review article Diabetes, Obesity and Metabolism 18: 641–647, 2016.

© 2016 John Wiley & Sons Ltd

ARTICLE
REVIEW
Diabetic nephropathy: where are we on the journey
from pathophysiology to treatment?
H. Gallagher & R. J. Suckling
SW Thames Renal Unit, St Helier Hospital, Carshalton, Surrey, UK

Diabetic nephropathy affects 30–40% of people with diabetes, and is the leading cause of end-stage kidney disease. The current treatment paradigm relies
on early detection, glycaemic control and tight blood pressure management with preferential use of renin-angiotensin system blockade. This strategy
has transformed outcomes in diabetic kidney disease over the last 20 years. Over the last two decades we have also witnessed significant advances in the
understanding of the pathophysiology of diabetic nephropathy; however, despite this new knowledge, we have yet to develop new treatments of proven
efficacy. Whilst a continued emphasis on preclinical and clinical research is clearly needed, clinicians treating people with diabetes should not forget that,
in the short term, the greatest gains are likely to be realised by more consistent deployment of existing therapies.
Keywords: diabetic nephropathy, glycaemic control

Date submitted 7 September 2015; date of first decision 17 October 2015; date of final acceptance 29 December 2015

Significance of Diabetic Nephropathy
Diabetes mellitus is a major cause of morbidity and mortality
worldwide. According to the International Diabetes Federation
in 2013, the global prevalence of diabetes was 382 million
people (with 46% undiagnosed), which will rise to 592 million
within 25 years. The global health expenditure attributable
to diabetes is expected to increase from $548 bn in 2013 to
$627 bn in 2035 [1]. Global mortality attributable to diabetes is
5.1 million deaths per year (one death every 6 s); the majority
are as a result of cardiovascular disease [2]. More than 80%
of diabetes-related deaths occur in low- and middle-income
countries [3].
In the European Union the number of people with diabetes in
2013 was estimated at 56 million, representing 7% of the Euro-
pean population. By 2035, this number is expected to rise by
22% to 68.9 million people. Diabetes accounted for 10% of all
European deaths in 2013. Type 2 diabetes accounts for 90%
of cases in all high-income countries. The current European
healthcare expenditure required for people with diabetes is
€105 bn per annum in 2013, which will rise to €125.1 bn per
year by 2035. This is ∼11% of the total European adult health-
care budget [1].
In England and Wales diabetes was associated with almost
20 000 premature deaths in 2011/2012 [4]. The associated social
and economic burdens are enormous: although the direct costs
of treating diabetes in UK are >£13 bn annually, of which the
major component is inpatient care, the indirect costs, including
absenteeism and early retirement, are far greater [5]. It is esti-
mated by Diabetes UK that there are a further 6 30 000 people in
the UK with undiagnosed diabetes [6]. The care of people with
Correspondence to : H. Gallagher, SW Thames Renal Unit, St Helier Hospital, Carshalton, Surrey,
SM5 1AA, UK.
E-mail: hugh.gallagher@esth.nhs.uk
diabetes in England and Wales is financially incentivised under
the Quality and Outcomes Framework (QOF) and assessed via
QOF data returns and through the National Diabetes Audit,
which has been running since 2003.
Chronic kidney disease (CKD) affects up to 13% of adults
[7] but is often unrecognized by both healthcare professionals
and patients, with up to 30% of those with the most advanced
stages of disease (CKD stages 3–5) undiagnosed [7]. Diabetes
substantially increases the risk of developing moderate to severe
CKD. In men, the risk of developing CKD is increased by a
factor of 12 in type 1 diabetes and 6 in type 2 diabetes, as
compared with individuals without diabetes [8]. Up to 30% of
people with diabetes have moderate to severe CKD [9,10]. Reg-
istry data across the developed world consistently show that
diabetic nephropathy is the most common cause of end-stage
renal disease (ESRD) requiring renal replacement therapy [11].
The development of kidney disease in diabetes has great signif-
icance; excess mortality in diabetes is seen exclusively in type 1
[12] and predominantly in type 2 diabetes in people with an
impaired estimated glomerular filtration rate (eGFR) and/or
albuminuria [13].
