Clinical Challenges in Diagnosis and Management of Diabetic

Kidney Disease
Robert C. Stanton, MD

Diabetic kidney disease (DKD) is a major and increasing worldwide public health issue. There is a great
need for implementing treatments that either prevent or significantly slow the progression of DKD. Although
there have been significant improvements in management, the increasing numbers of patients with DKD
illustrate that current management is not wholly adequate. The reasons for suboptimal management include
the lack of early diagnosis, lack of aggressive interventions, and lack of understanding about which in-
terventions are most successful. There are a number of challenges and controversies regarding the current
management of patients with DKD. Understanding of these issues is needed in order to provide the best care
to patients with DKD. This article describes some of the clinically important challenges associated with DKD:
the current epidemiology and cost burden and the role of biopsy in the diagnosis of DKD. Treatment con-
troversies regarding current pharmacologic and nonpharmacologic approaches are reviewed and recom-
mendations based on the published literature are made.
Am J Kidney Dis. 63(2)(S2):S3-S21. 2014 by the National Kidney Foundation, Inc.

INDEX WORDS: Diabetic kidney disease (DKD); diabetes mellitus; renal disease; prevalence; public health.

EXECUTIVE SUMMARY people. Moreover, it is debatable whether micro-

albuminuria routinely reects kidney disease.
Diabetic kidney disease (DKD) accounts for a large
In addition, the specic impact of DKD on CKD can
proportion of nephrology practice, and there is an
be questioned because there often is inaccuracy of
overwhelming need to implement treatments that will
documentation of medical diagnoses or a patient
either prevent the development or signicantly slow
labeled with DKD may have another diagnosis (eg,
the progression of DKD. Current approaches are not
hypertension or IgA nephropathy). Any individual
adequate because the number of patients who develop
patient may have additional processes that can cause
DKD or have progressive DKD continues to increase.
kidney disease.
Many controversies exist regarding standard ap-
Perhaps a more accurate reection of the impact of
proaches to patients with both diabetes and renal
DKD (and CKD) in the United States is seen in end-
disease. This review discusses some of the clinically
stage kidney disease data because there is no dispute
important challenges associated with the diagnosis
about the number of people who are receiving dialysis
and management of DKD.
or have a transplant. The number of new end-stage
Chronic kidney disease (CKD; estimated glomer-
kidney disease cases reported each year has been
ular ltration rate [eGFR] , 60 mL/min/1.73 m2 or
steady since 2002, but the total number of patients
urine albumin-creatinine ratio . 30 mg/g) is esti-
with end-stage kidney disease (prevalence) continues
mated to affect 13.1% of the US population. Diabetes
to increase at a rapid rate, with diabetes being the
is the most prevalent cause of end-stage kidney dis-
principal cause. Considering that there is greater
ease, followed by hypertension. The Centers for
likelihood of death than progressing to end-stage
Disease Control and Prevention (CDC) estimate that
kidney disease and that mortality rates on dialysis
1 in 3 adults in the United States will have diabetes
therapy are 15%-20% per year, there must be a very
by 2050 if current trends continue, suggesting that
there will be a very signicant increase in DKD
in the future. However, data for the prevalence of
CKD could be disputed in multiple ways that could From the Kidney and Hypertension Division, Joslin Diabetes
either increase or decrease the reported impact Center, Boston, MA.
Received May 31, 2013. Accepted in revised form October 8,
of CKD, and in particular DKD, on the overall 2013.
health of the population and on the reported costs This article is part of a supplement that was developed with
to the health care system. Physicians routinely use funding from Novo Nordisk.
eGFR , 60 mL/min/1.73 m2 as a marker of kidney Address correspondence to Robert C. Stanton, MD, Kidney and
disease, but the formulas are general estimates Hypertension Division, Joslin Diabetes Center, One Joslin Pl,
Boston, MA 02215. E-mail: robert.stanton@joslin.harvard.edu
of GFR (there may 15%-20% variance between  2014 by the National Kidney Foundation, Inc.
GFR estimates and true GFR), and normal aging 0272-6386/$36.00
will result in eGFR , 60 mL/min/1.73 m2 in many http://dx.doi.org/10.1053/j.ajkd.2013.10.050

Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21 S3


large CKD population even if the exact number is not
well dened.
Race and ethnicity have a major impact on the
risk for the development of kidney disease and
progression to end-stage kidney disease, also evident
in people with end-stage kidney disease caused by
diabetes. Rates of end-stage kidney disease due to
diabetes in the African American, Native American,
and Hispanic populations are increasing, whereas
rates have been unchanged for the past 10 years in
the white and Asian populations in the United
States. The major health disparity needs to be
addressed by providers so that screening for signs of
DKD is done routinely and aggressive interventions
are started as early as possible to slow progression.
It is of paramount importance that the nephrology
community provides leadership in early diagnosis,
best practices, aggressive management, cost-
effective interventions, research, and education so
that the health care community might slow this
epidemic.
Nephrologists do not make the initial diagnosis of
DKD; they rely on primary care and endocrinology
physicians to make the diagnosis. Thus, a major goal
for nephrologists is to provide much wider education
to non-nephrology physicians who care for patients
with diabetes so that they routinely evaluate for DKD
and either institute appropriate treatment or refer to a
nephrologist. The diagnosis of DKD usually is based
on a clinical history of diabetes, an appropriate sedi-
ment (usually bland), and absence of signs and
symptoms of another kidney disease. In general,
people with type 1 diabetes do not show clinical signs
of kidney disease until about 3-5 years after the
diagnosis of type 1 diabetes, whereas people with
type 2 diabetes may be given a diagnosis of DKD at
any time. Using a denition of DKD as micro-
albuminuria, overt proteinuria, decreased GFR, or
end-stage kidney disease in patients with diabetes, the
prevalence of DKD in patients with type 1 diabetes
may be as high as 50%, but lower in patients with
type 2 diabetes.
There essentially are 3 reasons to perform biopsy
on a patient with diabetes and kidney disease: diag-
nosis, prognosis, and research purposes. There is no
clinical indication to determine whether a patient with
diabetes primarily has DKD or hypertensive kidney
disease because the treatment is the same. As for IgA
nephropathy, there may be a reason to biopsy if a
patient has a urinary protein excretion . 1 g and
eGFR . 60 mL/min/1.73 m2 because recent research
has shown that intervening in the appropriate patient
may slow progression. There may be indications for
biopsy if the patient or physician wants to know the
extent of scarring. Routine prognostic biopsy
currently is not indicated in DKD. However, with new
S4
Robert C. Stanton
therapeutic approaches, knowing the degree of dam-
age perhaps will be important for determining the
utility, timing, or efcacy of a particular drug therapy.
Biopsy for research purposes is an important issue;
most biopsy studies have been performed in patients
with type 1 diabetes and much less is known about
DKD pathology in type 2 diabetic nephropathy. In
2010, the Research Committee of the Renal Pathol-
ogy Association tackled the issue of pathologic clas-
sication of DKD, with the goal of producing a
uniform classication system. This and the develop-
ment of future targeted therapies might be assisted
through tissue biobanks. We should consider whether
we could enhance our knowledge and improve patient
care by performing more biopsies on patients with
diabetes.
Regarding treatment, the primary interventions that
slow the progression of DKD are control of glycated
hemoglobin (HbA1c; goal of , 7.0%), control of
blood pressure (BP; goal of ,130/80 mm Hg),
smoking cessation, and lowering of urine albumin
levels. Weight loss also may play an important role in
the prevention and slowing the progression of DKD.
There currently are a number of challenges and
shifting ideas about clinically important issues for the
treatment of DKD. Data suggest that lower BP (to an
extent) better preserves kidney function, but each
patient should have individualized BP goals. A general
goal of BP , 130/80 mm Hg should be targeted in
patients with DKD unless there is signicant concom-
itant cardiovascular disease or microalbuminuria alone
with normal GFR.
There currently is little or no indication for the use
of angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs) in the preven-
tion of DKD in patients with diabetes and normal
urine albumin excretion and BP. They offer reason-
able rst-line treatment for patients with hypertension
and normal urine albumin levels; however, selection
of antihypertensive agents should be made on an
individual basis, taking into account factors such as
comorbid conditions, cost, and patient adherence to
treatment. It is appropriate to use ACE inhibitors or
ARBs in patients with microalbuminuria to help
prevent the progression to macroalbuminuria. For
overt proteinuria (.300 mg/g of urine albumin), there
is a clear indication for treatment with ACE inhibitors
or ARBs. Multiple studies using a combination of
an ACE inhibitor and ARB therapies suggest little
benet and possibly harm.
Aldosterone inhibition, when added to an ACE
inhibitor or ARB, conveys a signicant decrease in
proteinuria. Although treatment is associated with an
increased risk of hyperkalemia, the overall benet of
aldosterone inhibition appears to outweigh the risks.
There are no long-term studies that show a denitive
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD
benet of a low-protein diet on DKD, although some
studies have reported reduced albuminuria. It is
strongly recommended that all patients with DKD
cease smoking, considering the effects of smoking on
general health and diabetes specically. At present,
there is no specic recommendation on the benets
of lowering cholesterol and/or triglyceride levels in
patients with DKD. Obesity is a clear risk factor for
kidney disease in general and for DKD, but it is not
clear whether the main reasons obesity is associated
with kidney disease are the factors associated with
obesity or other factors unique to the obese person
(eg, inammatory mediators).
INTRODUCTION
The number of people with diabetic kidney dis-
ease (DKD) continues to increase and is responsible
for a large proportion of the practice of all nephrolo-
gists. If present trends continue, DKD could soon
account for .50% of the patients in dialysis
units.1 Hence, there is an overwhelming need to
implement treatments that will either prevent the
development of DKD or signicantly slow the
progression. Research during the past 40 years has
led to major advances in early diagnosis and man-
agement and has led to treatments to prevent or slow
the progression of DKD, yet current approaches
clearly are not adequate because the number of
patients who develop DKD and the number of
patients with progressive DKD continue to increase.
Several recent reviews discuss current treatment op-
tions in great detail.2-5 Many controversies remain
regarding standard approaches to patients with both
diabetes and renal disease. The intent of this review is
to discuss some of the clinically important challenges
associated with the diagnosis and management of
DKD.
EPIDEMIOLOGY: HOW PREVALENT IS DKD?
Chronic kidney disease (CKD; dened as estimated
glomerular ltration rate [eGFR] , 60 mL/min/1.73 m2
or urine albumin-creatinine ratio . 30 mg/g) is esti-
mated to affect 13.1% of the US population, ac-
cording to the 2012 US Renal Data Survey (USRDS)
report.1 Diabetes is the most prevalent cause of end-
stage kidney disease, with hypertension second in
the cohort in 2005-2010. Data from the Centers
for Disease Control and Prevention (CDC) in
Atlanta, GA, report that there are approximately 22
million people in the United States with diabetes.6
Moreover, the CDC estimates that 1 in 3 adults in
the United States will have diabetes by 2050 if
current trends continue. Based on NHANES III
(Third National Health and Nutrition Examination
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
In the past 30 years, there have been signicant
improvements in slowing the progression of and pre-
venting DKD, yet DKD is a major and increasing
worldwide public health concern. The primary goals of
the health care system need to be the prevention and
slowing of progression of DKD, as well as identi-
cation of those at risk for the development and pro-
gression of DKD. Further education is required across
all health care providers to understand the scope of the
problem, implement interventions that prevent the
development of DKD, ensure proper screening, un-
derstand how to diagnose, and improve knowledge of
treatments and when to refer to nephrology.
Survey) data, 19.3% of all people with diabetes
had GFRs , 60 mL/min/1.73 m2, 29.9% had urine
albumin-creatinine ratios . 30 mg/g, and 8.6% of
all patients with diabetes had both.1 For those
reporting hypertension without diabetes, reported
prevalences for the signs of CKD were 12.9% for
eGFR , 60 mL/min/1.73 m2, 14.8% for urine albu-
min level . 30 mg/g, and 4.1% for both.1 However,
these estimates may not accurately reect the prev-
alence of DKD for several reasons. The data for the
CKD population could be disputed in multiple ways
that could either increase or decrease the reported
impact of CKD, and in particular DKD, on the
overall health of the population, as well as on re-
ported costs to the health care system.
First, one could question the accuracy of docu-
mentation of medical diagnoses (diagnosis code
selection, diagnosis code documentation, time over
which diagnostic codes are selected, and others).7
Current coding allows separate codes for diabetes,
CKD stages, and proteinuria, as well as combined
codes for diabetes with kidney disease (sub-
categorized into type 1 and type 2 diabetes). Hence,
there may be bias in which code(s) the clinician
selects and which codes are selected by the researcher
for studies. Research results could be affected by
the tools, software, databases, and parameters that
researchers select to determine the incidence and
prevalence of DKD.
Second, any individual patient may have additional
processes that can cause kidney disease. The most
common cause of kidney disease in patients with
diabetes (other than diabetes) is hypertension, but
other entities such as IgA nephropathy also may be
present. For example, one study was designed to
evaluate the presence of kidney disease in patients
who had been given a diagnosis of DKD to deter-
mine whether nondiabetic kidney disease was ob-
served. Sixty-six kidney biopsies from patients with
diabetes showed that 10 had signicant deposits of
IgA consistent with IgA nephropathy (6 had type 1
S5

