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 in England and Wales is financially incentivised under
the Quality and Outcomes Framework (QOF) and assessed via
Diabetes mellitus is a major cause of morbidity and mortality
QOF data returns and through the National Diabetes Audit,
worldwide. According to the International Diabetes Federation
which has been running since 2003.
in 2013, the global prevalence of diabetes was 382 million
Chronic kidney disease (CKD) affects up to 13% of adults
people (with 46% undiagnosed), which will rise to 592 million
[7] but is often unrecognized by both healthcare professionals
within 25 years. The global health expenditure attributable
to diabetes is expected to increase from $548 bn in 2013 to and patients, with up to 30% of those with the most advanced
$627 bn in 2035 [1]. Global mortality attributable to diabetes is stages of disease (CKD stages 3–5) undiagnosed [7]. Diabetes
5.1 million deaths per year (one death every 6 s); the majority substantially increases the risk of developing moderate to severe
are as a result of cardiovascular disease [2]. More than 80% CKD. In men, the risk of developing CKD is increased by a
of diabetes-related deaths occur in low- and middle-income factor of 12 in type 1 diabetes and 6 in type 2 diabetes, as
countries [3]. compared with individuals without diabetes [8]. Up to 30% of
In the European Union the number of people with diabetes in people with diabetes have moderate to severe CKD [9,10]. Reg-
2013 was estimated at 56 million, representing 7% of the Euro- istry data across the developed world consistently show that
pean population. By 2035, this number is expected to rise by diabetic nephropathy is the most common cause of end-stage
22% to 68.9 million people. Diabetes accounted for 10% of all renal disease (ESRD) requiring renal replacement therapy [11].
European deaths in 2013. Type 2 diabetes accounts for 90% The development of kidney disease in diabetes has great signif-
of cases in all high-income countries. The current European icance; excess mortality in diabetes is seen exclusively in type 1
healthcare expenditure required for people with diabetes is [12] and predominantly in type 2 diabetes in people with an
€105 bn per annum in 2013, which will rise to €125.1 bn per impaired estimated glomerular filtration rate (eGFR) and/or
year by 2035. This is ∼11% of the total European adult health- albuminuria [13].
care budget [1]. The vast majority of patients with CKD do not progress to
In England and Wales diabetes was associated with almost ESRD, with only 1–2% of patients with CKD stage 3 requiring
20 000 premature deaths in 2011/2012 [4]. The associated social renal replacement therapy over a 10-year period [14]. For many,
and economic burdens are enormous: although the direct costs the importance of CKD lies in its role as a powerful independent
of treating diabetes in UK are >£13 bn annually, of which the risk factor for cardiovascular disease. Recent epidemiological
major component is inpatient care, the indirect costs, including data, that are both large-scale and robust, indicate that the risks
absenteeism and early retirement, are far greater [5]. It is esti- of both all-cause and cardiovascular mortality in the general
mated by Diabetes UK that there are a further 6 30 000 people in population increase where eGFR is <60 ml/min/1.73 m2 , and
the UK with undiagnosed diabetes [6]. The care of people with where the albumin:creatinine ratio is >1 mg/mmol. The risks
are graded, and eGFR and albumin:creatinine ratio are mul-
Correspondence to : H. Gallagher, SW Thames Renal Unit, St Helier Hospital, Carshalton, Surrey, tiplicatively associated with mortality risk, with no evidence
SM5 1AA, UK. of interaction [15]. Albuminuria and eGFR are similarly pre-
E-mail: hugh.gallagher@esth.nhs.uk
dictive of mortality in high-risk population cohorts [16] and
review article DIABETES, OBESITY AND METABOLISM

kidney disease cohorts [17], and in people with and without observational follow-up study. Although glycaemic control was
diabetes [18] and hypertension [19]. The findings hold true in similar in the two groups after the DCCT closed, the incidence
older people [20], both sexes [21] and across races [22]. of an impaired eGFR in participants originally assigned to
Identifying and treating CKD in people with diabetes is intensive treatment was 50% lower than that in the conven-
therefore a major target for public health. In the present paper, tionally treated group after a median follow-up of 22 years [33].
we review the key aspects of the pathogenesis of diabetic This effect also operates in type 2 diabetes; long-term outcome
nephropathy and describe the implications of its pathophysi- data from the UK Prospective Diabetes Study show improved
ology on treatment. We also reflect on the extent to which the outcomes in participants initially assigned to intensive treat-
increase in our understanding of disease has been paralleled ment evident after 10 years of follow-up, despite the loss of
by advances in therapeutics and consider how best we might between-group differences in glycaemic control after the first
deploy our efforts in the short to medium term in order to year [34].
improve outcomes.