The vast majority of patients with CKD do not progress to
ESRD, with only 1–2% of patients with CKD stage 3 requiring
renal replacement therapy over a 10-year period [14]. For many,
the importance of CKD lies in its role as a powerful independent
risk factor for cardiovascular disease. Recent epidemiological
data, that are both large-scale and robust, indicate that the risks
of both all-cause and cardiovascular mortality in the general
population increase where eGFR is <60 ml/min/1.73 m2 , and
where the albumin:creatinine ratio is >1 mg/mmol. The risks
are graded, and eGFR and albumin:creatinine ratio are mul-
tiplicatively associated with mortality risk, with no evidence
of interaction [15]. Albuminuria and eGFR are similarly pre-
dictive of mortality in high-risk population cohorts [16] and
review article
kidney disease cohorts [17], and in people with and without
diabetes [18] and hypertension [19]. The findings hold true in
older people [20], both sexes [21] and across races [22].
Identifying and treating CKD in people with diabetes is
therefore a major target for public health. In the present paper,
we review the key aspects of the pathogenesis of diabetic
nephropathy and describe the implications of its pathophysi-
ology on treatment. We also reflect on the extent to which the
increase in our understanding of disease has been paralleled
by advances in therapeutics and consider how best we might
deploy our efforts in the short to medium term in order to
improve outcomes.
Hyperglycaemia and Diabetic Nephropathy
Glucose and the Pathogenesis of Kidney Disease
Hyperglycaemia is a prerequisite for the development of dia-
betic nephropathy. The effects of hyperglycaemia on the kidney
have been well described and are mediated through a number
of pathways, including the non-enzymatic reaction of glucose
with proteins, resulting in the formation of advanced glycation
end-products (AGE) [23], the activation of protein kinase C
[24] and the stimulation of the polyol pathway [25].
The overall effects of hyperglycaemia on the kidney include
oxidative stress [26] and the activation of various signal trans-
duction cascades, leading to the release of proinflammatory
[27] and profibrotic mediators [28]. This is compounded by
important alterations in intra-renal haemodynamics. Together,
these result in the classic structural and functional alterations
of diabetic kidney disease with alterations in glomerular per-
meability, glomerular hyperfiltration, glomerular basement
membrane thickening, mesangial matrix synthesis and, ulti-
mately, the development of glomerulosclerosis and interstitial
fibrosis.
Hyperglycaemia as a Treatment Target
Given its key pathogenic role, it should be of little surprise
that hyperglycaemia is an important target for preventative
and treatment strategies. The Diabetes Control and Complica-
tions Trial (DCCT) clearly showed that the level of glycaemic
control was closely related to development of nephropathy
in type 1 diabetes [29]. A similar association in type 2 dia-
betes was evident in the Atherosclerosis Risk in Communi-
ties study [30]. In established diabetic nephropathy, glycated
haemoglobin (HbA1c) is a powerful predictor of progression
to microalbuminuria [31].
Studies have provided powerful evidence for the benefits
of intervention to improve glycaemic control. This has been
demonstrated most clearly in the DCCT, where those partic-
ipants assigned to tight control, whose achieved HbA1c level
was 7.2% (55 mmol/mol), had a 39 and 54% relative reduction
in the development of microalbuminuria and macroalbumin-
uria, respectively, compared with the conventionally treated
group, whose HbA1c level was 9.1% (76 mmol/mol) [32]. Even
more striking has been the legacy effect observed in the 93%
of DCCT participants who continued to participate in the
Epidemiology of Diabetes Interventions and Complications
642 Gallagher and Suckling
DIABETES, OBESITY AND METABOLISM
observational follow-up study. Although glycaemic control was
similar in the two groups after the DCCT closed, the incidence
of an impaired eGFR in participants originally assigned to
intensive treatment was 50% lower than that in the conven-
tionally treated group after a median follow-up of 22 years [33].
This effect also operates in type 2 diabetes; long-term outcome
data from the UK Prospective Diabetes Study show improved
outcomes in participants initially assigned to intensive treat-
ment evident after 10 years of follow-up, despite the loss of
between-group differences in glycaemic control after the first
year [34].
Renin-angiotensin System in Diabetic
Nephropathy
Local Activation of the Renin-angiotensin System
in Diabetes
Glomerular hyperfiltration is a well recognized early marker
of diabetic nephropathy [35]. The renin-angiotensin system
(RAS) is the single most significant contributor to the observed
pathophysiogical changes [36,37]. The effects are primarily
local, with upregulation of the local intrarenal RAS [38] despite
suppressed circulating levels of renin in individuals with hyper-
tension, diabetes and nephropathy. This systemic suppression is
likely to be mediated through mechanisms including salt reten-
tion and volume expansion [39].
Locally generated angiotensin II has a number of important
haemodynamic actions. At the level of the proximal tubule,
sodium reabsorption is stimulated [40]. Angiotensin II pref-
erentially induces efferent arteriolar vasoconstriction and
increases glomerular capillary pressure and permeability [41].