diabetes and 4 had type 2 diabetes).8 Any type of
kidney disease can occur in patients with diabetes, but
depending on the country of origin of the study, other
biopsy-proven diseases in addition to IgA nephropa-
thy are focal and segmental glomerulosclerosis,
minimal change disease, and interstitial nephritis.9,10
Therefore, only routine kidney biopsies can deni-
tively differentiate the cause of kidney disease in
diabetes. Clinically, one usually would not perform a
kidney biopsy to differentiate DKD from hypertensive
kidney disease because it would not affect prognosis
or treatment. However, from an epidemiologic and
clinical research perspective, the lack of a precise
diagnosis is important in that the assumption that the
scientist is evaluating DKD may not be fully accurate.
Third, physicians generally use eGFR , 60 mL/min/
1.73 m2 as a marker of kidney disease. There are 2
matters to consider here. First, the equations used
to estimate GFR are not accurate reections of GFR,
but rather general estimates. In one study in which
GFR estimates from the Cockcroft-Gault, MDRD
(Modication of Diet in Renal Disease) Study, and
CKD-EPI (CKD Epidemiology Collaboration)
equations were compared with measured GFRs using
iothalamate clearances (271 participants), the mean
absolute difference from measured GFR ranged from
12-15 mL/min/1.73 m2.11 The authors found that the
accuracy (bias was described as the mean difference
between estimated and measured kidney function) of
all the equations was affected by age (generally more
accurate at older age), GFR level affected the MDRD
Study and CKD-EPI creatinine estimates (absolute
bias was greater in patients with higher GFRs), and
weight or body mass index (BMI) affected the accuracy
of the Cockroft-Gault formula (absolute bias was
greater in patients with higher weight or BMI). These
equations serve to inform the clinician of the relative
level of kidney function, which enables more accurate
estimates of prognosis, risk for complications of
kidney disease, need for intervention, drug dosing,
risk of dye studies, etc. However, the inherent lack
of precision of these equations must be considered in
the context of research studies. The second consider-
ation to bear in mind is that normal aging will result in
an eGFR , 60 mL/min/1.73 m2 in many people. Thus,
should everyone with eGFR , 60 mL/min/1.73 m2,
irrespective of age, be classied as having signicant
CKD? Perhaps it would be better to select age-
appropriate targets for the denition of stage 3 CKD.
For example, GFR , 60 mL/min/1.73 m2 is an
appropriate indicator for those 50 years or younger,
whereas the denition of stage 3 CKD should be
eGFR , 45 mL/min/1.73 m2 in people older than
50 years.
Perhaps a more accurate reection of the impact
of DKD (and CKD) in the United States is seen in
S6
Robert C. Stanton
end-stage kidney disease data. This is because there is
no dispute about the numbers of people who are
receiving dialysis or have a transplant. In 1978, there
were about 35,000 dialysis patients and about 6,000
transplant recipients.1 As of 2010, there were
approximately 415,000 dialysis patients and 180,000
transplant recipients. The incidence of end-stage
kidney disease has increased from 86.8 per million
to 347 per million cases per year. Of interest, inci-
dence rates of end-stage kidney disease had been
increasing steadily up to 2002, but have remained
almost stable since, although the prevalence continues
to increase. There has been a slowing of incidence
rates of end-stage kidney disease due to diabetes
when corrected for the increase in patients with dia-
betes. Many studies have documented that a person
with CKD and declining GFR is much more likely to
die of a cardiovascular event rather than surviving to
receive dialysis or a transplant for diabetic nephrop-
athy in type 2 diabetes.12-15 A recently published
study determined that patients with diabetes with
CKD compared to nondiabetic kidney disease have
much higher death rates for a given level of GFR.12
Hence, there is a close correlation between GFR
and mortality in patients with type 2 diabetes. The
authors concluded that all excess mortality in the type
2 diabetes population compared to the population
without diabetes is associated with declining GFR.
Another recent study from the United States showed
that 51% of dialysis patients are alive 3 years after
starting dialysis therapy and 82% who received a pre-
emptive transplant are alive at 3 years.1 Taking this
information together, there must be a very large
number of patients with CKD (and patients with CKD
with diabetes) because the dialysis and transplant
patient numbers continue to increase every year.1
Since 1990, the rate of end-stage kidney disease
cases due to diabetes has increased at a signicantly
higher rate than any other cause (hypertension cases
also have increased, but at a much lower rate; Fig 1).
As noted, the number of new end-stage kidney dis-
ease cases per year has been steady since 2002, but
the total number of patients with end-stage kidney
disease (prevalence) continues to increase at a rapid
rate, with diabetes being the principal cause (Fig 2).
There is some hope that this trend might not continue
because there are recent reports suggesting that this
rapid increase may be slowing.16 Whether these
reports reect a true slowing of new cases or just
a temporary lull will become evident over the next
5-10 years.
Another important issue to consider in apprecia-
ting the impact of DKD is the effect of race and
ethnicity. In the United States, this becomes evident
by regional differences in the incidence of end-stage
kidney disease. The Southern United States, from
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD
Figure 1. Incidence counts and rates for the major causes of
end-stage kidney disease. Diabetes mellitus has become the
main cause for new cases of end-stage kidney disease. Repro-
duced from the US Renal Data System 2012 Annual Data
Report.1
Southern California to Southern Texas, has an espe-
cially high incidence of end-stage kidney disease, as
does the Midwest (rates ranging from 450-950 cases
per million in these areas compared with 200-300
cases per million in other regions).1 This likely
reects the important nding that race and ethnicity
have a major impact on risk for the development of
kidney disease and the progression to end-stage kid-
ney disease.1 The racial and ethnic disparities that are
seen in the overall end-stage kidney disease data also
are evident in the people with end-stage kidney dis-
ease caused by diabetes (Fig 3). Although the white
population has the highest overall number of patients
with end-stage kidney disease in the United States,
African Americans have the highest incidence rates
per capita (Fig 3).1 Additionally, Native Americans17
and people of Hispanic origin18 have signicantly
higher incidence and prevalence rates per capita
compared with the white population (Figs 3 and 4).
Rates of end-stage kidney disease due to diabetes in
the African American, Native American, and His-
panic populations, especially in younger age groups,
are increasing, whereas rates have been unchanged for
the past 10 years19 in the white and Asian populations
in the United States. This major health disparity needs
to be addressed by providers, by recognizing who is at
risk so that screening for any signs of DKD is done
routinely and aggressive interventions are started
as early as possible in order to slow progression.
Research to address these issues is ongoing,20-23 but
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Figure 2. Prevalence counts and rates for the major causes
of end-stage kidney disease. Diabetes mellitus has become the
main cause for all cases of end-stage kidney disease. Repro-
duced from the US Renal Data System 2012 Annual Data
Report.1
more is required to understand the underlying mech-
anisms responsible for this health disparity.
The nancial costs of the end-stage kidney dis-
ease population are staggering.1 The approximately
595,000 patients who are either receiving dialysis or
have a transplant constitute w0.2% of the US popu-
lation. This patient population cost Medicare w$30
billion in 2010, which is almost 6% of the annual
Medicare budget.1 In this era of rapidly increasing
health care costs, lawmakers certainly will be paying
signicant attention to very expensive services. The
personal burden of the combination of diabetes and
kidney disease includes decreased quality of life and
increased nancial costs. It is of paramount impor-
tance that the nephrology community provide lead-
ership in early diagnosis, best practices, aggressive
management, cost-effective interventions, research,
and education so that the health care community as a
whole might work together to slow this epidemic.
A sobering statistic in the USRDS data is that
nephrologists do not make the initial diagnosis of
DKD; they rely on primary care and endocrinology
physicians to make the diagnosis. In 2010, a total of
43% of patients started dialysis therapy without ever
seeing a nephrologist.1 Even when patients were
known to have diabetes, 38.9% started dialysis therapy
without ever seeing a nephrologist. This means it is
likely that providers were not adequately screening
patients and did not recognize declining kidney
function. It does not mean that nephrologists need to
S7