Renin-angiotensin System in Diabetic

Hyperglycaemia and Diabetic Nephropathy Nephropathy
Glucose and the Pathogenesis of Kidney Disease Local Activation of the Renin-angiotensin System
Hyperglycaemia is a prerequisite for the development of dia- in Diabetes
betic nephropathy. The effects of hyperglycaemia on the kidney Glomerular hyperfiltration is a well recognized early marker
have been well described and are mediated through a number of diabetic nephropathy [35]. The renin-angiotensin system
of pathways, including the non-enzymatic reaction of glucose (RAS) is the single most significant contributor to the observed
with proteins, resulting in the formation of advanced glycation pathophysiogical changes [36,37]. The effects are primarily
end-products (AGE) [23], the activation of protein kinase C local, with upregulation of the local intrarenal RAS [38] despite
[24] and the stimulation of the polyol pathway [25]. suppressed circulating levels of renin in individuals with hyper-
The overall effects of hyperglycaemia on the kidney include tension, diabetes and nephropathy. This systemic suppression is
oxidative stress [26] and the activation of various signal trans- likely to be mediated through mechanisms including salt reten-
duction cascades, leading to the release of proinflammatory tion and volume expansion [39].
[27] and profibrotic mediators [28]. This is compounded by Locally generated angiotensin II has a number of important
important alterations in intra-renal haemodynamics. Together, haemodynamic actions. At the level of the proximal tubule,
these result in the classic structural and functional alterations sodium reabsorption is stimulated [40]. Angiotensin II pref-
of diabetic kidney disease with alterations in glomerular per- erentially induces efferent arteriolar vasoconstriction and
meability, glomerular hyperfiltration, glomerular basement increases glomerular capillary pressure and permeability [41].
membrane thickening, mesangial matrix synthesis and, ulti- Local, non-haemodymamic effects include: increased cytokine
mately, the development of glomerulosclerosis and interstitial production; glomerular and tubular cell proliferation; extra-
fibrosis. cellular matrix accumulation; and the generation of reactive
oxygen species [42]. Alongside the effects of hyperglycaemia,
Hyperglycaemia as a Treatment Target which itself stimulates release of angiotensin II [43], this creates
a powerful local cocktail for the development and progression
Given its key pathogenic role, it should be of little surprise of diabetic kidney disease.
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 Renin-angiotensin System as a Treatment Target
control was closely related to development of nephropathy The current mainstay of treatment for proteinuric diabetic
in type 1 diabetes [29]. A similar association in type 2 dia- nephropathy is RAS blockade. This approach is supported by
betes was evident in the Atherosclerosis Risk in Communi- a vast body of evidence. The benefits extend beyond blood
ties study [30]. In established diabetic nephropathy, glycated pressure effects alone, with blood pressure-independent reno-
haemoglobin (HbA1c) is a powerful predictor of progression protective properties observed in individuals with type 1
to microalbuminuria [31]. diabetes and nephropathy [44,45] and in those with type
Studies have provided powerful evidence for the benefits 2 diabetes and both incipient [46] and established [47,48]
of intervention to improve glycaemic control. This has been nephropathy. Together with the widespread adoption of strict
demonstrated most clearly in the DCCT, where those partic- glycaemic control, the use of angiotensin-converting enzyme
ipants assigned to tight control, whose achieved HbA1c level (ACE) inhibitors and angiotensin receptor blockers (ARBs) has
was 7.2% (55 mmol/mol), had a 39 and 54% relative reduction transformed renal outcomes over the last 20 years, reducing
in the development of microalbuminuria and macroalbumin- the development of ESRD in individuals with type 1 diabetes
uria, respectively, compared with the conventionally treated from 8% over 30 years, if diagnosed between 1965 and 1999
group, whose HbA1c level was 9.1% (76 mmol/mol) [32]. Even [49], to only 1% in the intensively treated group in the DCCT
more striking has been the legacy effect observed in the 93% over a similar time period [50].
of DCCT participants who continued to participate in the Although established as the standard of care for the treat-
Epidemiology of Diabetes Interventions and Complications ment of proteinuric diabetic nephropathy, the role of RAS

