blood glucose, blood
pressure and lipid, and smoking cessation can significantly
improve the prognosis of cardiovascular events and help to
slow down the progression of renal disease, including
macroalbuminuria and decreased eGFR for patients with
type 2 DM and DKD.64
Glucose control
When normoalbuminuric patients with type 1 DM receive
glycemic control that achieving near-normal blood sugar
level, glomerular hyperfiltration may be corrected after
short period. Meta-analysis showed that patients with type
1 DM receiving intensive blood glucose control for 8e60
months reduced the risk of progression of nephropathy.65
DCCT (Diabetes Control and Complications Trial) study
showed that intensified blood glucose control reduced
albuminuria, and EDIC (Epidemiology of Diabetes In-
terventions and Complications) study indicated that
intensive DM therapy reduced the risk of an impaired GFR
by 50%. Even receiving intensified blood glucose control
667
for 9 years, microalbuminuria still occurred in 16% of pa-
tients in the primary prevention group and 26% of patients
in the secondary prevention group.66 Hence, other stra-
tegies of treatment are still required to decrease the
burden of DKD.
For patients with type 1 or type 2 DM, a number of risk
factors related to deterioration from microalbuminuria to
overt diabetes nephropathy consist of urinary albumin
excretion, glycated hemoglobin (HbA1c) concentration,
smoking, hypertension, and serum cholesterol concentra-
tions.67,68 Intensified multi-factorial interventions,
including medical control of hyperglycemia, hypertension,
dyslipidemia, and microalbuminuria, slow progression to
overt diabetic nephropathy, retinopathy, autonomic neu-
ropathy and ESRD in microalbuminuric patients with type 2
DM.62,69
A large prospective observational study indicated that
intensive glycemic control played an important role for
deterioration of diabetic nephropathy.70 The Action in
Diabetes and Vascular Disease: Preterax and Diamicron
Modified Release Controlled Evaluation (ADVANCE) trial
showed that intensive glucose control can reduce devel-
opment of microalbuminuria and macroalbuminuria.62
In conclusion, glucose control in diabetes patients
should be individualized according to the patient’s alert of
hypoglycemia, underlying CKD or cardiovascular disease
status, and age. The National Kidney Foundation’s Kidney
Disease Outcomes Quality Initiative (KDOQI) guideline
generally suggests keep HbA1c levels to 7.0% or less for
patients with type 1 or type 2 diabetes mellitus. For in-
dividuals with multiple co-morbidities, limited life expec-
tancy and risks of hypoglycemia episodes, target HbA1c
levels can be extended above 7.0%.71
Blood pressure control
Animal studies showed that controlling the blood pressure
to normal level improved glomerular capillary hypertension
in diabetic rats and can effectively reduce the incidence of
proteinuria and focal segmental glomerular lesions.72 Some
observational studies suggested that the glomerular hy-
pertension is the major cause of diabetic glomerulopathy.
Reducing systemic blood pressure without control glomer-
ular capillary pressure simultaneously is insufficient to
prevent from glomerular damage.73
Previous randomized trials revealed that angiotensin-
converting enzyme inhibitor (ACEi) is beneficial to reduce
occurrence of microalbuminuria in normotensive and nor-
moalbuminuric patients with type 1 and type 2 DM. United
Kingdom Prospective Diabetes Study (UKPDS) showed that
microalbuminuria only occurred in a small portion of pa-
tients with strict blood pressure control for 6 years follow-
up. Besides, strict control of blood pressure can signifi-
cantly reduce incidence of microalbuminuria by 29%
(p < 0.009).74
RAAS inhibitors reduce the frequency of micro-
albuminuria in hypertensive normoalbuminuric patients.