Figure 3. Prevalence counts of end-stage kidney disease by
race. Although the white population has the highest number of
cases, the prevalence rate is significantly higher in African Amer-
icans and Native Americans. Reproduced from the US Renal
Data System 2012 Annual Data Report.1
see every patient with a GFR , 60 mL/min/1.73 m2
and urine albumin level . 30 mg/g, but that non-
nephrologists need to routinely screen by calculating
eGFR and measuring urine albumin-creatinine ratios
in patients with diabetes. Referral should occur if
eGFR is declining (,45 mL/min/1.73 m2 should at
least prompt a screening visit to a nephrologist) and
urine albumin levels are increasing, certainly if urine
albumin-creatinine ratio is .300 mg/g (or urine
protein-creatinine ratio is .0.5 g/g). Thus, another
major goal for nephrologists to achieve is to provide
much wider education in many different forms to
non-nephrology health care practitioners who care
for patients with diabetes so that they routinely
evaluate for DKD and either institute appropriate
treatment or refer to a nephrologist for diagnosis and
concomitant care.
DIAGNOSIS: IS A KIDNEY BIOPSY INDICATED?
The diagnosis of DKD usually is based on a clinical
history of diabetes and an appropriate sediment
(generally bland, but a small number of red blood cells
may be present) and absence of signs and symptoms of
another kidney disease. In general, people with type 1
diabetes do not show clinical signs of kidney disease
(decreased GFR and/or increased urine albumin-
creatinine ratio) until about 3-5 years after the diag-
nosis of type 1 diabetes, whereas in people with type 2
diabetes, DKD may be diagnosed at any time.2,24 Es-
timates of the prevalence of DKD vary widely and
S8
Robert C. Stanton
Counts Non-Hispanic
500
400
Number of patients
(in thousands)
300
200
100 Hispanic
0
Rates
2500
Hispanic
Rate per million population
2000
All
1500
Non-Hispanic
1000
96 98 00 02 04 06 08 10
Figure 4. Prevalence counts of end-stage kidney disease in
the Hispanic population. The Hispanic population has a signifi-
cantly higher prevalence than the non-Hispanic population.
Data supplied by the US Renal Data System.1
range from 10%-40% for both type 1 and type 2 dia-
betes patient groups, depending in part on the denition
of the disease.2,24 In general, using a denition of DKD
as microalbuminuria, overt proteinuria, decreased
GFR, or end-stage kidney disease in patients with
diabetes, the prevalence of DKD in patients with type 1
diabetes may be as high as 50%, but lower in patients
with type 2 diabetes.25,26 A recent study from Spain
determined a DKD prevalence of 27.2% in patients
with type 2 diabetes.26 So when is a biopsy indicated in
a patient with diabetes and kidney disease?
There are essentially 3 reasons to biopsy: diagnosis,
prognosis, and for research purposes. First, from a
diagnostic perspective, it always is important to
consider diseases other than diabetes as the cause of
kidney disease in patients with diabetes and kidney
disease. In the United States, the most common dis-
eases that cause nondiabetic kidney disease in people
with diabetes (and reasonably bland sediment) are
hypertension and, less commonly, IgA nephropathy.
There is no clinical indication to determine whether a
patient with diabetes primarily has DKD or hyper-
tensive kidney disease because the treatment is
the same. As for IgA nephropathy, there may be
a reason to biopsy if a patient has a urinary protein
excretion . 1 g and eGFR . 60 mL/min/1.73 m2
because recent research has shown that intervening
with steroids in the appropriate patient may slow
progression.27 The decision to biopsy also is affected
signicantly by other factors, such as the likelihood of
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD
discovering another kidney disease in a specic
population. For example, in China, where the esti-
mated prevalence of CKD is about 10%-11%,28,29
primary glomerulonephritis (mostly IgA nephropa-
thy) is the major cause of CKD (w40% of all cases of
CKD), with DKD being a smaller percentage
(w10%).30 However, new research suggests that the
ongoing epidemic of diabetes in China will lead to a
very substantial increase in DKD.31
Other diagnostic reasons to perform biopsy on
patients with diabetes are rapidly declining eGFR,
rapidly increasing urine protein or very high protein
level, active urinary sediment, signs or symptoms
suggestive of a nondiabetic cause for kidney disease,
concerns that a medication might be causing reduced
kidney function (eg, interstitial nephritis), or a sudden
change in eGFR, urine albumin excretion, or urine
sediment in a patient with known DKD. Of note, the
absence of diabetic retinopathy in the absence of other
indications is not a reason to biopsy. Although it used
to be stressed that the lack of diabetic retinopathy
indicates a high likelihood for a nondiabetic cause of
kidney disease, it now is clear that this is not the case,
especially in patients with type 2 diabetes and kidney
disease. For example, a study of 323 patients with
type 1 diabetes and 906 patients with type 2 diabetes
determined that a majority of patients with type 1
diabetes and macroalbuminuria had some retinopathy,
whereas 47.5% of patients with hypertension and
type 2 diabetes with overt proteinuria did not have
retinopathy.32 Therefore, the absence of diabetic
retinopathy in a patient with DKD should raise the
question of whether the kidney disease process is due
to a disease other than diabetes, especially in people
with type 1 diabetes. However, if there are no other
supporting signs or symptoms from the patients
history, physical, or laboratory results, there usually is
little indication for biopsy.
Also relevant to the use of biopsy for diagnosis, the
absence of an increase in urine albumin level despite
decreasing GFR is not necessarily an indication for
biopsy. Although it is common for urine albumin
level to increase prior to any decrease in GFR, it now
is well established, especially in patients with type 1
diabetes, that GFR can decrease independently of
urine albumin level. In a study of 103 patients with
normoalbuminuric type 1 DKD, patients underwent
biopsy for research purposes and were stratied into
normal (mean, 121 mL/min/1.73 m2) or low (mean,
75 mL/min/1.73 m2) eGFR categories.33 Evaluation
of the biopsy specimens revealed multiple signs
of diabetic nephropathy (ie, thickened glomerular
basement membrane and mesangial expansion).
Another study designed to assess the predictive value
of microalbuminuria as a predictor for pathologic
changes consistent with DKD in patients with type 1
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
diabetes34,35 revealed that there was a signicant in-
crease in pathologic indicators of DKD in the group
with persistent microalbuminuria (ie, increased
glomerular basement membrane thickness) compared
with other groups (eg, intermittent microalbuminuria)
over a 5-year period. However, 64% of research par-
ticipants had reversion of microalbuminuria to nor-
moalbuminuria. This may reect improvement in
pathology or possibly a disconnect between albumin-
uria and pathology. Other researchers have reported
similar ndings in patients with type 1 diabetes,
including reversion of microalbuminuria to normoal-
buminuria36 and disconnect between level of albu-
minuria and rate of GFR decline37; that is, GFR may
decline in the absence of albuminuria. Similar ndings
have been reported in patients with type 2 diabetes.
The DEMAND (Developing Education on Micro-
albuminuria for Awareness of Renal and Cardiovas-
cular Risk in Diabetes) Study evaluated a large cohort
of patients with type 2 diabetes (32,208 patients aged
18-80 years).38 The authors reported that CKD was
noted in 17% of those with normoalbuminuria (CKD
stages 3-5), and signicantly reduced kidney function
was found in 27% of those with microalbuminuria
and 31% of those with overt proteinuria. Creatinine
clearance was ,60 mL/min/1.73 m2 in 20.5% of
those with normoalbuminuria, 30.7% of those with
microalbuminuria, and 35.0% of those with macro-
albuminuria. Hence, in patients with either type 1 or
type 2 diabetic nephropathy, increasing urine albumin
levels are associated with declining GFR, but it also is
clear that people with diabetic nephropathy may have
reduced GFR and normal urine albumin levels.
Therefore, a patient with diabetes, declining GFR, and
normal urine albumin level does not necessarily have a
clinical indication for biopsy unless there are other
signs or symptoms that suggest a disease other than
diabetes.
As for prognosis, there may be indications for
biopsy if the patient or physician wants to know the
percent of scarring. The level of albuminuria may not
correlate with severity of disease and the inherent
variability of eGFR may not accurately reect the
degree of damage to the kidneys. There are not many
studies that relate test values to kidney damage;
however, a study from 2005 reported on biopsies
from 105 patients with diabetic glomerulosclerosis
and followed up for 56 months.39 The prognostic
values (how many progressed to dialysis therapy) of
duration of diabetes, creatinine level, proteinuria, and
histologic score were evaluated. Serum creatinine
level and histologic score were statistically signicant
predictors, whereas duration of diabetes and protein-
uria were not. A routine prognostic clinical biopsy
currently is not indicated in patients with DKD.
However, with new therapeutic approaches, knowing
S9

Table 1. Recently Revised Pathologic Classification of Diabetic Kidney Disease
Class Description
I Mild or nonspecific LM changes and EM-proven
GBM thickening
IIa Mild mesangial expansion
IIb Severe mesangial expansion
III Nodular sclerosis (Kimmelstiel-Wilson lesion)
IV Advanced diabetic glomerulosclerosis
Abbreviations: EM, electron microscopy; GBM, glomerular basement membrane; LM, light microscopy.
a
On the basis of direct measurement of GBM width by EM, these individual cutoff levels may be considered indicative when other
GBM measurements are used.
Reproduced with permission of American Society of Nephrology from Tervaert et al.44
the degree of damage perhaps will be important for
determining the utility, timing, or potential efcacy of
administering a particular drug.
Biopsy for research purposes is an important issue.
There has been much discussion about the pathologic
natural history of DKD. Glomerular basement mem-
brane thickening is considered to be the earliest
measureable sign of DKD, followed by expansion of
the mesangial matrix and hyalinosis of the afferent
and efferent arterioles.40 Most longitudinal biopsy
studies have been performed in patients with type 1
diabetes,40 and much less is known about DKD
pathology in type 2 diabetic nephropathy. Further-
more, there is signicant interest and growing data on
potential roles for tubulointerstitial disease as an
initiating factor of DKD.41-43 Biopsy material poten-
tially could help determine how important tubu-
lointerstitial disease is in the pathogenesis and
progression of diabetic nephropathy. It also is not
clear what cells in the glomerulus are primarily at risk
for the damage caused by hyperglycemia: the
glomerular endothelial cell, mesangial cell, podocyte,
or a combination. As such, there has been growing
interest in establishing tissue biobanks in order to
examine diabetic kidneys at all stages of the disease to
answer these important pathophysiologic questions.
Clearly determining the cell type or types at risk
(along with determining underlying mechanisms) will
provide necessary information that can be used for the
development of future targeted therapies.
In 2010, the Research Committee of the Renal
Pathology Association tackled the issue of pathologic
classication of DKD, with the goal of producing a
uniform classication system that would assist in
ascribing uniform chronicity and staging criteria for
clinicians and researchers.44 The committee proposed
4 stages (Table 1), with glomerular basement mem-
brane thickening as class I and advanced
S10
Robert C. Stanton
Inclusion Criteria
Biopsy does not meet any of the criteria mentioned below for
class II, III, or IV; GBM . 395 nm in female and .430 nm
in male individuals 9 years and oldera
Biopsy does not meet criteria for class III or IV; mild mesangial
expansion in .25% of the observed mesangium
Biopsy does not meet criteria for class III or IV; severe mesangial
expansion in .25% of the observed mesangium
Biopsy does not meet criteria for class IV; at least 1 convincing
Kimmelstiel-Wilson lesion
Global glomerular sclerosis in .50% of glomeruli; lesions from
classes I through III
glomerulosclerosis as class IV. Of note, degree of
interstitial brosis (scored 0-2), interstitial inamma-
tion, and vascular lesions (Table 2) also were
included. The researchers reported very good inter-
observer variability when using these criteria. To test
their system, 5 pathologists classied 25 biopsy
specimens and found an intraclass correlation coef-
cient of 0.84. This classication is important for all
nephrologists to know because it provides a potential
framework for clinical prognosis and research. Only
with sufcient material will further insights into the
pathogenesis, prognosis, and interventions of DKD be
achieved. To date, there have been no truly successful
animal models of DKD, although many have been
working on this.45 Thus, we should consider whether
we could enhance our knowledge and improve patient
care by performing more biopsies on patients with
diabetes.
TREATMENT CONTROVERSIES
Overview
The primary interventions that slow the progression
of DKD are control of glycated hemoglobin (HbA1c)
levels,46-51 control of blood pressure (BP),52-55
smoking cessation,56,57 and lowering of urine albu-
min levels.58,59 Furthermore, weight loss60,61 also
may play an important role in prevention and slowing
the progression of DKD. Blood glucose management
issues are discussed in detail elsewhere in this sup-
plement.62 Two excellent reviews of overall BP
management in patients with diabetes or diabetic
nephropathy, as well as thoughtful discussions about
albuminuria management, recently have been pub-
lished.63,64 The rst focuses on optimal antihyper-
tensive therapy in patients with type 2 diabetes and
hypertension and discusses areas of uncertainty.63
The second discusses the mechanisms involved in
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD

Table 2. Recently Revised Pathologic Classification of multiple interventions on cardiovascular outcomes in

Interstitial and Vascular Lesions in Diabetic Kidney Disease high-risk patients with diabetes, including the benets
Lesion Criteria Score of intensively treating BP (,120 mm Hg) versus con-
ventional treatment (140 mm Hg). The primary
Interstitial lesions outcome was rst occurrence of a major cardiovascular
IFTA No IFTA 0 event, dened as the composite of nonfatal myocardial
,25% 1 infarction, nonfatal stroke, or cardiovascular death.
25%-50% 2 The study found no benecial effect of intensive BP
.50% 3 control (systolic BP [SBP] , 120 mm Hg) on risk
Interstitial inflammation Absent 0 of myocardial infarction or cardiovascular death,
Infiltration only in relation 1 although it found signicant lowering of stroke risk.
to IFTA From a diabetic nephropathy perspective, it is impor-
Infiltration in areas without 2 tant to note that the vast majority of patients in this
IFTA
study did not have DKD (mean GFR, 91.6 mL/min/
Vascular lesions
Arteriolar hyalinosis Absent 0
1.73 m2, and mean urine albumin-creatinine ratio,
At least 1 area of arteriolar 1
14.5 mg/g). The INVEST (International Verapamil-
hyalinosis Trandolapril Study), in which patients were 50 years
More than 1 area of 2 or older and had diabetes, also showed no benet of
arteriolar hyalinosis lowering SBP beyond the goal of ,140 mm Hg
Presence of large Yes/no (signicantly decreased kidney function was present
vessels in #5% in the INVEST group).68
Arteriosclerosis No intimal thickening 0
(score worst artery)
Conversely, a number of studies have found that for
Intimal thickening less 1
than thickness of media
patients with DKD, BP , 130/80 mm Hg delayed the
Intimal thickening greater 2
progression of kidney disease. For example, a BP
than thickness of media analysis of the RENAAL (Reduction of Endpoints in
Abbreviation: IFTA, intersitial fibrosis and tubular atrophy.
NIDDM with the Angiotensin II Antagonist Losartan)
Reproduced with permission of American Society of Study in patients with type 2 diabetes determined that
Nephrology from Tervaert et al.44 those with SBP , 140 mm Hg had signicantly
improved outcomes.69 Likewise, an analysis of multi-
hypertension in patients with diabetic nephropathy ple studies correlated signicant slowing of loss of
and reviews clinical trials using single agents as GFR as BP decreased (Fig 5).70 Although these data
therapeutics and trials involving novel drugs or drug suggest that the lower the BP, the better preserved
combinations used to treat these patients.64 However, the kidney function, there is reason not to lower it
there currently are a number of challenges and shift- too much. In the IDNT (Irbesartan Diabetic Nephrop-
ing ideas on clinically important issues for the treat- athy Trial), SBP # 120 mm Hg was associated with an
ment of DKD, and they are addressed next. increase in all-cause mortality and cardiovascular
mortality compared with those with higher BP.71 Of
Hypertension Management: What Is the BP Target? note, w60% of participants had cardiovascular disease.
There are considerable data supporting an essential In a subgroup analysis of 6,400 patients in INVEST,
role of achieving BP goals in patients with DKD increased cardiovascular mortality was observed in
for both primary prevention and slowing of disease participants with SBP , 115 mm Hg (Fig 6).68
progression.52,54,55,64,65 The National Kidney Foun-
dationKidney Disease Outcomes Quality Initiative
(NKF-KDOQI)-recommended goal for BP in patients MAP (mmHg)
with diabetic nephropathy is ,130/80 mm Hg.4 95 98 101 104 107 110 113 116 119
0
However, recent studies have prompted some major
-2
organizations, such as the American Diabetes Associ- r=0.69; P<0.05
-4
(ml/min/year)

ation, to alter their guidelines for BP goals from 130/80

-6
GFR

to 140/80 mm Hg, which may have an impact on the Untreated

primary prevention of DKD.66 The impetus for these -8 HTN

changes came primarily from the ACCORD (Action to -10

Control Cardiovascular Risk in Diabetes) Study.67 -12

130/85 140/90
ACCORD was a prospective, randomized, multi- -14

center clinical trial of 4,733 patients with type 2

Figure 5. Rate of decline in glomerular filtration rate slows as
diabetes who were followed up for an average of mean arterial pressure is decreased. Adapted from Bakris et al70
4.7 years. The study was designed to assess the with permission of National Kidney Foundation.

Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21 S11


10
1
<110 110 115 120 125
<115 <120 <125 <130
Systolic Blood Pressure mmHg
No. at risk 35 98 306 757 1059
No. of deaths 12 17 38 69 112
Figure 6. There is an increase in all-cause mortality in peo-
ple with cardiovascular disease when systolic blood pressure
is ,115 mm Hg. Reproduced with permission of American Med-
ical Association from Cooper-DeHoff et al.68
There is a growing recognition that BP goals need
to be targeted to the individual patient. In patients
with coronary artery disease, lowering SBP to
,140 mm Hg likely is sufcient and lowering to
,120 mm Hg appears to lead to worse outcomes.
However, although lower BP reduced the risk of
stroke in the ACCORD Study, this effect was not ob-
served in INVEST. Furthermore, SBP , 130 mm Hg
leads to improved kidney-related outcomes in patients
with DKD. Thus, the ideal BP for a patient with
diabetes needs to be tailored to the patient. A general
goal of ,140/80 mm Hg should sufce provided the
patient has no evidence of DKD. However, a goal
of ,130/80 mm Hg should be targeted in patients
with DKD unless there is signicant concomitant
cardiovascular disease or microalbuminuria alone
with normal GFR.
ReninAngiotensinAldosterone Axis: Focus on
Angiotensin II Inhibition
Many studies have demonstrated increased activity
in the renin-angiotensin-aldosterone system (RAAS)
in patients with diabetes and patients with DKD.5,72-74
Blockade of this system (especially of angiotensin II)
has been the mainstay of DKD treatment for 30 years.
A number of recent studies have provided further
insights into the best use of these medications.
What Is the Mechanism of Action for ACE-Inhibitor and
ARB Medications?
The effects of blockade of the RAAS on angio-
tensin II and glomerular pressures has generated much
attention because decreased angiotensin II leads to
vasodilation of the efferent arteriole with a resultant
decrease in glomerular pressure gradient across the
basement membrane and a subsequent decline in
GFR.74 This decrease in intraglomerular pressures has
S12
Robert C. Stanton
been presumed to be the primary mechanism by
which these medications work; there certainly is
evidence for this from animal studies.74 However,
animal studies are problematic because all animal
models of DKD to date are thought to not accurately
reect human DKD.45 In addition, the measurements
(whether single-nephron GFR using micropuncture
techniques or by whole-animal clearance studies) are
snapshots and may be misleading. Angiotensin II has
multiple other actions, including stimulation of
inammation by stimulation of factors such as trans-
forming growth factor b, activation of NADPH
(reduced nicotinamide adenine dinucleotide phos-
phate) oxidase, and other effects, all of which may be
mechanistically important to angiotensin IImediated
damage to the kidney.74 Moreover, these medications
may have actions independent of angiotensin II that
are benecial. For example, the enzyme kininase II is
the same enzyme as angiotensin-converting enzyme
(ACE); hence, ACE inhibitors may alter 2 pathways:
the RAAS and the bradykinin pathway.74 Kininase II
blockade leads to the increase in bradykinin levels
that is thought to be responsible for the cough seen in
some patients receiving an ACE inhibitor. Addition-
ally, increasing bradykinin levels may play a bene-
cial role in kidney disease progression. These
medications have been of signicant benet in the
treatment of patients with proteinuria and DKD.
Determining the exact mechanism by which they
work may lead to an even more effective treatment.
Regardless of the exact mechanism, it has been
determined that the decrease in GFR seen with ACE-
inhibitor/angiotensin receptor blocker (ARB) treat-
ments is at least an important indicator of their
effectiveness in slowing the progression of DKD.
Bakris et al70 reviewed this issue and reported that an
increase in serum creatinine level of up to 30% within
the rst 4 months of starting ACE-inhibitor treatment
(baseline up to 3 mg/dL) correlated with slower rates
of decline in kidney function after 3 or more years of
follow-up (Fig 7). In a recent subanalysis of the
RENAAL Study, in which losartan was given to
patients with type 2 diabetes to determine whether it
slowed disease progression,75 the authors found that
the greater the initial decline in GFR, the slower the
rate of progression of DKD (Fig 8). This important
nding emphasizes the need to monitor GFR after
prescribing these medicines. Measuring GFR (and
potassium) after starting treatment with an ACE
inhibitor or ARB anew or after increasing the dose
may be needed not only to determine whether GFR
has declined too much (or potassium increased too
much), but also to determine whether GFR has
declined at all. Hence, irrespective of whether the
protective effects of angiotensin II inhibition are due
to lowering of glomerular pressures, the decrease in
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD

Bakris Nielsen MDRD (low BP goal) MDRD (usual BP goal)

(n=18) (n=21) (n=293) (n=292)
Mean arterial pressure at
Initial GFR rate of decline Final GFR rate of decline at
(<4 months) trial end (16 years)
trial end
0 115
112
-2 -1.3
-2.8
110
Figure 7. Increases in serum creat- -4

mL/min/year
-4 -3.8
inine level of up to 30% from a baseline -6 105
105

mmHg
-5.7
up to 3 mg/dL within the first 4 months
-8 -7
of starting angiotensin-converting
-10 100 98
enzyme inhibitor treatment correlated -9.4
with slower rates of decline in renal -12 94
function. Adapted from Bakris et al70 95
-14
with permission of National Kidney -14.4
Foundation. -16 90