642 Gallagher and Suckling Volume 18 No. 7 July 2016

DIABETES, OBESITY AND METABOLISM review article
blockade in the primary prevention of diabetic renal disease Endothelin and Diabetic Nephropathy
is less clear. Whilst RAS inhibition appears to be effective in
Endothelin and the Kidney
preventing the development of albuminuria in people with
type 2 diabetes and hypertension [51–54], outcomes in nor- Changes in intrarenal haemodynamics in diabetic nephropathy
motensive people with type 2 diabetes have been conflicting are not mediated by angiotensin II alone. In the normal kid-
[51,55]. The role of RAS inhibition as primary prevention in ney, the endothelial cell-derived vasopressor endothelin-1 is a
normotensive individuals with type 1 diabetes [51,56] remains powerful vasoconstrictor [66], with a key role in sodium home-
uncertain. 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
Controversies in Renin-angiotensin System Inhibition of endothelin-1 is seen in diabetes [69] and is also implicated in
Despite continuous treatment with RAS inhibitors, a reduc- renal cellular proliferation, podocyte damage, matrix accumu-
tion in aldosterone levels may not be maintained, and lev- lation and fibrosis [70].
els may actually increase over time [57]. This phenomenon,
termed aldosterone breakthrough, has led to the consider-
A Role for Endothelin Antagonism?
ation of the use of combinations of agents to inhibit the
renin-angiotensin-aldosterone system (RAAS). Experimental The role of endothelin-1 in the pathogenesis of diabetic CKD
studies have shown that ACE inhibitors and ARBs have a syn- has lead to interest in endothelin inhibition as a potential thera-
ergistic effect on blood pressure and renin release [58]. Clini- peutic target in diabetic kidney disease. Novel agents inhibiting
cal studies of dual ACE inhibitor–ARB blockade have provided endothelin receptors showed promise in experimental studies
evidence of benefit on surrogate clinical markers, particular with beneficial effects on diabetic nephropathy and protein-
a reduction in albuminuria. A meta-analysis, which included uria [71]. Receptor selectivity is key in these agents, with initial
people with and without diabetes, showed that dual blockade studies using less selective agents being hampered by adverse
with ACE inhibitor and ARB reduced proteinuria to a greater effects, which were thought to be mediated primarily through
extent than either agent alone [59]. sodium retention mediated by inhibition of Endothelin Recep-
Two key outcome trials of dual blockade, ONTARGET [60] tor Type B (ETb) receptors.
and VA-NEPHRON D [61], however, have since shown neg- Clinical studies of two predominantly endothelin receptor A
ative results. Despite a greater reduction in proteinuria in the antagonists, avosentan and atrasentan, as an add-on therapy to
combination therapy groups, there was no clear benefit in an ACE inhibitor to treat residual proteinuria in people with
terms of hard primary endpoints such as reduction in eGFR, advanced proteinuric diabetic kidney disease have, however,
ESRD and death, with a clear and widely reported increase been disappointing. A trial with avosentan was terminated early
in adverse outcomes, notable hyperkalaemia and acute kidney because of safety concerns related to an increase in cardiovascu-
injury. These results also highlight the limitations of albumin- lar side effects, primarily fluid overload and congestive cardiac
uria reduction as a surrogate marker in clinical trials of reno- failure [72,73]. Peripheral oedema was also observed to com-
protective strategies in diabetes. plicate therapy with atrasentan [75], although in a more recent
The direct renin inhibitor, aliskiren, has also been used as small subsequent study, the lowest dose of atrasentan effectively
an adjuvant to ACE or ARB inhibition. Again, these stud- reduced blood pressure and proteinuria in participants with
ies highlighted safety concerns with no beneficial effects on proteinuric diabetic kidney disease and type 2 diabetes without
primary renal outcomes [62]. A systematic review of com- significant fluid retention [73,74].
bination RAAS blockade with an aldosterone antagonist
together with an ACE inhibitor or ARB reported similar
findings [63]. Sodium and Diabetic Nephropathy
The European Medicines Agency now recommends that
combination use should be strictly avoided in people with Sodium/Glucose Reabsorption in the Kidney: a New
diabetes and in all individuals with moderate to severe renal Therapeutic Target?
impairment, although the door to dual blockade may not Increased proximal tubular reabsorption and sodium/glucose
be completely closed: the opinion of some experts on the cotransport with deactivation of tubuloglomerular feedback
Scientific Advisory Group in Cardiovascular Issues was that induced by hyperglycaemia may have an important role in
‘dual RAS blockade therapy might be prescribed in (younger) the development of hyperfiltration in diabetic nephropathy.
patients with nephropathy and severe proteinuria without Experimental studies have suggested that selective inhibitors
comorbidities’ [64]; however, there are limited outcome data of sodium-glucose cotransporter 2 reduces glomerular
in this group, and use should be restricted to RAS inhibitor hyperfiltration independently of blood glucose levels [75].
monotherapy in people with diabetes, both with and without A randomized controlled study found that treatment with
nephropathy. Judicious prescribing, monitoring and patient such an agent, dapagliflozin, may have a protective effect
education are important; in particular, consideration should on eGFR (with an initial fall followed by stabilization) and
be given to short-term cessation of RAS inhibitors in sit- albuminuria; however, the primary endpoint in that study,
uations where people are at increased risk of acute kidney change in HbA1c, was not significantly different from that in
injury [65]. controls [76].