This effect is not significant for patients with normal blood
pressure. It is likely that intrarenal RAAS is enhanced in
patients with hypertension, but not in those without hy-
pertension. Hence, ACEi or other anti-hypertensive drugs
668
are not suggested to use for primary prevention of DKD in
normoalbuminuric patients with normal blood pressure.75
RAAS blockers have the benefits for changes of glomer-
ular structures in patients with early stage of DKD. ACEi and
angiotensin receptor blocker (ARB) can significantly lower
blood pressure and urinary albumin excretion rate for
microalbuminuric patients with type 2 DM. Anti-
hypertensive medications is beneficial to disease itself
and cost effectiveness for microalbuminuric patients with
DM.76e78 Long-term intensified multi-factorial interven-
tional treatment can reduce 50% of microvascular and
cardiovascular events, decrease incidence of ESRD and
absolute risks of death by 20% in microalbuminuric patients
with type 2 DM.79
RAAS blockers have effects of relieving occurrence of
renal diseases for patients with type 1 or type 2 DM. ACEi
and ARB are considered to have similar effects on lowering
blood pressure and decreasing albuminuria.80 Present rec-
ommendations suggest that RAAS blockers can relieve the
deterioration of nephropathy for albuminuric patients with
DM, hypertension and advanced chronic kidney
disease.63,81,82
Combination of ACEi and ARB has additional renal and
cardiovascular protective effects for albuminuric patients
with DM.83 Ongoing Telmisartan Alone and in Combination
With Ramipril Global Endpoint Trial (ONTARGET) showed
that the combination of telmisartan and ramipril reduced
albuminuria to normal range but increased the risk of
doubling the concentration of serum creatinine, needs to
receive renal replacement therapy and mortality.84 Veter-
ans Affair Nephro Diabetes (VA Nephron D) study also
revealed there is no significant difference between com-
bination of ACEi and ARB and single ACEi or ARB treatment.
Instead, combined therapy may increase the risks of
hyperkalemia and acute kidney injury.85
Direct renin inhibitor, aliskiren, has been used to treat
hypertension, which can inhibit initial rate-determining
step of RAAS. However, many large clinical trials indicate
that it is not recommended to use combined therapy of
aliskiren and ACEi or ARB to patients with DM and hyper-
tension or renal insufficiency. The above combined therapy
not only lacks significant benefit for prognosis, but also
increases the risks of hyperkalemia, hypotension, acute
kidney injury and even cardiovascular events. Hence, Food
and Drug Administration (FDA) and European Medicines
Authority (EMA) regard the combined therapy with aliskiren
plus ACEi or ARB as contraindication of patients with DM or
renal insufficiency.86
The recent Kidney Disease: Improving Global Outcome
(KDIGO) guideline for patients with DKD suggests a target
blood pressure of 140/90 mmHg or less for all for all dia-
betic patients, and 130/80 mmHg or less for micro-
albuminuric patients with DM. Besides, use of ACEi or ARB is
recommended for patients with DKD and urine albumin
excretion of 30 mg per 24 h or more.87
Lipid profiles control
Dyslipidemia is common in patients with DKD. Diabetic
patients with persistent albuminuria may increase the risks
of cardiovascular events, which are the common causes of
Y.-C. Lin et al.
morbidity and mortality in this population. Some statin
seems to have benefits with improving proteinuria in pa-
tients with DKD. In the Prospective Evaluation of Protein-
uria and Renal Function in Diabetic Patients With
Progressive Renal Disease trial (PLANET I trial), atorvastatin
has more renoprotective effects with reducing proteinuria
and renal events than rosuvastatin in patients with DKD
under ACEi or ARB treatment.88 KDOQI guideline recom-
mends that patients with DKD should receive statin-based
therapies to lower low-density lipoprotein cholesterol
(LDL-C) levels, to reduce risks of major atherosclerotic
events.71 Recent American College of Cardiology and the
American Heart Association (ACC/AHA) blood cholesterol
guideline suggests that use the most tolerated statin dosage
for primary and secondary prevention according to the
degrees of patient’s atherosclerotic cardiovascular disease
(ASCVD) risks. For all patients older than 21 years of age
with primary LDL-C level more than 190 mg/dL and those
40e75 years of age with DM and LDL-C level between 70 and
189 mg/dL, statin therapy should be initiated. Among pa-
tients with DM who are younger than 40 years or older than
75 years of age, or whose LDL-C level is less than 70 mg/dL,
statin therapy should be individualized by the ASCVD risk-
reduction benefits, the potential adverse effects, and pa-
tient preferences.89
Life style modifications
For all diabetic patients, lifestyle modifications, including
dietary restriction of sodium and protein, adequate exer-
cise and weight reduction, and smoking cessation, are
important to lower the risk of diabetic kidney disease and
cardiovascular events.