GFR directly reects the efcacy of the medications.
It is important to educate non-nephrology physicians
and counsel patients in the proper use of these med-
ications because too often these medication treatments
are stopped when GFR decreases.
Are ACE Inhibitors and ARBs Effective for Primary
Prevention of DKD?
This question has received considerable attention
during the past 10 years due to the public health
implications of suggesting that all patients with dia-
betes be placed on ACE-inhibitor or ARB therapy for
the primary prevention of DKD. Two recent detailed
analyses have come to different conclusions.4,76 The
Cochrane review recommends the use of ACE
inhibitors (though not ARBs; the authors state that to
date, studies do not support use of ARBs for primary
prevention) for primary prevention in normotensive
normoalbuminuric patients,76 whereas the NKF-
KDOQI guidelines recommend against using these
medications in this clinical scenario.4 The Cochrane
review stated the following: We identied 26 studies
enrolling 61,264 participants. ACE-Is reduced the risk
Tertiles of initial fall in eGFR
-8.6 -2.4 +4.2
0 diabetes showed no benet. Study participants were
(ml/min per 1.73 m2 per year)
of new onset of microalbuminuria, macroalbuminuria
or both when compared to placebo (eight studies,
11,906 patients: RR 0.71, 95% CI 0.56 to 0.89), with
similar benets in people with and without hyper-
tension (P 5 0.74).76(p1) The weight of this recom-
mendation is based primarily on albuminuria.
NKF-KDOQI reviewed many of the same studies,
but was swayed more by the lack of denitive evi-
dence for such outcomes as differences in pathologic
signs of DKD. For example, with respect to ACE
inhibitors and ARBs for primary prevention in type 1
diabetes, researchers studied 285 patients with type 1
diabetes and no evidence of DKD who were treated
with enalapril, losartan, or placebo for 5 years.77 At
the beginning of the study, 90% of patients had a
kidney biopsy that was repeated 5 years later. The
study showed that neither losartan nor enalapril pre-
vented the development of microalbuminuria. Like-
wise, the biopsy data showed that there was no
prevention of early signs of DKD (Table 3). The
strength of the conclusions was greatly enhanced
because the study involved biopsy material.
There are conicting study results regarding the use
of ARBs for primary prevention. One large study in
which candesartan was prescribed to prevent the
-8.6 -2.4 +4.2 development of microalbuminuria in patients with

normoalbuminuric and mostly normotensive in 3

Long-term eGFR slope

-1 separate clinical trials that included a total of about

-2
3,300 people with type 1 diabetes and 1,900 with type
2 diabetes.78 The study showed no benet for pre-
-3 -3.8 -3.6
-3.9 vention of the development of microalbuminuria
-4.1
-4.4 during a 4.7-year period.
-4 -4.8 Although the Cochrane review and NKF-KDOQI
guidelines differ in the utility of ACE inhibitors for
-5
primary prevention, they agree on the lack of utility of
-6 P=0.0089 P=0.0497 ARBs in primary prevention. Some large studies of
Unadjusted analysis Adjusted analysis patients with type 2 diabetes have shown a benet in
slowing the development of albuminuria.79 However,
Figure 8. In the RENAAL Study, the greater the initial decline the estimated development of microalbuminuria
in glomerular filtration rate, the slower the rate of progression of
diabetic kidney disease. Reproduced with permission of Macmil- ranges from 10%-40% in patients with type 2 dia-
lan Publishers Ltd from Holtkamp et al.75 betes, which means that 60%-90% will not develop

Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21 S13


Table 3. Effects of Enalapril or Losartan Treatment on Primary Prevention of Development of an Early Pathologic Lesion of Diabetic
Kidney Disease
End Point (mesangial fractional volume) Enalapril
Mean at baseline 0.201 6 0.044
Mean change at 5 y 0.005 6 0.050
Change vs placebo
Mean difference 20.011
P value 0.16
Adjusted change vs placebo
Mean difference 20.006
P value 0.38
Reproduced with permission of the Massachusetts Medical Society from Mauer et al.77
microalbuminuria.2,24-26 This would mean there
would be a signicant number of individuals taking a
medication they do not need. It is not clear at this time
whether prescribing an ACE inhibitor or ARB to all
patients with type 2 diabetes without kidney disease
and hypertension would cause more harm or good. If
the patient is hypertensive, an ACE inhibitor or ARB
may be the best initial medication.
Should ACE Inhibitors and ARBs Be Used in
Combination?
There were a number of studies showing the
benets of ACE inhibitors used in combination with
ARBs for the treatment of DKD.80-85 A meta-analysis
published in 2007 reviewed these studies and
concluded that there was therapeutic benet to using
the combination, but cautioned that their ndings may
be misleading by noting that many of the studies were
of short duration.84 In 2008, ONTARGET (Ongoing
Telmisartan Alone and in Combination With Ramipril
Global End-point Trial) changed attitudes about using
the combination of ACE inhibitors and ARBs.86
ONTARGET compared the efcacy of telmisartan
and ramipril in combination with that of telmisartan or
ramipril monotherapy with the intent of showing
noninferiority of telmisartan compared to ramipril.
This large study, about 25,500 participants, showed
that the combination was not superior to using these
medications alone. There appeared to be more adverse
events (decreased GFR and hyperkalemia) in patients
using the combination compared with those on
monotherapy. This large well-done study led many to
conclude that physicians should not use these medi-
cations in combination. The ONTARGET population
consisted of 38% with diabetes and 13% with
microalbuminuria, and the average GFR decreased
to within the normal range. Thus, the relevance of
ONTARGET to the population of patients with
stage 3 (GFR , 60 mL/min/1.73 m2) or worse CKD
and macroalbuminuria (the patient cohort with the
highest risk for progression to end-stage kidney dis-
ease) was unclear. To answer this issue, a subgroup
S14
Robert C. Stanton
Losartan Placebo
0.189 6 0.041 0.187 6 0.045
0.026 6 0.054 0.016 6 0.048
0.010 0 (reference)
0.17
0.008 0 (reference)
0.26
analysis of ONTARGET was performed to determine
whether combination therapy improved outcomes in
participants with decreased GFR and/or increased
urine albumin level. Overall, the study did not show a
benet for combination therapy and may even have led
to worse outcomes. This analysis concluded that dual
blockade likely is not better than monotherapy and the
combination may well have been detrimental. How-
ever, the cause of the kidney disease in this population
was not clear (it was not specically evaluated).87
A recent study was published that evaluated
the effect of the combination of lisinopril and irbe-
sartan versus lisinopril or irbesartan monotherapy in
patients with type 2 diabetes and average GFR of
w48 mL/min/1.73 m2 at maximal dose with the study
end points of .50% increase in serum creatinine
level, end-stage kidney disease, and death over a
4-year period.88 Results showed no benet of the
combination therapy compared to monotherapy, and
there were no differences in adverse events. Although
this is one of the rst studies to address this issue in
type 2 diabetes, it has limitations, as the authors noted
(the study included only 133 patients, mostly men,
with a mean age of 67 years). The study was not
double blind and the outcome event rate was lower
than expected in all groups. Because a number of
studies have demonstrated the benet of lowering
albumin excretion in patients with macroalbuminuria
for slowing the progression of DKD,15,58,89 it is
justiable to use a variety of methods to lower urine
albumin levels. Two debates published in 2010 pro-
vide excellent discussions of the pros and cons of
using an ACE inhibitor and an ARB in combination
for the treatment of CKD.90,91 A meta-analysis
recently was published that addressed the specic
question of whether there is support for using dual
RAAS blockade for treating patients with DKD.85
The detailed analysis concluded that dual blockade
should be used in patients with diabetes, macro-
albuminuria, and normal potassium levels. Recently,
2 long-term studies were designed to develop better
understanding of the role of combination therapy in
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD
patients with DKD: the VA NEPHRON-D Study,
which consists of 1,448 patients with type 2 diabetes
and a wide range of GFRs and was scheduled to be
completed by October 201492; and the VALID
(Preventing ESRD in Overt Nephropathy in Type 2
Diabetes) Study, which consists of approximately
100 patients with type 2 diabetes and signicant
kidney disease, as dened by serum creatinine level
of 1.8-3.5 g/dL and urine albumin-creatinine ratio
. 1,000 mg/g, and is due to be completed December
2015.93 The VA NEPHRON-D Study was stopped
earlier this year by the Data and Safety Monitoring
Board due to what was reported as increased acute
kidney injury and hyperkalemia events in the dual-
blockade cohort, and due to lack of efcacy. This
result certainly brings into question the safety and
efcacy of dual blockade.
Should ACE Inhibitors and ARBs Be Discontinued at a
Particular eGFR Level?
There are several acute situations that require at
least temporary discontinuation of these medications.
Signicant side effects should prompt a clinician to
stop the medication. However, in the absence of
complications and acute events, should these medi-
cations be continued until dialysis or transplantation?
In 2001, a secondary post hoc analysis of the REIN
(Ramipril Efcacy in Nephropathy) trial, consisting
of 322 patients with nondiabetic proteinuric CKD and
different levels of kidney function, was done to
evaluate this question.94 It was found that the best
effect for slowing the progression to end-stage kidney
disease was achieved in the group with the lowest
GFR. Moreover, the earlier ramipril treatment was
started and maintained, the better the protection.
Furthermore, data from the RENAAL Study with
losartan also suggested that prolonged use slows the
progression to end-stage kidney disease.95 There have
not been many detailed studies about this issue, but in
the absence of a reason to stop ACE-inhibitor or ARB
treatment in a patient nearing dialysis, it may make
sense to maintain the patients on these medications.
Recommendations for Use of ACE Inhibitors and ARBs
in DKD
1. There currently is little or no indication for the use
of ACE inhibitors or ARBs in the prevention of
DKD in patients with diabetes and normal urine
albumin excretion and BP.
2. They are a reasonable rst-line treatment for pa-
tients with hypertension and normal urine albumin
levels; however, selection of antihypertensive
agents should be made on an individual basis,
taking into account factors such as comorbid
conditions, cost, and treatment adherence.
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
3. Consider using ACE inhibitors or ARBs in patients
with microalbuminuria to help prevent progression
to macroalbuminuria.
4. For overt proteinuria (.300 mg/g of urine albu-
min), there is a clear indication for ACE-inhibitor
or ARB treatment. The stopping of VA
NEPHRON-D brings into question whether there
is any role for combination ACE-inhibitor/ARB
treatment for patients with DKD. The VALID
Study may be the nal arbiter as to whether there is
a role for dual blockade in patients with DKD.
An interesting question is whether these medica-
tions are of benet in patients with DKD who have
normal albumin levels but decreased GFR. There are
few data for this particular scenario. It may be rec-
ommended to use these medications if the patient also
is hypertensive. However, if complications arise as a
result of using these medications (such as hyper-
kalemia or cough), switching to another antihyper-
tensive agent would be indicated.
ReninAngiotensinAldosterone Axis: Is There a Role
for Renin Inhibition?
There was much interest when the renin inhibitor
aliskiren was launched as an inhibitor of the
RAAS.96 One short-term study showed a promising
reduction in urine albumin excretion using aliskiren
and losartan combination therapy in patients with
diabetes.97 As such, aliskiren could be used in
combination with either an ACE inhibitor or ARB to
lower urine albumin levels and slow progression.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes
Using Cardio-Renal Endpoints) was designed to
evaluate whether the addition of aliskiren to ACE
inhibitor or ARB treatment provided further reno-
protective benets.98 In late 2011, the study was
stopped prematurely by the data safety and moni-
toring board for the study due to the occurrence of
excess adverse events (nonfatal stroke, hyper-
kalemia, hypotension, and decreased kidney func-
tion).99 Considering that generic forms of ACE
inhibitors provide a much more cost-effective solu-
tion to managing urine albumin levels than aliskiren,
the precise role for aliskiren in the treatment of DKD
is not clear at this time.
ReninAngiotensinAldosterone Axis: Focus on
Aldosterone Inhibition
Aldosterone inhibition has been widely underused
for DKD treatment. In addition to aldosterone effects
on sodium, potassium, and pH regulation, aldoste-
rone leads to increased levels of reactive oxygen
species, transforming growth factor b, and plasmin-
ogen activator inhibitor and other effects that can
lead to glomerular podocyte loss, as well as tubu-
lointerstitial brosis.100 Numerous articles have been
S15