Local, non-haemodymamic effects include: increased cytokine
production; glomerular and tubular cell proliferation; extra-
cellular matrix accumulation; and the generation of reactive
oxygen species [42]. Alongside the effects of hyperglycaemia,
which itself stimulates release of angiotensin II [43], this creates
a powerful local cocktail for the development and progression
of diabetic kidney disease.
Renin-angiotensin System as a Treatment Target
The current mainstay of treatment for proteinuric diabetic
nephropathy is RAS blockade. This approach is supported by
a vast body of evidence. The benefits extend beyond blood
pressure effects alone, with blood pressure-independent reno-
protective properties observed in individuals with type 1
diabetes and nephropathy [44,45] and in those with type
2 diabetes and both incipient [46] and established [47,48]
nephropathy. Together with the widespread adoption of strict
glycaemic control, the use of angiotensin-converting enzyme
(ACE) inhibitors and angiotensin receptor blockers (ARBs) has
transformed renal outcomes over the last 20 years, reducing
the development of ESRD in individuals with type 1 diabetes
from 8% over 30 years, if diagnosed between 1965 and 1999
[49], to only 1% in the intensively treated group in the DCCT
over a similar time period [50].
Although established as the standard of care for the treat-
ment of proteinuric diabetic nephropathy, the role of RAS
Volume 18 No. 7 July 2016
DIABETES, OBESITY AND METABOLISM
blockade in the primary prevention of diabetic renal disease
is less clear. Whilst RAS inhibition appears to be effective in
preventing the development of albuminuria in people with
type 2 diabetes and hypertension [51–54], outcomes in nor-
motensive people with type 2 diabetes have been conflicting
[51,55]. The role of RAS inhibition as primary prevention in
normotensive individuals with type 1 diabetes [51,56] remains
uncertain.
Controversies in Renin-angiotensin System Inhibition
Despite continuous treatment with RAS inhibitors, a reduc-
tion in aldosterone levels may not be maintained, and lev-
els may actually increase over time [57]. This phenomenon,
termed aldosterone breakthrough, has led to the consider-
ation of the use of combinations of agents to inhibit the
renin-angiotensin-aldosterone system (RAAS). Experimental
studies have shown that ACE inhibitors and ARBs have a syn-
ergistic effect on blood pressure and renin release [58]. Clini-
cal studies of dual ACE inhibitor–ARB blockade have provided
evidence of benefit on surrogate clinical markers, particular
a reduction in albuminuria. A meta-analysis, which included
people with and without diabetes, showed that dual blockade
with ACE inhibitor and ARB reduced proteinuria to a greater
extent than either agent alone [59].
Two key outcome trials of dual blockade, ONTARGET [60]
and VA-NEPHRON D [61], however, have since shown neg-
ative results. Despite a greater reduction in proteinuria in the
combination therapy groups, there was no clear benefit in
terms of hard primary endpoints such as reduction in eGFR,
ESRD and death, with a clear and widely reported increase
in adverse outcomes, notable hyperkalaemia and acute kidney
injury. These results also highlight the limitations of albumin-
uria reduction as a surrogate marker in clinical trials of reno-
protective strategies in diabetes.
The direct renin inhibitor, aliskiren, has also been used as
an adjuvant to ACE or ARB inhibition. Again, these stud-
ies highlighted safety concerns with no beneficial effects on
primary renal outcomes [62]. A systematic review of com-
bination RAAS blockade with an aldosterone antagonist
together with an ACE inhibitor or ARB reported similar
findings [63].
The European Medicines Agency now recommends that
combination use should be strictly avoided in people with
diabetes and in all individuals with moderate to severe renal
impairment, although the door to dual blockade may not
be completely closed: the opinion of some experts on the
Scientific Advisory Group in Cardiovascular Issues was that
‘dual RAS blockade therapy might be prescribed in (younger)
patients with nephropathy and severe proteinuria without
comorbidities’ [64]; however, there are limited outcome data
in this group, and use should be restricted to RAS inhibitor
monotherapy in people with diabetes, both with and without
nephropathy. Judicious prescribing, monitoring and patient
education are important; in particular, consideration should
be given to short-term cessation of RAS inhibitors in sit-
uations where people are at increased risk of acute kidney
injury [65].
Volume 18 No. 7 July 2016
review article
Endothelin and Diabetic Nephropathy
Endothelin and the Kidney
Changes in intrarenal haemodynamics in diabetic nephropathy
are not mediated by angiotensin II alone. In the normal kid-
ney, the endothelial cell-derived vasopressor endothelin-1 is a
powerful vasoconstrictor [66], with a key role in sodium home-
ostasis and blood pressure control [67,68]. The former func-
tion is mediated through endothelin receptor A and the latter
through endothelin receptor B. Increased renal gene expression
of endothelin-1 is seen in diabetes [69] and is also implicated in
renal cellular proliferation, podocyte damage, matrix accumu-
lation and fibrosis [70].