Individualized diet planning according to disease
severity, blood pressure, electrolyte status and cultures are
suggested for patients with DKD in the effective educa-
tional program because of high prevalence of multiple
metabolic abnormalities.90 It is important that dietary so-
dium restriction can give the most benefit in proteinuric
patients with DM.91 However, it still debated whether the
restrictive protein diet slows the progression of DKD. Ac-
cording to the potential benefits and known risks of various
protein diet, the Kidney Disease Improving Global Out-
comes (KDIGO) and the National Kidney Foundation (NKF)
suggest a target dietary protein intake of 0.8 g/kg/day for
people with or without diabetes and eGFR less than 30 ml/
min/1.73 m2.90
Physical activity has been considered to improve physical
health, blood pressure, lipid profiles, insulin sensitivity, and
cardiovascular outcomes in patients with diabetes.92,93 Be-
sides, regular exercise has been shown to improve protein-
uria in rat models of diabetes.94 By the known overall health
benefits of physical activity, the American Diabetes Associ-
ation suggests at least 150 min per week of moderate to
vigorous aerobic exercise at least 3 days a week for patient
with type 2 diabetes.95 Some small investigations have been
shown the benefit effect of weight loss on DKD by low-calorie
diet or bariatric surgery for obesity. For patients with dia-
betes and obesity, weight reduction seems a positive strat-
egy for DKD. It needs larger researches to understand the
association with DKD and obesity or weight loss.96,97
Update of pathophysiology and management of diabetic kidney disease
Smoking in particular is an independent risk factor for
the development of nephropathy in type 2 diabetes. Many
researches indicate the significantly negative effect of
smoking on cardiovascular events and global health. KDIGO
guideline encourage to avoid and quit smoking as possible
for patients with established and at risk of DKD.87
Novel treatments of diabetic kidney disease
Some novel treatments of DKD are developed and investi-
gated in recent years (Table 2).
Glucose-lowering agents
Some glucose-lowering agents for patients with type 2 DM,
especially novel ones, are found to be able to protect
kidney other than the effect of controlling hyperglycemia.
Renal sodium glucose cotransporter 2 (SGLT2) is
responsible for reabsorption of the glucose in the glomer-
ular infiltrate, and its inhibitors have been used for type 2
DM. In patients with type 2 DM and high cardiovascular
risks, empagliflozin, an SGLT2 inhibitor, is associated with
slower progression of kidney disease and lower rates of
clinically relevant renal events than placebo when added to
standard care.74,98 Another SGLT2 inhibitor canagliflozin, in
a recently published trial (CANVAS trial), showed benefit of
canagliflozin with respect to the progression of albuminuria
(hazard ratio 0.73) and the composite outcome of a sus-
tained 40% reduction in the estimated GFR, the need for
RRT, or death due to renal causes (hazard ratio 0.60).99
According to these recent studies, SGLT2 inhibitors have
benefits for delaying DKD progression.
Glucagon-like peptide-1 (GLP-1) is one of the incretins,
released from the intestine in response to food intake. GLP-
1 can stimulate insulin secretion and then keep stable ho-
meostasis of glucose and GLP-1 level is decreased in pa-
tients with type 2 diabetes. Several GLP-1 analogs have
been used to treat type 2 DM. In one study of 23 patients
with type 2 DM and overt DN, who had already been treated
with blockade of renin-angiotensin system under dietary
sodium restriction, GLP-1 analog liraglutide for a period of
12 months caused a significant decrease in proteinuria
(p Z 0.002) and substantially diminished the rate of decline
in eGFR (p Z 0.003).100 In another study including 31 pa-
tients with type 2 diabetes, short-term or long-term (one
year) treatment of liraglutide were associated with signif-
icant reversible decline in GFR, and reduction of 27% urine
albumin excretion rate (p Z 0.020) and systolic blood
pressure (p Z 0.048).101 According to the LEADER (Lir-
aglutide Effect and Action in Diabetes: Evaluation of Car-
diovascular Outcomes Results) double-blind trial with 9340
patients with type 2 DM and high cardiovascular risk, pa-
tients with liraglutide had lower rate of the first occurrence
of death from cardiovascular causes, nonfatal myocardial
infarction, nonfatal stroke, and new onset of persistent
macroalbuminuria (hazard ratio Z 0.74, p Z 0.004) than
with those with placebo. In this trial, liraglutide also caused
lower rates of progression of DKD than placebo.102,103
Another randomized study of 3297 patients with type 2
diabetes under standard-care regimen, patients using
semaglutide (another GLP-1 analog) had lower rates of new
or deteriorating nephropathy than those with placebo
669
(hazard ratio Z 0.64; p Z 0.005).104 By these recent
studies results, GLP-1 analogs have benefits to DKD devel-
opment or progression.