published in the cardiovascular literature that discuss
the benecial effects of spironolactone, especially in
patients with congestive heart failure and/or cardio-
vascular disease.101-103 The benets of spi-
ronolactone for CKD, and in particular DKD, have
become apparent over the past 10 years.104 There
now are multiple studies showing a signicant
decrease in proteinuria when aldosterone inhibition
is added to ACE-inhibitor or ARB therapy. Treat-
ment is associated with an increased risk of hyper-
kalemia, but the overall benet of aldosterone
inhibition may outweigh the risks.104,105 At this
time, spironolactone may be considered to possibly
be of benet for patients with DKD. However, there
are no long-term studies with spironolactone alone or
in combination with other RAAS inhibitors showing
improved kidney outcomes. Larger and long-term
studies are needed to better understand the relation-
ship between aldosterone inhibition and DKD
outcomes.
Do Nondihydropyridine Calcium Channel Blockers
Lower Proteinuria and Help Slow the Progression
of DKD?
Studies during the past 15 years appeared to show
that nondihydropyridine medications (eg, diltiazem
and verapamil) slightly decreased proteinuria inde-
pendently of any BP-lowering effects.106-108 A
recent study evaluated the effects of diltiazem on the
development of urinary albumin excretion in patients
with hypertension and type 2 diabetes, with persis-
tent microalbuminuria despite ACE-inhibitor treat-
ment.109 Thirty-six patients with type 2 diabetes,
hypertension, and microalbuminuria persisting after
more than 1 year of treatment with ACE inhibitors
were randomly assigned to receive captopril
(n 5 22) or captopril and 120 mg of diltiazem
combined therapy (n 5 14) for 2 years. There was no
increase in albumin excretion in the combined-
therapy group, whereas absolute albumin excretion
increased in the captopril monotherapy group. The
benecial effects of the addition of diltiazem were
independent of BP and metabolic control. More
recently, a head-to-head study of patients with type 2
diabetes compared trandolapril/verapamil combina-
tion therapy with benazepril/amlodipine combination
therapy, and both combinations were seen to reduce
proteinuria.110 Recommendations at this time are to
use either type of calcium channel blocker as an
addition to RAAS inhibitors, mostly for BP man-
agement. For patients unable to tolerate RAAS in-
hibitors (usually due to hyperkalemia) for the
reduction of proteinuria (not considering antihyper-
tensive actions), there are data supporting the use of
nondihydropyridine monotherapy when compared
with dihydropyridine monotherapy.
S16
Robert C. Stanton
Is There a Role for Pentoxifylline in Treating DKD?
Pentoxifylline is a methylxanthine phosphodies-
terase inhibitor that has been used for many years to
improve vascular blood ow, but also has been shown
to have anti-inammatory and immunoregulatory
effects.111-113
During the past 10 years, pentoxifylline has shown
antiproteinuria effects.111-113 All studies to date gen-
erally have been small and short in duration and have
focused entirely on reduction of proteinuria.111-113
Thus, it is difcult to know the utility of this
different class of medication, but it still may nd a
role in the treatment of DKD.
Protein Intake and DKD: Should Low-Protein Diets
Routinely Be Prescribed?
A role for protein in the progression of DKD has
been discussed for many years.95 Initial observations
illustrated that GFR increases signicantly after a
high-protein meal.95 Many subsequent studies using
animal models of DKD illustrated that a high-protein
diet accelerated the rate of increase in urine protein
levels and rate of decline in GFR in animal models of
DKD.114,115 The primary mechanism (determined by
single-nephron GFR micropuncture studies) illus-
trated that a high-protein diet (50% of the diet was
protein compared to a usual rat diet of 12% protein)
caused an increase in intracapillary glomerular pres-
sure with a resultant increase in GFR.114,115 A low-
protein diet (6% protein in the diet) slowed the
decline in GFR and development of proteinuria.
These ndings led to the MDRD Study,116,117 which
was designed to show the benet of a low-protein diet
(,0.8 g/kg/d) in slowing the progression of CKD.
Unfortunately, there was no benet seen in this study.
There may be a number of reasons for this, including
the length of the study, that there are benecial effects
for certain subgroups that were not seen when
examining the entire cohort, and difculty maintain-
ing a low-protein diet. The MDRD Study had a
relatively small subgroup with DKD. Subsequent
studies of patients with diabetes have used diets with
protein as low as ,0.4 g/kg/d (with supplementation
of essential amino acids), with most studies using
protein lower than 0.6-0.8 g/kg/d.118,119 Almost all
these studies have focused on patients with type 1
diabetes, are of short duration, and are small.
Although some studies have reported reduced albu-
minuria, there are no long-term studies that clearly
show a denitive benet for a low-protein diet. An
extensive review of protein intake and DKD is
beyond the scope of this review, but the published
data lead to the following recommendations:
1. There are no long-term data supporting the pre-
scription of a low-protein diet (,0.6-8 g/kg/d) in
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD
patients with DKD. The prescribed diet should
balance all the patients nutritional needs and
protein level should be prescribed in this context
primarily.
2. A low-protein diet may offer additional benets,
especially in patients who have maximized other
therapeutic approaches.
3. There are additional benets to low-protein diets
independent of protein level in that reduced protein
intake also is associated with reduced phosphate,
sodium, and fat intake and other potentially bene-
cial effects.120 One study suggests that the
benecial effect of a low-protein diet might be due
primarily to the reduction in sodium intake and
subsequent improvement in BP.119
4. It is likely that high-protein diets are deleterious.
There are no studies of humans denitively
showing this, but the work in animal is very
compelling.115 Also, the exact denition of a
high-protein diet is not clear. Nevertheless,
avoiding protein supplements and weight-loss diets
that consist of a high-protein component seems
prudent for patients with DKD.
Smoking Cessation and DKD
Studies dating back 30 years showed that smoking
is a risk factor for both the development and pro-
gression of DKD.56,57,121 The data seem to be as
relevant for patients with type 1 DKD as for those
with type 2 DKD.56,57,121 There also are data sug-
gesting slowing of DKD progression in smokers who
quit smoking.122 Hence, although the data are not
extensive or based on large studies, considering the
effects of smoking on general health and diabetes
specically, it is strongly recommended that all
patients with DKD cease smoking.
Is There a Specic Unique Role for Lipid Management
in DKD?
There have been a number of studies revealing an
association between hypercholesterolemia and rate
of progression of DKD.123-126 Elevated serum
cholesterol levels are correlated with decreased
GFRs in patients with either type 1 or type 2
DKD.127 Thus, it has been suggested that elevated
serum cholesterol level is a risk factor for the pro-
gression of kidney disease. Interestingly, in a study
that showed regression of microalbuminuria in pa-
tients with type 1 diabetes,36 low cholesterol and
triglyceride levels correlated with regression. The
FIELD Study evaluated fenobrate treatment on
albuminuria and eGFR and found that during a 5-
year period, fenobrate treatment modestly lowered
albuminuria and slowed eGFR decline compared
with groups not treated with fenobrate, especially
in patients with hypertriglyceridemia (but no
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
difference in end-stage kidney disease was seen).128
Fenobrate increased creatinine levels initially, but
this was not maintained, and 2 more recent studies
suggest that fenobrate likely is safe to use in pa-
tients with moderate kidney disease.129,130 However,
more studies clearly are needed to determine whether
treatment of cholesterol and/or triglyceride levels
will prevent the development or slow the progression
of DKD. Thus, no specic recommendation on the
benets of lowering cholesterol and/or triglyceride
levels can be made at this time. Perhaps a multi-
factorial approach to management (that includes
lipid management, BP control, blood glucose con-
trol, etc) as was done in the STENO-2 Study will
provide the best outcomes.131
Is There a Role for Weight Loss in DKD?
Obesity has been observed to be a clear risk factor
for kidney disease in general and for DKD.132 Obesity
is associated with increased lipid levels, hypertension,
endothelial cell dysfunction, and other metabolic
abnormalities.132 Thus, it is not clear whether the
main reason obesity is associated with kidney disease
are the factors associated with obesity or other factors
unique to the obese person, such as release of
inammatory mediators from visceral fat cells. Inter-
estingly, one case report describes resolution of
albuminuria following bariatric surgery.133 It is not
clear whether this improvement is due to an intrinsic
change in cellular physiology associated with the
alteration in body habitus from obese to nonobese or
to improved blood glucose and BP control. A recent
review discusses the evidence linking obesity to
CKD.134
CONCLUSION
Much has been learned in the past 30 years that has
led to signicant improvements in treatments for
DKD that slow progression and interventions for
the prevention of DKD, yet DKD is a major, ever
increasing, worldwide public health problem. The
primary goals of the health care system need to be
focused on the prevention and slowing of progres-
sion of DKD. The nephrology community has a
dual task: to determine the best approach for both
diagnosis and management. However, further educa-
tion also is required across all health care providers
(eg, endocrinologists, primary care physicians, nurse
practitioners, physician assistants, and nurses) to
understand the scope of the problem, implement in-
terventions that prevent the development of DKD,
ensure proper screening, understand how to diagnose,
understand treatments if they do not want to refer, and
understand when to refer to nephrology. It is a tall
order, but a critical one.
S17