A Role for Endothelin Antagonism?
The role of endothelin-1 in the pathogenesis of diabetic CKD
has lead to interest in endothelin inhibition as a potential thera-
peutic target in diabetic kidney disease. Novel agents inhibiting
endothelin receptors showed promise in experimental studies
with beneficial effects on diabetic nephropathy and protein-
uria [71]. Receptor selectivity is key in these agents, with initial
studies using less selective agents being hampered by adverse
effects, which were thought to be mediated primarily through
sodium retention mediated by inhibition of Endothelin Recep-
tor Type B (ETb) receptors.
Clinical studies of two predominantly endothelin receptor A
antagonists, avosentan and atrasentan, as an add-on therapy to
an ACE inhibitor to treat residual proteinuria in people with
advanced proteinuric diabetic kidney disease have, however,
been disappointing. A trial with avosentan was terminated early
because of safety concerns related to an increase in cardiovascu-
lar side effects, primarily fluid overload and congestive cardiac
failure [72,73]. Peripheral oedema was also observed to com-
plicate therapy with atrasentan [75], although in a more recent
small subsequent study, the lowest dose of atrasentan effectively
reduced blood pressure and proteinuria in participants with
proteinuric diabetic kidney disease and type 2 diabetes without
significant fluid retention [73,74].
Sodium and Diabetic Nephropathy
Sodium/Glucose Reabsorption in the Kidney: a New
Therapeutic Target?
Increased proximal tubular reabsorption and sodium/glucose
cotransport with deactivation of tubuloglomerular feedback
induced by hyperglycaemia may have an important role in
the development of hyperfiltration in diabetic nephropathy.
Experimental studies have suggested that selective inhibitors
of sodium-glucose cotransporter 2 reduces glomerular
hyperfiltration independently of blood glucose levels [75].
A randomized controlled study found that treatment with
such an agent, dapagliflozin, may have a protective effect
on eGFR (with an initial fall followed by stabilization) and
albuminuria; however, the primary endpoint in that study,
change in HbA1c, was not significantly different from that in
controls [76].
doi:10.1111/dom.12630 643
review article
Blood Pressure, Sodium and Diabetic Nephropathy
It is well established that salt is important in regulating blood
pressure, and that a modest salt reduction lowers blood
pressure, leading to recommendations in international guide-
lines for salt reduction in patients with CKD [77]. This is
supported by experimental evidence. Salt-induced renal dam-
age is mediated through the effect of salt on blood pressure
and urinary albumin excretion and through direct renal
effects. Enhanced distal tubular reabsorption of sodium pro-
moted by hyperinsulinaemia [78,79], increased activity of
the sodium-glucose cotransporter and increased activity of
the RAS leads to elevated total body exchangeable sodium in
people with diabetes compared with healthy individuals, even
before the onset of overt nephropathy [80,81].
Clinical evidence for salt reduction in diabetic nephropathy
is more limited. Although cohort studies in people with dia-
betes have shown increased mortality in those patients with
lowest salt intake, these studies are observational in nature.
A meta-analysis of a modest reduction in salt intake in peo-
ple with diabetes showed a reduction in blood pressure and
albuminuria without affecting insulin resistance [82]. Dietary
sodium restriction is also an important adjunct to established
therapies, with studies showing that salt restriction enhances
the effects of inhibitors of the RAAS on proteinuria in people
with diabetes [83]. Although the effects on harder endpoints
is unknown and there remains debate over the optimum salt
intake for people with diabetes, there is no evidence to suggest
the current recommendations of modest salt reduction are
unsafe.
Conclusions and Perspectives
Kidney disease is a critical determinant of outcomes in dia-
betes, and diabetic nephropathy remains a key area of focus
for both preclinical and clinical research. We have witnessed
major advances in treatment over the last 20 years, with out-
comes transformed by the use of RAS blockade and tight, but
judicious, glycaemic control. Nevertheless, our understanding
of how best to deploy existing therapies is incomplete. The role
of glycaemic control in primary prevention is incontrovertible,
whilst the data on RAS blockade in this setting are conflicting.
Despite a sound scientific rationale and encouraging early data,
the use of combination RAS antagonism appears to do more
harm than good. More studies are needed before combination
therapy can be recommended in any group, even the younger
patients with type 1 diabetes in whom there remains enthusi-
asm for dual blockade from some quarters. Unless and until
such data become available, we may be better served direct-
ing our clinical efforts on potentiating RAS blockade though
lifestyle measures, and in particular dietary sodium restriction.