Volume 18 No. 7 July 2016 doi:10.1111/dom.12630 643

review article DIABETES, OBESITY AND METABOLISM

Blood Pressure, Sodium and Diabetic Nephropathy a major influence on clinical practice [84]. Early studies indi-
It is well established that salt is important in regulating blood cated that bardenoloxone, which inhibits the transcription fac-
pressure, and that a modest salt reduction lowers blood tor NF-𝜅B, increased eGFR in people with CKD stage 3B and
pressure, leading to recommendations in international guide- 4 [85], but a subsequent phase III trial was terminated early
lines for salt reduction in patients with CKD [77]. This is because of significant increases in the risks of major adverse
supported by experimental evidence. Salt-induced renal dam- cardiovascular events in the bardenoloxone-treated group [86].
age is mediated through the effect of salt on blood pressure Furthermore, whilst the benefits of glycaemic control in gen-
and urinary albumin excretion and through direct renal eral are well established, we do not yet have long-term safety
effects. Enhanced distal tubular reabsorption of sodium pro- data on the newer hypoglycaemic agents. For example, the early
moted by hyperinsulinaemia [78,79], increased activity of suggestions that dipeptidyl peptidase 4 (DPP-4) inhibitors had
the sodium-glucose cotransporter and increased activity of protective cardiovascular effects have not been confirmed in
the RAS leads to elevated total body exchangeable sodium in large-scale clinical trials, with one reporting an increased inci-
people with diabetes compared with healthy individuals, even dence of hospitalization for heart failure in the DPP-4-treated
before the onset of overt nephropathy [80,81]. arm [87].
Clinical evidence for salt reduction in diabetic nephropathy A number of novel approaches to treatment are currently
is more limited. Although cohort studies in people with dia- being evaluated, directed at targets including transforming
betes have shown increased mortality in those patients with growth factor-𝛽, a key profibrotic factor, and a wide range of
lowest salt intake, these studies are observational in nature. proinflammatory intracellular signalling pathways [84]. Many
A meta-analysis of a modest reduction in salt intake in peo- of these are at the early stages of development. We should also
ple with diabetes showed a reduction in blood pressure and not underplay the role of basic lifestyle interventions in the pre-
albuminuria without affecting insulin resistance [82]. Dietary vention and treatment of diabetes and nephropathy. The role of
sodium restriction is also an important adjunct to established salt restriction has already been discussed. A position statement
therapies, with studies showing that salt restriction enhances from the American Diabetes Association summarizes the prob-
the effects of inhibitors of the RAAS on proteinuria in people able benefits of physical activity and exercise in people with dia-
with diabetes [83]. Although the effects on harder endpoints betes; these include increased insulin sensitivity and improved
is unknown and there remains debate over the optimum salt glycaemic control, cardiovascular disease prevention and blood
intake for people with diabetes, there is no evidence to suggest pressure reduction [88]. There is good evidence that diabetes
the current recommendations of modest salt reduction are itself can be prevented in people at high risk through lifestyle
unsafe. 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,
Conclusions and Perspectives in the kidney, has been shown to inhibit mesangial matrix accu-
Kidney disease is a critical determinant of outcomes in dia- mulation in response to glucose loading [91]. Recent data sug-
betes, and diabetic nephropathy remains a key area of focus gest that a dietary supplement including carnosine (together
for both preclinical and clinical research. We have witnessed with cinnamon and chromium) reduces fasting plasma glucose
major advances in treatment over the last 20 years, with out- in people with a raised body mass index [92].
comes transformed by the use of RAS blockade and tight, but We also need to learn more about the 60–70% of individuals
judicious, glycaemic control. Nevertheless, our understanding with diabetes who do not develop kidney disease irrespective
of how best to deploy existing therapies is incomplete. The role of their level of glycaemic control. People with type 1 diabetes
of glycaemic control in primary prevention is incontrovertible, who do not develop nephropathy after 15 years of diabetes
whilst the data on RAS blockade in this setting are conflicting. appear to be protected, suggesting that genetic factors may
Despite a sound scientific rationale and encouraging early data, be involved [93]. Some ethnic groups are at particularly high
the use of combination RAS antagonism appears to do more risk, notably Pima Indians [94] and South Asians [95]. Indeed,
harm than good. More studies are needed before combination a large number of genetic variants have been associated with
therapy can be recommended in any group, even the younger diabetic nephropathy, with some differences evident in Euro-
patients with type 1 diabetes in whom there remains enthusi- pean and Asian subgroups [96]. The variants associated with
asm for dual blockade from some quarters. Unless and until altered risk included those involving the RAS, oxidative stress,
such data become available, we may be better served direct- inflammation, the polyol pathway and the glomerular base-
ing our clinical efforts on potentiating RAS blockade though ment membrane, consistent with our current understanding
lifestyle measures, and in particular dietary sodium restriction. of aspects of the mechanisms of nephropathy. Genetic vari-
The mechanisms by which hyperglycaemia promotes the ants coding for apolipoprotein-E and apolipoprotein-C1 have
development of nephropathy are now relatively well under- also been reproducibly associated, suggesting a role of lipid
stood; however, the hope that an increased understanding of metabolism in the pathogenesis. Indeed, lipid abnormalities
the pathogenesis of diabetic renal disease would lead to effective are found at an early stage of nephropathy [97,98], and may
targeted strategies has largely yet to be realised, and attempts to also be a risk factor for progression [99–101].
target specific pathways, including AGE formation, mesangial We should also remember that advancing our knowledge
matrix accumulation and protein kinase C, have yet to exert of the pathogenesis of nephropathy is necessary but not