ACKNOWLEDGEMENTS
For the data reported here that were supplied by the USRDS, the
interpretation and reporting of these data are the responsibility of
the author and in no way should be seen as an ofcial policy or
interpretation of the US government.
Support: The development of this journal supplement was
funded by Novo Nordisk. Technical editing was provided by
Watermeadow Medical, funded by Novo Nordisk. Costs associ-
ated with publication were funded by Novo Nordisk. The author
received no remuneration for this work.
Financial Disclosure: The author declares that he has no rele-
vant nancial interests.
REFERENCES
1. Collins AJ, Foley RN, Herzog C, et al. US Renal Data
System 2012 annual data report. Am J Kidney Dis. 2013;61(1)
(suppl 1):e1-e480.
2. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH,
Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis,
prevention, and treatment. Diabetes Care. 2005;28(1):164-176.
3. Heerspink HJ, de Zeeuw D. The kidney in type 2 diabetes
therapy. Rev Diabet Stud. 2011;8(3):392-402.
4. National Kidney Foundation. KDOQI clinical practice
guideline for diabetes and CKD: 2012 update. Am J Kidney Dis.
2012;60(5):850-886.
5. Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the
pathogenesis and treatment of diabetic nephropathy. Nat Rev
Nephrol. 2010;6(6):319-330.
6. Centers for Disease Control and Prevention. Diabetes report
card 2012: national and state prole of diabetes and its complica-
tions. http://www.cdc.gov/diabetes/pubs/reportcard.htm. Accessed
April 3, 2013.
7. Wilchesky M, Tamblyn RM, Huang A. Validation of diag-
nostic codes within medical services claims. J Clin Epidemiol.
2004;57(2):131-141.
8. Sessa A, Meroni M, Battini G, Vaccari M, Giordano F, Torri
Tarelli L. IgA nephropathy complicating diabetic glomerulo-
sclerosis. Nephron. 1998;80(4):488-489.
9. Bi H, Chen N, Ling G, Yuan S, Huang G, Liu R. Nondia-
betic renal disease in type 2 diabetic patients: a review of our
experience in 220 cases. Ren Fail. 2011;33(1):26-30.
10. Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA. Prev-
alence of nondiabetic renal disease in diabetic patients. Am J
Nephrol. 2007;27(3):322-328.
11. Michels WM, Grootendorst DC, Verduijn M, Elliott EG,
Dekker FW, Krediet RT. Performance of the Cockcroft-Gault,
MDRD, and new CKD-EPI formulas in relation to GFR, age,
and body size. Clin J Am Soc Nephrol. 2010;5(6):1003-1009.
12. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney
disease and increased mortality risk in type 2 diabetes. J Am Soc
Nephrol. 2013;24(2):302-308.
13. Jude EB, Anderson SG, Cruickshank JK, et al. Natural
history and prognostic factors of diabetic nephropathy in type 2
diabetes. QJM. 2002;95(6):371-377.
14. Muntner P, Bowling CB, Gao L, et al. Age-specic asso-
ciation of reduced estimated glomerular ltration rate and albu-
minuria with all-cause mortality. Clin J Am Soc Nephrol.
2011;6(9):2200-2207.
15. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria
and kidney function independently predict cardiovascular and
renal outcomes in diabetes. J Am Soc Nephrol. 2009;20(8):1813-
1821.
S18
Robert C. Stanton
16. Couchoud C, Villar E. End-stage renal disease epidemic in
diabetics: is there light at the end of the tunnel? Nephrol Dial
Transplant. 2013;28(5):1073-1076.
17. Pavkov ME, Knowler WC, Hanson RL, Nelson RG. Dia-
betic nephropathy in American Indians, with a special emphasis on
the Pima Indians. Curr Diab Rep. 2008;8(6):486-493.
18. Debnath S, Thameem F, Alves T, et al. Diabetic ne-
phropathy among Mexican Americans. Clin Nephrol. 2012;77(4):
332-344.
19. Collins AJ, Foley RN, Gilbertson DT, Chen SC. The state of
chronic kidney disease, ESRD, and morbidity and mortality in the
rst year of dialysis. Clin J Am Soc Nephrol. 2009;4(suppl 1):S5-S11.
20. Crook ED, Patel SR. Diabetic nephropathy in African-
American patients. Curr Diab Rep. 2004;4(6):455-461.
21. Hanson RL, Millis MP, Young NJ, et al. ELMO1 variants
and susceptibility to diabetic nephropathy in American Indians.
Mol Genet Metab. 2010;101(4):383-390.
22. McDonough CW, Bostrom MA, Lu L, et al. Genetic
analysis of diabetic nephropathy on chromosome 18 in African
Americans: linkage analysis and dense SNP mapping. Hum Genet.
2009;126(6):805-817.
23. McDonough CW, Palmer ND, Hicks PJ, et al. A genome-
wide association study for diabetic nephropathy genes in African
Americans. Kidney Int. 2011;79(5):563-572.
24. Ritz E, Orth SR. Nephropathy in patients with type 2 dia-
betes mellitus. N Engl J Med. 1999;341(15):1127-1133.
25. Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-
Riska C. Incidence of end-stage renal disease in patients with type
1 diabetes. JAMA. 2005;294(14):1782-1787.
26. Rodriguez-Poncelas A, Garre-Olmo J, Franch-Nadal J,
et al. Prevalence of chronic kidney disease in patients with type
2 diabetes in Spain: PERCEDIME2 Study. BMC Nephrol.
2013;14:46.
27. Lv J, Xu D, Perkovic V, et al. Corticosteroid therapy in IgA
nephropathy. J Am Soc Nephrol. 2012;23(6):1108-1116.
28. Couser WG, Remuzzi G, Mendis S, Tonelli M. The
contribution of chronic kidney disease to the global burden
of major noncommunicable diseases. Kidney Int. 2011;80(12):
1258-1270.
29. Zhang QL, Rothenbacher D. Prevalence of chronic kidney
disease in population-based studies: systematic review. BMC
Public Health. 2008;8:117.
30. Kiryluk K, Li Y, Sanna-Cherchi S, et al. Geographic dif-
ferences in genetic susceptibility to IgA nephropathy: GWAS
replication study and geospatial risk analysis. PLoS Genet.
2012;8(6):e1002765.
31. Cao Y, Li W, Yang G, Liu Y, Li X. Diabetes and hyper-
tension have become leading causes of CKD in Chinese elderly
patients: a comparison between 1990-1991 and 2009-2010. Int
Urol Nephrol. 2012;44(4):1269-1276.
32. Wolf G, Muller N, Mandecka A, Muller UA. Association
of diabetic retinopathy and renal function in patients with types 1
and 2 diabetes mellitus. Clin Nephrol. 2007;68(2):81-86.
33. Caramori ML, Fioretto P, Mauer M. Low glomerular
ltration rate in normoalbuminuric type 1 diabetic patients: an
indicator of more advanced glomerular lesions. Diabetes.
2003;52(4):1036-1040.
34. Steinke JM, Mauer M; International Diabetic Nephropathy
Study Group. Lessons learned from studies of the natural history
of diabetic nephropathy in young type 1 diabetic patients. Pediatr
Endocrinol Rev. 2008;5(suppl 4):958-963.
35. Steinke JM, Sinaiko AR, Kramer MS, et al. The early
natural history of nephropathy in type 1 diabetes: III.
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD
Predictors of 5-year urinary albumin excretion rate patterns
in initially normoalbuminuric patients. Diabetes. 2005;54(7):
2164-2171.
36. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM,
Warram JH, Krolewski AS. Regression of microalbuminuria
in type 1 diabetes. N Engl J Med. 2003;348(23):2285-2293.
37. Perkins BA, Ficociello LH, Ostrander BE, et al. Micro-
albuminuria and the risk for early progressive renal function
decline in type 1 diabetes. J Am Soc Nephrol. 2007;18(4):1353-
1361.
38. Dwyer JP, Parving HH, Hunsicker LG, Ravid M,
Remuzzi G, Lewis JB. Renal dysfunction in the presence of nor-
moalbuminuria in type 2 diabetes: results from the DEMAND
Study. Cardiorenal Med. 2012;2(1):1-10.
39. Mazzucco G, Bertani T, Fortunato M, Fop F, Monga G.
The prognostic value of renal biopsy in type 2 diabetes mellitus
patients affected by diabetic glomerulosclerosis. J Nephrol.
2005;18(6):696-702.
40. Najaan B, Mauer M. Progression of diabetic nephropathy
in type 1 diabetic patients. Diabetes Res Clin Pract. 2009;83(1):1-8.
41. Gilbert RE, Cooper ME. The tubulointerstitium in pro-
gressive diabetic kidney disease: more than an aftermath of
glomerular injury? Kidney Int. 1999;56(5):1627-1637.
42. Kanasaki K, Taduri G, Koya D. Diabetic nephropathy: the
role of inammation in broblast activation and kidney brosis.
Front Endocrinol (Lausanne). 2013;4:7.
43. Singh DK, Farrington K. The tubulointerstitium in early
diabetic nephropahty: prime target or innocent bystander? Int J
Diabetes Dev Countries. 2010;30(4):185-190.
44. Tervaert TW, Mooyaart AL, Amann K, et al. Pathologic
classication of diabetic nephropathy. J Am Soc Nephrol.
2010;21(4):556-563.
45. Soler MJ, Riera M, Batlle D. New experimental models of
diabetic nephropathy in mice models of type 2 diabetes: efforts to
replicate human nephropathy. Exp Diabetes Res. 2012;2012:
616313.
46. The Diabetes Control and Complications Trial Research
Group. The effect of intensive treatment of diabetes on the
development and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):
977-986.
47. UK Prospective Diabetes Study (UKPDS) Group. Intensive
blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients
with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):
837-853.
48. The Diabetes Control and Complications Trial/Epidemi-
ology of Diabetes Interventions and Complications Research
Group. Retinopathy and nephropathy in patients with type 1 dia-
betes four years after a trial of intensive therapy. N Engl J Med.
2000;342(6):381-389.
49. Group DER; de Boer IH, Sun W, et al. Intensive diabetes
therapy and glomerular ltration rate in type 1 diabetes. N Engl J
Med. 2011;365(25):2366-2376.
50. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin
therapy prevents the progression of diabetic microvascular com-
plications in Japanese patients with non-insulin-dependent dia-
betes mellitus: a randomized prospective 6-year study. Diabetes
Res Clin Pract. 1995;28(2):103-117.
51. Writing Team for the Diabetes Control and Complications
Trial/Epidemiology of Diabetes Intervention and Complications
Research Group. Sustained effect of intensive treatment of type 1
diabetes mellitus on development and progression of diabetic
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
nephropathy: the Epidemiology of Diabetes Interventions and
Complications (EDIC) Study. JAMA. 2003;290(16):2159-2167.
52. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH.
Remission and regression in the nephropathy of type 1 diabetes
when blood pressure is controlled aggressively. Kidney Int.
2001;60(1):277-283.
53. Lasaridis AN, Saradis PA. Diabetic nephropathy and
antihypertensive treatment: what are the lessons from clinical tri-
als? Am J Hypertens. 2003;16(8):689-697.
54. Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ. Effect of
intensive blood pressure control on the course of type 1 diabetic
nephropathy. Collaborative Study Group. Am J Kidney Dis.
1999;34(5):809-817.
55. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of
aggressive blood pressure control in normotensive type 2 diabetic
patients on albuminuria, retinopathy and strokes. Kidney Int.
2002;61(3):1086-1097.
56. Chakkarwar VA. Smoking in diabetic nephropathy: sparks
in the fuel tank? World J Diabetes. 2012;3(12):186-195.
57. Tonstad S. Cigarette smoking, smoking cessation, and
diabetes. Diabetes Res Clin Pract. 2009;85(1):4-13.
58. Bakris GL. Slowing nephropathy progression: focus on pro-
teinuria reduction. Clin J Am Soc Nephrol. 2008;3(suppl 1):S3-S10.
59. de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a
target for renoprotection in patients with type 2 diabetic
nephropathy: lessons from RENAAL. Kidney Int. 2004;65(6):
2309-2320.
60. Eknoyan G. Obesity, diabetes, and chronic kidney disease.
Curr Diab Rep. 2007;7(6):449-453.
61. Praga M, Morales E. Obesity, proteinuria and progression of
renal failure. Curr Opin Nephrol Hypertens. 2006;15(5):481-486.
62. Williams ME, Garg R. Glycemic management in ESRD and
earlier stages of CKD. Am J Kidney Dis. 2014;63(2)(suppl 2):
S22-S38.
63. Reboldi G, Gentile G, Angeli F, Verdecchia P. Optimal
therapy in hypertensive subjects with diabetes mellitus. Curr
Atheroscler Rep. 2011;13(2):176-185.
64. Van Buren PN, Toto R. Hypertension in diabetic
nephropathy: epidemiology, mechanisms, and management. Adv
Chronic Kidney Dis. 2011;18(1):28-41.
65. Estacio RO, Coll JR, Tran ZV, Schrier RW. Effect of
intensive blood pressure control with valsartan on urinary albumin
excretion in normotensive patients with type 2 diabetes. Am J
Hypertens. 2006;19(12):1241-1248.
66. Clinical Practice Guidelines. Diabetes Care. 2013;36(suppl 1):
S29-S31.
67. Accord Study Group; Cushman WC, Evans GW,
Byington RP, et al. Effects of intensive blood-pressure control in
type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
68. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight
blood pressure control and cardiovascular outcomes among
hypertensive patients with diabetes and coronary artery disease.
JAMA. 2010;304(1):61-68.
69. Bakris GL, Weir MR, Shanifar S, et al. Effects of blood
pressure level on progression of diabetic nephropathy: results from
the RENAAL Study. Arch Intern Med. 2003;163(13):1555-1565.
70. Bakris GL, Williams M, Dworkin L, et al. Preserving renal
function in adults with hypertension and diabetes: a consensus
approach. National Kidney Foundation Hypertension and Diabetes
Executive Committees Working Group. Am J Kidney Dis.
2000;36(3):646-661.
71. Berl T, Hunsicker LG, Lewis JB, et al. Impact of achieved
blood pressure on cardiovascular outcomes in the Irbesartan
S19