The mechanisms by which hyperglycaemia promotes the
development of nephropathy are now relatively well under-
stood; however, the hope that an increased understanding of
the pathogenesis of diabetic renal disease would lead to effective
targeted strategies has largely yet to be realised, and attempts to
target specific pathways, including AGE formation, mesangial
matrix accumulation and protein kinase C, have yet to exert
644 Gallagher and Suckling
DIABETES, OBESITY AND METABOLISM
a major influence on clinical practice [84]. Early studies indi-
cated that bardenoloxone, which inhibits the transcription fac-
tor NF-𝜅B, increased eGFR in people with CKD stage 3B and
4 [85], but a subsequent phase III trial was terminated early
because of significant increases in the risks of major adverse
cardiovascular events in the bardenoloxone-treated group [86].
Furthermore, whilst the benefits of glycaemic control in gen-
eral are well established, we do not yet have long-term safety
data on the newer hypoglycaemic agents. For example, the early
suggestions that dipeptidyl peptidase 4 (DPP-4) inhibitors had
protective cardiovascular effects have not been confirmed in
large-scale clinical trials, with one reporting an increased inci-
dence of hospitalization for heart failure in the DPP-4-treated
arm [87].
A number of novel approaches to treatment are currently
being evaluated, directed at targets including transforming
growth factor-𝛽, a key profibrotic factor, and a wide range of
proinflammatory intracellular signalling pathways [84]. Many
of these are at the early stages of development. We should also
not underplay the role of basic lifestyle interventions in the pre-
vention and treatment of diabetes and nephropathy. The role of
salt restriction has already been discussed. A position statement
from the American Diabetes Association summarizes the prob-
able benefits of physical activity and exercise in people with dia-
betes; these include increased insulin sensitivity and improved
glycaemic control, cardiovascular disease prevention and blood
pressure reduction [88]. There is good evidence that diabetes
itself can be prevented in people at high risk through lifestyle
changes [89,90]. The 𝛽-alanine and histidine dipeptide carno-
sine appears to be a protective factor in diabetic nephropathy
and is a new potential therapeutic approach. Carnosine may
inhibit the production of AGE and reactive oxygen species and,
in the kidney, has been shown to inhibit mesangial matrix accu-
mulation in response to glucose loading [91]. Recent data sug-
gest that a dietary supplement including carnosine (together
with cinnamon and chromium) reduces fasting plasma glucose
in people with a raised body mass index [92].
We also need to learn more about the 60–70% of individuals
with diabetes who do not develop kidney disease irrespective
of their level of glycaemic control. People with type 1 diabetes
who do not develop nephropathy after 15 years of diabetes
appear to be protected, suggesting that genetic factors may
be involved [93]. Some ethnic groups are at particularly high
risk, notably Pima Indians [94] and South Asians [95]. Indeed,
a large number of genetic variants have been associated with
diabetic nephropathy, with some differences evident in Euro-
pean and Asian subgroups [96]. The variants associated with
altered risk included those involving the RAS, oxidative stress,
inflammation, the polyol pathway and the glomerular base-
ment membrane, consistent with our current understanding
of aspects of the mechanisms of nephropathy. Genetic vari-
ants coding for apolipoprotein-E and apolipoprotein-C1 have
also been reproducibly associated, suggesting a role of lipid
metabolism in the pathogenesis. Indeed, lipid abnormalities
are found at an early stage of nephropathy [97,98], and may
also be a risk factor for progression [99–101].
We should also remember that advancing our knowledge
of the pathogenesis of nephropathy is necessary but not
Volume 18 No. 7 July 2016
DIABETES, OBESITY AND METABOLISM
sufficient to improve care and outcomes. Whilst we wait for the
seeds of our improved understanding to bear fruit, we should
not be distracted from the need for more consistent delivery
of established interventions, both on an individual-patient
and system-wide basis. Early detection is essential to patient
management, and is encouraged in the UK through a system
of payment by results. Despite this, the evidence from the
National Diabetes Audit, the largest annual clinical audit in the
world, is that we continue to miss opportunities to delay and
prevent renal disease. Safety is a critical issue: people with dia-
betes, many of whom are treated with drugs with nephrotoxic
potential, are vulnerable to avoidable harm as a result of poor
prescribing and acute kidney injury. We should better exploit
our knowledge of a glycaemic legacy effect to deliver models of
care that provide early intensive input, with greater emphasis
on the provision of information and the complementary roles
of non-pharmacological and pharmacological therapies.
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