Dipeptidyl peptidase 4 (DPP4) inhibitors linagliptin and
saxagliptin (SAVOR-TIMI 53 trial) can reduce the amount of
albuminuria.105,106 However, whether DPP4 inhibitors have
more effectiveness on renal protection beyond decrease of
blood glucose level still needs further research to confirm
the clinical outcomes.
Some studies revealed that rosiglitazone, a kind of
thiazolidinedione, reduced microalbuminuria independent
on the hyperglycemic state.107,108
Other novel agents for DKD
Pentoxifylline (PTF) has been shown to attenuate the pro-
gression of renal fibrosis through inhibition of cell prolif-
eration, reducing kidney inflammation and decreasing the
accumulation of extracellular matrix in animal
studies.109,110 In recent studies enrolling 169 patients with
type 2 DM and following up 2 years, it displayed that the use
of RAAS plus PTF relieved the reduction of GFR and
decreased urinary albumin excretion.111e113
Vitamin D or vitamin D analogs play important roles on
inhibition of occurrence of DKD. Vitamin D is a negative
regulator of RAAS.114 In experimental studies, combined
therapy with vitamin D analogs and ARB prevented from
kidney injury and is more effective than any single one
use.115 In short-term study assessing safety of the use of
vitamin D analogs, paricalcitol had proteinuria-lowering
effect in patients with CKD.116 VITAL (Selective Vitamin D
Receptor Activator for Albuminuria Lowering) study
enrolled patients with type 2 DM and albuminuria, and
showed that the addition of 2 mg paricalcitol to RAAS inhi-
bition reduced albuminuria by 18%e28% (p Z 0.014 vs
placebo). However, the long-term effects are still
lacking.117
Pyridoxamine belongs to the family of vitamin B6. It can
remove free radicals and carbonyl products, and block
synthesis of AGEs. Pyridoxamine phase II trial showed that
although the serum creatinine level did not have difference
after using pyridoxamine for 52 weeks, but subgroup anal-
ysis showed that patients with normal renal function had
lower average serum creatinine level after using pyridox-
amine. Currently, PIONEER-CSG-17 trial is trying to prove
such benefits about use of pyridoxamine.118 On contrast, in
a randomized, double-blind placebo control trial of 238
participants with type 1 or type 2 diabetes and DN, patients
taking high dose of B-vitamin containing folic acid (2.5 mg/
day), vitamin B6 (25 mg/day) and vitamin B12 (1 mg/day)
decreased more GFR significantly than those taking placebo
(p Z 0.02). It needs larger and systemic investigations to
confirm this view of point.119
Avosentan, an endothelin-1 receptor A antagonist, can
reduce urinary albumin excretion. However, the associated
study was terminated early because of excessive cardio-
vascular events during the treatment course.120 Another
study of 211 patients showed atrasentan, a kind of selective
endothelin receptor A antagonist, had proteinuria-lowering
effect and less accumulation of body fluid.10
In a phase 2 randomized controlled trial for patients with
type 2 DM, ruboxistaurin, an inhibitor of protein kinase C-b,
significantly reduced albuminuria without decrease of
670 Y.-C. Lin et al.

Table 2 Novel medical treatments for diabetic kidney disease (DKD).

Medication & recent studies Action mechanism/molecular targets Study population/effects on renal outcomes
Glucose-lowering agents
SGLT2 inhibitors:
Empagliflozin Inhibition of SGLT-2 to decrease Type 2 DM and high CV risks
(EMPA-REG OUTCOME)98 glucose reabsorption Lower rates of incident or deteriorating
nephropathy, doubling of serum creatinine
level and RRT.