644 Gallagher and Suckling Volume 18 No. 7 July 2016

DIABETES, OBESITY AND METABOLISM review article
sufficient to improve care and outcomes. Whilst we wait for the 15. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde
seeds of our improved understanding to bear fruit, we should M, Astor BC et al. Association of estimated glomerular filtration rate and
albuminuria with all-cause and cardiovascular mortality in general population
not be distracted from the need for more consistent delivery
cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073–2081.
of established interventions, both on an individual-patient
and system-wide basis. Early detection is essential to patient 16. Van der Velde M, Matsushita K, Coresh J et al. Lower estimated glomerular
filtration rate and higher albuminuria are associated with all-cause and
management, and is encouraged in the UK through a system
cardiovascular mortality. A collaborative meta-analysis of high-risk population
of payment by results. Despite this, the evidence from the cohorts. Kidney Int 2011; 79: 1341–1352.
National Diabetes Audit, the largest annual clinical audit in the
17. Astor BCMK, Gansevoort RT, van der Velde M et al. Lower estimated glomerular
world, is that we continue to miss opportunities to delay and
filtration rate and higher albuminuria are associated with mortality and
prevent renal disease. Safety is a critical issue: people with dia- end-stage renal disease. A collaborative meta-analysis of kidney disease
betes, many of whom are treated with drugs with nephrotoxic population cohorts. Kidney Int 2011; 79: 1331–1340.
potential, are vulnerable to avoidable harm as a result of poor 18. Fox CS, Matsushita K, Woodward M et al. Associations of kidney disease
prescribing and acute kidney injury. We should better exploit measures with mortality and end-stage renal disease in individuals with and
our knowledge of a glycaemic legacy effect to deliver models of without diabetes: a meta-analysis. Lancet 2012; 380: 1662–1673.
care that provide early intensive input, with greater emphasis 19. Mahmoodi BK, Matsushita K, Woodward M et al. Associations of kidney disease
on the provision of information and the complementary roles measures with mortality and end-stage renal disease in individuals with and
of non-pharmacological and pharmacological therapies. without hypertension: a meta-analysis. Lancet 2012; 380: 1649–1661.
20. Hallan SI, Matsushita K, Sang Y et al. Age and association of kidney measures
with mortality and end-stage renal disease. JAMA 2012; 308: 2349–2360.
References 21. Nitsch D, Grams M, Sang Y et al. Associations of estimated glomerular filtration
rate and albuminuria with mortality and renal failure by sex: a meta-analysis.
1. International Diabetes Federation. IDF Diabetes Atlas. 7th edn. Brus-
BMJ 2013; 346: f324.
sels: International Diabetes Federation, 2015. Available from URL:
http://www.diabetesatlas.org. Accessed 1 December 2015. 22. Wen CP, Matsushita K, Coresh J et al. Relative risks of chronic kidney disease
for mortality and end-stage renal disease across races are similar. Kidney Int
2. World Health Organisation. Diabetes: The Cost of Diabetes. Fact sheet no. 236.
2014; 86: 819–827.
Geneva: WHO, 1999.
23. Makita Z, Radoff S, Rayfield EJ et al. Advanced glycosylation end products in
3. World Health Organisation. Diabetes. Fact Sheet no. 312. Geneva: WHO, 2013.
patients with diabetic nephropathy. N Engl J Med 1991; 325: 836–842.
4. Health and Social Care Information Centre. National Diabetes Audit 2011/12.
24. Derubertis FR, Craven PA. Activation of protein kinase C in glomerular cells
Report 2: complications and mortality [Internet]. YYYY. Available from URl:
in diabetes: mechanisms and potential links to the pathogenesis of diabetic
http://www.hscic.gov.uk/catalogue/PUB12738. Accessed 27 October 2014.
glomerulopathy. Diabetes Care 1994; 43: 1–8.
5. Kanavos P, van den Aardweg S, Schurer W. Diabetes Expenditure, Burden of
25. Dunlop M. Aldose reductase and the role of the polyol pathway in diabetic
Disease and Management in 5 EU Countries. London: LSE Health, London
nephropathy. Kidney Int 2000; 58(S77): S3–S12.
School of Economics, 2012.
26. Vasavada N, Agarwal R. Role of oxidative stress in diabetic nephropathy. Adv
6. Diabetes UK. Diabetes facts and stats version 3, March 2014. Available
from URL: https://www.diabetes.org.uk/Documents/About%20Us/Statistics/ Chronic Kidney Dis 2005; 12: 146–154.
Diabetes-key-stats-guidelines-April2014.pdf. Accessed 30 October 2014. 27. Navarro-González JF, Mora-Fernández C. The role of inflammatory cytokines
7. NHS Information Centre. Quality and Outcomes Framework Achievement Data in diabetic nephropathy. J Am Soc Nephrol 2008; 19: 433–442.
2010/11 [Internet]. Leeds: NHS Information Centre; 2011. Available from URL: 28. Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression
http://www.hscic.gov.uk/catalogue/PUB05673. Accessed 9 October 2014. of transforming growth factor beta is elevated in human and experimental
8. Hippisley-Cox J, Coupland C. Predicting the risk of chronic kidney disease in diabetic nephropathy. Proc Natl Acad Sci 1993; 90: 1814–1818.
men and women in England and Wales: prospective derivation and external 29. Molitch ME, Steffes MW, Cleary PA et al. Baseline analysis of renal function
validation of the QKidney® Scores. BMC Fam Pract 2010; 11: 49. in the Diabetes Control and Complications Trial. The Diabetes Control and
9. Middleton RJ, Foley RN, Hegarty J et al. The unrecognized prevalence of chronic Complications Trial Research Group [corrected]. Kidney Int 1993; 43: 668–674.
kidney disease in diabetes. Nephrol Dial Transplant 2006; 21: 88–92. 30. Bash LD, Selvin E, Steffes M et al. Poor glycemic control in diabetes and the
10. New JP, Middleton RJ, Klebe B et al. Assessing the prevalence, monitoring risk of incident chronic kidney disease even in the absence of albuminuria and
and management of chronic kidney disease in patients with diabetes com- retinopathy: Atherosclerosis Risk in Communities (ARIC) Study. Arch Intern
pared with those without diabetes in general practice. Diabet Med 2007; 24: Med 2008; 168: 2440–2447.
364–369. 31. Giorgino F, Laviola L, Cavallo Perin P et al. Factors associated with progression
11. Byrnea C, Ford D, Gilga J et al. UK Renal Registry 2009. 12th Annual Report to macroalbuminuria in microalbuminuric type 1 diabetic patients: the EURO-
of the Renal Association: Chapter 3 UK ESRD Incident Rates in 2008: national DIAB Prospective Complications Study. Diabetologia 2004; 47: 1020–1028.
and centre-specific analyses. Nephron Clin Pract 2010; 115 (Suppl. 1): c9–40. 32. The Diabetes Control and Complications Trial Research Group. The effect
12. Groop PH, Thomas MC, Moran JL et al. The presence and severity of chronic of intensive treatment of diabetes on the development and progression of
kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 2009; long-term complications in insulin-dependent diabetes mellitus. N Engl J Med
58: 1651–1658. 1993; 329: 977–986.
13. Afkarian M, Sachs MC, Kestenbaum B et al. Kidney disease and increased 33. DCCT/EDIC Research Group, de Boer IH, Sun W et al. Intensive diabetes therapy
mortality risk in type 2 diabetes. J Am Soc Nephrol 2013; 24: 302–308. and glomerular filtration rate in type 1 diabetes. N Engl J Med 2011; 265:
2366–2376.
14. Hallan S, Dahl K, Oien CM et al. Screening strategies for chronic kidney disease
in the general population: follow-up of cross sectional health survey. BMJ 34. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose
2006; 333: 104. control in type 2 diabetes. N Engl J Med 2008; 359: 1577–1589.