Canagliflozin (CANVAS)99 Inhibition of SGLT-2 to decrease Type 2 DM and high CV risks
glucose reabsorption Possible benefit with progression of
albuminuria, reduction of eGFR, need of
RRT and death from renal causes.
GLP-1 RAs:
Liraglutide (LEADER)103 Enhance GLP-1 expression to increase Type 2 DM and high CV risks
insulin secretion Lower rates of progression and development
of DKD
Semaglutide (SUSTAIN-6)104 Enhance GLP-1 expression to increase Type 2 DM and CV risks or CKD stage3
insulin secretion Lower rates of new or deteriorating
nephropathy
DPP-4 inhibitors:
Linagliptin105 Inhibition of DPP-4 to preserve GLP Type 2 DM with microalbuminuria or higher
effect and receiving stable dose of RAAS inhibitors
Reduction in albuminuria
Saxagliptin Inhibition of DPP-4 to preserve GLP Type 2 DM with albuminuria
(SAVOR-TIMI 53 trial)106 effect Improved albuminuria
Thiozolidinediones:
Rosiglitazone108 Activation of PPARg to increase Type 2 DM with albuminuria
insulin sensitivity of tissue Decreased albuminuria
Other novel agents
Phosphodiesterase inhibitors:
Pentoxifylline109,110,112 Inhibition of cell proliferation, kidney Type 2 DM and CKD stage 3e4 with RAAS
(PREDIAN trial) inflammation and accumulation of inhibitors
extracellular matrix Less decreased in eGFR; higher reduction of
albuminuria
Vitamin D analogs:
Paricalcitol116,117 Inhibition of RAAS Type 2 DM and albuminuria with RAAS
(VITAL study) inhibitors
Reduction of albuminuria
Pyridoxamine118 Remove free radicals and carbonyl Type 1 and type 2 DM with overt DN
products; block synthesis of AGEs Significant reduction of the changes of
serum creatinine
Endothelium A Type 2 DM and CKD stage 2e3
receptor antagonists:
Atrasentan10 Selective endothelin receptor A Reduced albuminuria
antagonist
Protein kinase C inhibitor:
Ruboxistaurin121 Inhibition of protein kinase C-b and Type 2 DM and albuminuria
reduce of oxidative stress Reduced albuminuria and maintain eGFR
Sulodexide123 Restores the anionic heparan sulfate Type 1 and type 2 DM with albuminuria
charges on the glomerular basement Reduced albuminuria
membrane
TGF-b blockade
Pirfenidone125 Antagonize MAPK pathway to Animal study
attenuate EMT and fibrosis Reduce the decline of GFR
Anti-inflammation
Bardoxolone methyl126 Activation of Nrf2 and inhibit NF-kB Type 2 DM and impaired renal function
pathway No influence of albuminuria
Update of pathophysiology and management of diabetic kidney disease 671

Table 2 (continued )
Medication & recent studies Action mechanism/molecular targets Study population/effects on renal outcomes
JAK inhibitor:
Baricitinib26 Selective JAK-1 and JAK-2 inhibitor to Type 2 DM and DKD
reduce innate immune response in Reduced albuminuria
kidney cells
Non-steroidal minerocorticoid antagonist:
Finerenone130 Inhibition of RAAS Type 2 DM and albuminuria with RAAS
inhibitors
Reduced albuminuria
SGLT2: Sodium/glucose cotransporter 2; GLP-1 RA: Glucagon-like peptide 1 receptor agonist; DPP-4: Dipeptidyl peptidase 4; PPARg:
peroxisome proliferators-activated receptor-gamma; MAPK: mitogen-activated protein kinases; EMT: epithelial to mesenchymal tran-
sition; Nrf2: nuclear factor (erythroid-derived 2) -like 2; JAK: Janus kinase; RRT: renal replacement therapy; eGFR: estimated
glomerular filtration rate.