Volume 18 No. 7 July 2016 doi:10.1111/dom.12630 645

review article DIABETES, OBESITY AND METABOLISM

35. Cooper ME. Interaction of metabolic and haemodynamic factors in mediating 57. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone
experimental diabetic nephropathy. Diabetologia 2001; 44: 1957–1972. breakthrough. Nat Clin Pract Nephrol 2007; 3: 486–492.
36. Hollenberg NK, Price DA, Fisher ND et al. Glomerular hemodynamics and the 58. Ménard J, Campbell DJ, Azizi M et al. Synergistic effects of ACE inhibition
renin-angiotensin system in patients with type 1 diabetes mellitus. Kidney Int and Ang II antagonism on blood pressure, cardiac weight, and renin in
2003; 63: 172–178. spontaneously hypertensive rats. Circulation 1997; 96: 3072–3078.
37. Kobori H, Kamiyama M, Harrison-Bernard LM et al. Cardinal role of the 59. Kunz R, Friedrich C, Wolbers M et al. Meta-analysis: effect of monotherapy
intrarenal renin-angiotensin system in the pathogenesis of diabetic nephropa- and combination therapy with inhibitors of the renin angiotensin system on
thy. J Investig Med 2013; 61: 256–264. proteinuria in renal disease. Ann Intern Med 2008; 148: 30–48.
38. Carey RM, Siragy HM. The intrarenal renin-angiotensin system and diabetic 60. ONTARGET Investigators, Yusuf S, Teo K, Pogue J et al. Telmisartan, ramipril,
nephropathy. Trends Endocrinol Metab 2003; 14: 274–281. or both in patients at high risk for vascular events. N Engl J Med 2008; 358:
39. Christlieb AR, Kaldany A, D’Elia JA. Plasma renin activity and hypertension in 1547–1559.
diabetes mellitus. Diabetes 1976; 1: 969–974. 61. Fried LF, Emanuele N, Zhang JH et al. Combined angiotensin inhibition for the
40. Johnson MD, Malvin RL. Stimulation of renal sodium reabsorption by treatment of diabetic nephropathy. N Engl J Med 2013; 369: 1892–1903.
angiotensin II. Am J Physiol 1977; 232: F298–F306.
62. Parving H-H, Persson F, Lewis JB et al. Aliskiren combined with losartan in type
41. Zatz R, Dunn BR, Meyer TW et al. Prevention of diabetic glomerulopathy 2 diabetes and nephropathy. N Engl J Med 2008; 358: 2433–2446.
by pharmacological amelioration of glomerular capillary hypertension. J Clin
63. Bomback AS, Kshirsagar AV, Amamoo MA et al. Change in proteinuria after
Invest 1986; 77: 1925–1930.
adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers
42. Leehey DJ, Singh AK, Alavi N et al. Role of angiotensin II in diabetic nephropa- in CKD: a systematic review. Am J Kidney Dis 2008; 51: 199–211.
thy. Kidney Int Suppl 2000; 77: S93–S98.
64. Pharmacovigilance Risk Assessment Committee. PRAC. Assessment report
43. Singh R, Alavi N, Singh AK et al. Role of angiotensin II in glucose-induced for renin-angiotensin system (RAS)-acting agents. 2014. Available from
inhibition of mesangial matrix degradation. Diabetes 1999; 10: 2066–2073. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_
44. Björck S, Mulec H, Johnsen SA et al. Renal protective effect of enalapril in document/Renin-angiotensin_system_(RAS)-acting_agents/Opinion_
diabetic nephropathy. BMJ 1992; 304: 339–343. provided_by_Committee_for_Medicinal_Products_for_Human_Use/WC500
167966.pdf. Accessed 1 July 2015.
45. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-
enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N 65. National Institute for Health and Care Excellence. Acute kidney injury:
Engl J Med 1993; 329: 1456–1462. prevention, detection and management of acute kidney injury up to the
46. Parving HH, Lehnert H, Bröchner-Mortensen J et al. The effect of irbesartan on point of renal replacement therapy [Internet]. 2013. Available from URL:
the development of diabetic nephropathy in patients with type 2 diabetes. N https://www.nice.org.uk/guidance/cg169/chapter/1-recommendations#pre
Engl J Med 2001; 345: 870–878. venting-acute-kidney-injury. Accessed 2 November 2014.

47. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and 66. Yanagisawa M, Kurihara H, Kimura S et al. A novel potent vasoconstrictor
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N peptide produced by vascular endothelial cells. Nature 1988; 332: 411–415.
Engl J Med 2001; 345: 861–869. 67. Garvin JL, Herrera M, Ortiz PA. Regulation of renal NaCl transport by nitric
48. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the oxide, endothelin, and ATP: clinical implications. Annu Rev Physiol 2011; 73:
angiotensin-receptor antagonist irbesartan in patients with nephropathy due 359–376.
to type 2 diabetes. N Engl J Med 2001; 345: 851–860. 68. Miller WL, Redfield MM, Burnett JC. Integrated cardiac, renal, and endocrine
49. Finne P, Reunanen A, Stenman S et al. Incidence of end-stage renal disease in actions of endothelin. J Clin Invest 1989; 83: 317–320.
patients with type 1 diabetes. JAMA 2005; 294: 1782–1787. 69. Hargrove GM, Dufresne J, Whiteside C et al. Diabetes mellitus increases
50. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interven- endothelin-1 gene transcription in rat kidney. Kidney Int 2000; 58:
tions and Complications (DCCT/EDIC) Research Group, Nathan DM, Zinman B, 1534–1545.
Cleary PA et al. Modern-day clinical course of type 1 diabetes mellitus after
70. Benz K, Amann K. Endothelin in diabetic renal disease. Contrib Nephrol 2011;
30 years’ duration: the diabetes control and complications trial/epidemiology
172: 139–148.
of diabetes interventions and complications and Pittsburgh epidemiology of
diabetes complications experience (1983–2005). Arch Intern Med 2009; 169: 71. Benigni A, Colosio V, Brena C et al. Unselective inhibition of endothelin
1307–1316. receptors reduces renal dysfunction in experimental. Diabetes 1998; 47:
450–456.
51. Bilous R, Chaturvedi N, Sjølie AK et al. Effect of candesartan on microalbu-
minuria and albumin excretion rate in diabetes: three randomized trials. Ann 72. Mann JFE, Green D, Jamerson K et al. Avosentan for overt diabetic nephropathy.
Intern Med 2009; 151: 11–20. J Am Soc Nephrol 2010; 21: 527–535.
52. Haller H, Ito S, Izzo JL et al. Olmesartan for the delay or prevention of 73. Kohan DE, Pritchett Y, Molitch ME et al. Addition of atrasentan to
microalbuminuria in type 2 diabetes. N Engl J Med 2011; 364: 907–917. renin-angiotensin system blockade reduces albuminuria in diabetic
53. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J et al. Effects nephropathy. J Am Soc Nephrol 2011; 22: 763–772.
of a fixed combination of perindopril and indapamide on macrovascular 74. de Zeeuw D, Coll B, Andress D et al. The endothelin antagonist atrasentan
and microvascular outcomes in patients with type 2 diabetes mellitus (the lowers residual albuminuria in patients with type 2 diabetic nephropathy. J
ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829–840. Am Soc Nephrol 2014; 25: 1083–1093.
54. Ruggenenti P, Fassi A, Ilieva AP et al. Preventing microalbuminuria in type 2 75. De Nicola L, Gabbai FB, Lierti ME et al. Sodium/glucose cotransporter 2
diabetes. N Engl J Med 2004; 351: 1941–1951. inhibitors and prevention of diabetic nephropathy: targeting the renal tubule
55. Ravid M, Brosh D, Levi Z et al. Use of enalapril to attenuate decline in renal in diabetes. Am J Kidney Dis 2014; 64: 16–24.
function in normotensive, normoalbuminuric patients with type 2 diabetes 76. Kohan DE, Fioretto P, Tang W et al. Long-term study of patients with type
mellitus. A randomized, controlled trial. Ann Intern Med 1998; 128: 982–988. 2 diabetes and moderate renal impairment shows that dapagliflozin reduces
56. Mauer M, Zinman B, Gardiner R et al. Renal and retinal effects of enalapril and weight and blood pressure but does not improve glycemic control. Kidney Int
losartan in type 1 diabetes. N Engl J Med 2009; 361: 40–51. 2014; 85: 962–971.

646 Gallagher and Suckling Volume 18 No. 7 July 2016

DIABETES, OBESITY AND METABOLISM review article
77. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 91. Koppel H, Riedl E, Braunagel M et al. L-carnosine inhibits
2012 Clinical practice guideline for the evaluation and management of Chronic high-glucose-mediated matrix accululation in human mesangial cells
Kidney Disease. Kidney Int 2012; (Suppl. 3): 1–150. by interfering with TGF-𝛽 production and signalling. Nephrol Dial Transplant
2011; 26: 3852–3858.
78. DeFronzo RA. The effect of insulin on renal sodium metabolism. A review with
clinical implications. Diabetologia 1981; 21: 165–171. 92. Liu Y, Cotillard A, Vatier C et al. A dietary supplement containing cinnamon,
chromium and carnosine decreases fasting plasma glucose and increases
79. Woods LL, Mizelle HL, Hall JE. Control of renal hemodynamics in hyper-
lean mass in overweight or obese pre-diabetic subjects: a randomized,
glycemia: possible role of tubuloglomerular feedback. Am J Physiol Renal Phys-
placebo-controlled trial. PLoS One 2015; 10: e0138646.
iol 1987; 252: F65–F73.
93. Krolewski AS, Warram JH, Rand LI et al. Epidemiologic approach to the etiology
80. De’Oliveira JM, Price DA, Fisher ND et al. Autonomy of the renin system in type
of type I diabetes mellitus and its complications. N Engl J Med 1987; 317:
II diabetes mellitus: dietary sodium and renal hemodynamic responses to ACE
1390–1398.
inhibition. Kidney Int 1997; 52: 771–777.
94. Nelson RG, Newman JM, Knowler WC et al. Incidence of end-stage renal
81. Price DA, De’Oliveira JM, Fisher ND et al. The state and responsiveness of
disease in type 2 (non-insulin-dependent) diabetes mellitus in Pima Indians.
the renin-angiotensin-aldosterone system in patients with type II diabetes
Diabetologia 1998; 10: 730–736.
mellitus. Am J Hypertens 1999; 12(Pt 1): 348–355.
95. Chandie Shaw PK, Baboe F, van Es LA et al. South-Asian type 2 diabetic
82. Suckling R, He F, MacGregor G. Altered dietary salt intake for preventing
patients have higher incidence and faster progression of renal disease
and treating diabetic kidney disease. Cochrane Database Syst Rev 2010; (12):
compared with Dutch-European diabetic patients. Diabetes Care 2006; 29:
CD006763.
1383–1385.
83. Houlihan CA, Allen TJ, Baxter AL et al. A low-sodium diet potentiates the effects
96. Mooyaart AL, Valk EJJ, van Es LA et al. Genetic associations in diabetic
of losartan in type 2 diabetes. Diabetes Care 2002; 25: 663–671.
nephropathy: a meta-analysis. Diabetologia 2011; 54: 544–553.
84. Fernandez-Fernandez B, Ortiz A, Gomez-Guerrero C et al. Therapeutic
97. Bruno G, Cavallo-Perin P, Bargero G et al. Prevalence and risk factors for
approaches to diabetic nephropathy: beyond the RAS. Nat Rev Nephrol 2014;
micro- and macroalbuminuria in an Italian population-based cohort of NIDDM
10: 325–346.
subjects. Diabetes Care 1996; 19: 43–47.
85. Pergola PE, Raskin P, Toto RD et al. Bardoxolone methyl and kidney function
98. Jones SL, Close CF, Mattock MB et al. Plasma lipid and coagulation factor
in CKD with type 2 diabetes. N Engl J Med 2011; 365: 327–336.
concentrations in insulin dependent diabetics with microalbuminuria. BMJ
86. de Zeeuw D, Akizawa T, Audhya P et al. Bardoxolone methyl in type 2 diabetes 1989; 298: 487–490.
and stage 4 chronic kidney disease. N Engl J Med 2013; 369: 2492–2503.
99. Ravid M, Neumann L, Lishner M. Plasma lipids and the progression of
87. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular out- nephropathy in diabetes mellitus type II: effect of ACE inhibitors. Kidney Int
comes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1995; 47: 907–910.
1317–1326.
100. Smulders YM, Rakic M, Stehouwer CD et al. Determinants of progression of
88. American Diabetes Association Position statements: physical activity/exercise microalbuminuria in patients with NIDDM.A prospective study. Diabetes Care
and diabetes mellitus. Diabetes Care 2003; 26(Suppl. 1): s73–s77. 1997; 20: 999–1005.
89. Tuomilehto J, Lindstram J, Eriksson JG et al. Prevention of type 2 diabetes mel- 101. Krolewski AS, Warram JH, Christlieb AR. Hypercholesterolemia–a determinant
litus by changes in lifestyle among subjects with impaired glucose tolerance. of renal function loss and deaths in IDDM patients with nephropathy. Kidney
N Engl J Med 2001; 344: 1343–1350. Int Suppl 1995; 45: S125–S131.
90. Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing NIDDM in
people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study.
Diabetes Care 1997; 20: 537–544.

Volume 18 No. 7 July 2016 doi:10.1111/dom.12630 647