estimated GFR.121 Nevertheless, the long-term renal out-
comes and mortality rate of ruboxistaurin are similar to
that of placebo.122
Sulodexide (Soludexide) is a kind of glycosaminoglycan
(GAG) mixture of 20% of dermatan sulfate and 80% low-
molecular-weight heparin. The precise mechanism of the
renoprotective effects of sulodexide remains unknown. A
simple explanation of the efficacy of sulodexide is that it
restores the anionic heparan sulfate charges on the glomer-
ular basement membrane. A recent meta-analysis showed
that sulodexide therapy was associated with a significant
reduction in urinary protein excretion (Odds ratio is 3.28,
p Z 0.01) and had renoprotective benefit on patients with
diabetes and microalbuminuria and macroalbuminuria.123
The development of other anti-fibrosis agents focuses on
antibodies against growth factors, including connective
tissue growth factor (CTGF) and TGF-b blockade, for
example, pirfenidone. Recent studies indicated that pirfe-
nidone had anti-fibrotic effects in many tissues. The po-
tential molecular mechanism remains unknown. Low dose
pirfenidone reduces the decline of GFR. The associated
study was terminated due to more side effects at higher
dose of pirfenidone.124 On the other hand, in an animal
study, pirfenidone was able to attenuate epithelial-to-
mesenchymal transition (EMT) and fibrosis in vivo and
in vitro through antagonizing the mitogen-activated protein
kinases (MAPK) pathway, providing a potential treatment to
alleviate renal tubulointerstitial fibrosis.125
Laboratory studies showed that agents against inflam-
mation or oxidative stress may have potential effects on
renal protection. Bardoxolone methyl reduces the genera-
tion of oxidative stress by the activation of nuclear factor
(erythroid-derived 2) -like 2 (Nrf2) and inhibition of NF-kB
pathway. Short-term study revealed that the use of bar-
doxolone methyl can increase the GFR in patients with type
2 DM and impaired renal function but have no influence of
albuminuria.126 However, the study was terminated early
because of more cardiovascular events.127
According to the growing evidences of Janus
kinaseesignal transducer and activator of transcription
(JAK-STAT) activation of DKD, baricitinib, a selective JAK-1
and JAK-2 inhibitor is developed. An unpublished Phase 2
multicenter, randomized, double-blind, placebo-controlled
study of the efficacy of a selective JAK1 and JAK2 inhibitor
had been conducted in type 2 diabetic participants with
DKD. In this trial, there was a reduction of albuminuria in
receiving the active inhibitor. This result supports the
further study of JAK inhibitors as a new therapy for DKD.26
A study demonstrated that spironolactone, a miner-
ocorticoid receptor antagonists (MRAs), in addition to ACE
inhibition, reduced proteinuria in patients with chronic
kidney disease (CKD) from either diabetes or nondiabetic
causes.128 However, MRAs increase the risk of hyperkalemia
in patients with stage 3 or more advanced chronic kidney
disease.129 Finerenone is a novel nonsteroidal MRA. In a
randomized, double-blind, placebo-controlled study,
finerenone for 90 days showed a significant dose-dependent
reduction of albuminuria (p < 0.05) in the patients with
type 2 DM who had received ACEi or ARB.130 Other long-
term or larger studies are needed to assure the efficacy
and safety of nonsteroidal MRA.
Conclusion
DKD is a clinical syndrome consisting of persistent albu-
minuria, sustained reduction in GFR, elevated blood pres-
sure, increased cardiovascular events and their related
mortality. The dialytic patients with DM have higher mor-
tality than those without DM. Recent studies showed that
multifactorial interventions with RAAS blockers, control of
blood pressure, blood glucose and lipid, and smoking
cessation can significantly improve the prognosis of pa-
tients with type 2 DM and nephropathy. Many novel medi-
cations for prevention and treatment of DKD are studied,
including SGLT2 inhibitors, GLP-1 analogs, DPP-4 inhibitors,
thiazolidinedione, pentoxifylline, vitamin D analog par-
icalcitol, pyridoxamine, ruboxistaurin, soludexide, JAK in-
hibitors and nonsteroidal minerocorticoid receptor
antagonists. In patients with DKD, further researches
focusing on the renal outcomes, not only on changes of
albuminuria, are needed to evaluate the long-term effects
of these novel medications.
Conflict of interest
No conflict of interest to declared.
672
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.jfma.2018.02.007.
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