Diabetic Nephropathy Trial. J Am Soc Nephrol. 2005;16(7):
2170-2179.
72. Gnudi L, Goldsmith D. Renin angiotensin aldosterone
system (RAAS) inhibitors in the prevention of early renal disease
in diabetes. F1000 Med Rep. 2010;2.
73. Schjoedt KJ. The renin-angiotensin-aldosterone system and
its blockade in diabetic nephropathy: main focus on the role of
aldosterone. Dan Med Bull. 2011;58(4):B4265.
74. Taal MW, Brenner BM. Renoprotective benets of RAS
inhibition: from ACEI to angiotensin II antagonists. Kidney Int.
2000;57(5):1803-1817.
75. Holtkamp FA, de Zeeuw D, Thomas MC, et al. An acute
fall in estimated glomerular ltration rate during treatment with
losartan predicts a slower decrease in long-term renal function.
Kidney Int. 2011;80(3):282-287.
76. Lv J, Perkovic V, Foote CV, Craig ME, Craig JC,
Strippoli GF. Antihypertensive agents for preventing diabetic
kidney disease. Cochrane Database Syst Rev. 2012;12:CD004136.
77. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal
effects of enalapril and losartan in type 1 diabetes. N Engl J Med.
2009;361(1):40-51.
78. Bilous R, Chaturvedi N, Sjolie AK, et al. Effect of can-
desartan on microalbuminuria and albumin excretion rate in dia-
betes: three randomized trials. Ann Intern Med. 2009;151(1):
11-20. W13-W14.
79. Remuzzi G, Macia M, Ruggenenti P. Prevention and
treatment of diabetic renal disease in type 2 diabetes: the BENE-
DICT Study. J Am Soc Nephrol. 2006;17(4)(suppl 2):S90-S97.
80. Hebert LA, Falkenhain ME, Nahman NS Jr, Cosio FG,
ODorisio TM. Combination ACE inhibitor and angiotensin II
receptor antagonist therapy in diabetic nephropathy. Am J Neph-
rol. 1999;19(1):1-6.
81. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised
controlled trial of dual blockade of renin-angiotensin system in
patients with hypertension, microalbuminuria, and non-insulin
dependent diabetes: the Candesartan and Lisinopril Micro-
albuminuria (CALM) Study. BMJ. 2000;321(7274):1440-1444.
82. Erman A, Veksler S, Gafter U, Boner G, Wittenberg C, van
Dijk DJ. Renin-angiotensin system blockade prevents the increase
in plasma transforming growth factor beta 1, and reduces pro-
teinuria and kidney hypertrophy in the streptozotocin-diabetic rat.
J Renin Angiotensin Aldosterone Syst. 2004;5(3):146-151.
83. Abe H, Minatoguchi S, Ohashi H, et al. Renoprotective
effect of the addition of losartan to ongoing treatment with an
angiotensin converting enzyme inhibitor in type-2 diabetic patients
with nephropathy. Hypertens Res. 2007;30(10):929-935.
84. Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J.
Combination therapy with an ACE inhibitor and an angiotensin
receptor blocker for diabetic nephropathy: a meta-analysis. Diabet
Med. 2007;24(5):486-493.
85. Pham JT, Schmitt BP, Leehey DJ. Effects of dual blockade of
the renin-angiotensin system in diabetic kidney disease: a systematic
review and meta-analysis. J Nephrol Ther 2012;(suppl 2):1-8.
86. ONTARGET Investigators; Yusuf S, Teo KK, Pogue J,
et al. Telmisartan, ramipril, or both in patients at high risk for
vascular events. N Engl J Med. 2008;358(15):1547-1559.
87. Tobe SW, Clase CM, Gao P, et al. Cardiovascular and renal
outcomes with telmisartan, ramipril, or both in people at high renal
risk: results from the ONTARGET and TRANSCEND studies.
Circulation. 2011;123(10):1098-1107.
88. Fernandez Juarez G, Luno J, Barrio V, et al. Effect of dual
blockade of the renin-angiotensin system on the progression of
S20
Robert C. Stanton
type 2 diabetic nephropathy: a randomized trial. Am J Kidney Dis.
2013;61(2):211-218.
89. Cravedi P, Ruggenenti P, Remuzzi G. Proteinuria should
be used as a surrogate in CKD. Nat Rev Nephrol. 2012;8(5):
301-306.
90. Bakris GL. Dual RAAS blockade is desirable in kidney
disease: con. Kidney Int. 2010;78(6):546-549.
91. Lattanzio MR, Weir MR. Have we fallen off target with
concerns surrounding dual RAAS blockade? Kidney Int.
2010;78(6):539-545.
92. Fried LF, Emanuele N, Zhang JH, et al. Combined angio-
tensin inhibition for the treatment of diabetic nephropathy. N Engl
J Med. 2013;369(20):1892-1903.
93. Remuzzi G. Preventing ESRD in Overt Nephropathy of
Type 2 Diabetes (VALID). http://clinicaltrials.gov/show/NCT004
94715. Accessed August 15, 2013.
94. Ruggenenti P, Perna A, Remuzzi G; Gruppo Italiano di
Studi Epidemiologici in Nefrologia. ACE inhibitors to prevent
end-stage renal disease: when to start and why possibly never to
stop: a post hoc analysis of the REIN trial results. Ramipril Ef-
cacy in Nephropathy. J Am Soc Nephrol. 2001;12(12):2832-2837.
95. Brenner BM, Meyer TW, Hostetter TH. Dietary protein
intake and the progressive nature of kidney disease: the role of
hemodynamically mediated glomerular injury in the pathogenesis
of progressive glomerular sclerosis in aging, renal ablation, and
intrinsic renal disease. N Engl J Med. 1982;307(11):652-659.
96. Angeli F, Reboldi G, Mazzotta G, et al. Safety and efcacy
of aliskiren in the treatment of hypertension and associated clinical
conditions. Curr Drug Saf. 2012;7(1):76-85.
97. Parving HH, Persson F, Lewis JB, Lewis EJ,
Hollenberg NK; ALTITUDE Study Investigators. Aliskiren com-
bined with losartan in type 2 diabetes and nephropathy. N Engl J
Med. 2008;358(23):2433-2446.
98. Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren
Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTI-
TUDE): rationale and study design. Nephrol Dial Transplant.
2009;24(5):1663-1671.
99. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal
end points in a trial of aliskiren for type 2 diabetes. N Engl J Med.
2012;367(23):2204-2213.
100. Briet M, Schiffrin EL. Aldosterone: effects on the kidney
and cardiovascular system. Nat Rev Nephrol. 2010;6(5):261-273.
101. Brown NJ. Aldosterone and end-organ damage. Curr
Opin Nephrol Hypertens. 2005;14(3):235-241.
102. Catena C, Colussi G, Brosolo G, Iogna-Prat L, Sechi LA.
Aldosterone and aldosterone antagonists in cardiac disease: what is
known, what is new. Am J Cardiovasc Dis. 2012;2(1):50-57.
103. Catena C, Colussi G, Marzano L, Sechi LA. Aldosterone
and the heart: from basic research to clinical evidence. Horm
Metab Res. 2012;44(3):181-187.
104. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF.
Aldosterone antagonists for preventing the progression of chronic
kidney disease: a systematic review and meta-analysis. Clin J Am
Soc Nephrol. 2009;4(3):542-551.
105. Kang YS, Cha DR. Aldosterone and diabetic kidney dis-
ease. Curr Diab Rep. 2009;9(6):453-459.
106. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S.
Calcium channel blockers versus other antihypertensive therapies
on progression of NIDDM associated nephropathy. Kidney Int.
1996;50(5):1641-1650.
107. Bakris GL, Mangrum A, Copley JB, Vicknair N,
Sadler R. Effect of calcium channel or beta-blockade on the
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
Challenges in Diagnosis and Management of DKD
progression of diabetic nephropathy in African Americans. Hy-
pertension. 1997;29(3):744-750.
108. Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effects
of an ACE inhibitor/calcium antagonist combination on proteinuria
in diabetic nephropathy. Kidney Int. 1998;54(4):1283-1289.
109. Perez-Maraver M, Carrera MJ, Micalo T, et al. Reno-
protective effect of diltiazem in hypertensive type 2 diabetic pa-
tients with persistent microalbuminuria despite ACE inhibitor
treatment. Diabetes Res Clin Pract. 2005;70(1):13-19.
110. Toto RD, Tian M, Fakouhi K, Champion A, Bacher P.
Effects of calcium channel blockers on proteinuria in patients with
diabetic nephropathy. J Clin Hypertens (Greenwich). 2008;10(10):
761-769.
111. Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M,
Abdollahi M. A review of the potential benets of pentoxifylline
in diabetic and non-diabetic proteinuria. J Pharm Pharm Sci.
2011;14(1):128-137.
112. Ghorbani A, Omidvar B, Beladi-Mousavi SS, Lak E,
Vaziri S. The effect of pentoxifylline on reduction of proteinuria
among patients with type 2 diabetes under blockade of angiotensin
system: a double blind and randomized clinical trial. Nefrologia.
2012;32(6):790-796.
113. Roozbeh J, Banihashemi MA, Ghezlou M, et al. Captopril
and combination therapy of captopril and pentoxifylline in reducing
proteinuria in diabetic nephropathy. Ren Fail. 2010;32(2):172-178.
114. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA,
Brenner BM. Hyperltration in remnant nephrons: a potentially adverse
response to renal ablation. Am J Physiol. 1981;241(1):F85-F93.
115. Zatz R, Meyer TW, Rennke HG, Brenner BM. Predomi-
nance of hemodynamic rather than metabolic factors in the path-
ogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A.
1985;82(17):5963-5967.
116. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary
protein restriction and blood-pressure control on the progression of
chronic renal disease. Modication of Diet in Renal Disease Study
Group. N Engl J Med. 1994;330(13):877-884.
117. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction
and the progression of chronic renal disease: what have all of the results
of the MDRD Study shown? Modication of Diet in Renal Disease
Study Group. J Am Soc Nephrol. 1999;10(11):2426-2439.
118. Robertson L, Waugh N, Robertson A. Protein restriction
for diabetic renal disease. Cochrane Database Syst Rev.
2007;17(4):CD002181.
119. Bellizzi V, Di Iorio BR, De Nicola L, et al. Very low
protein diet supplemented with ketoanalogs improves blood
Am J Kidney Dis. 2014;63(2)(suppl 2):S3-S21
pressure control in chronic kidney disease. Kidney Int. 2007;71(3):
245-251.
120. Fouque D, Aparicio M. Eleven reasons to control the
protein intake of patients with chronic kidney disease. Nat Clin
Pract Nephrol. 2007;3(7):383-392.
121. Orth SR, Ogata H, Ritz E. Smoking and the kidney.
Nephrol Dial Transplant. 2000;15(10):1509-1511.
122. Sawicki PT, Didjurgeit U, Muhlhauser I, Bender R,
Heinemann L, Berger M. Smoking is associated with progression
of diabetic nephropathy. Diabetes Care. 1994;17(2):126-131.
123. Bonnet F, Cooper ME. Potential inuence of lipids in
diabetic nephropathy: insights from experimental data and clinical
studies. Diabetes Metab. 2000;26(4):254-264.
124. Gin H, Rigalleau V, Aparicio M. Lipids, protein intake, and
diabetic nephropathy. Diabetes Metab. 2000;26(suppl 4):45-53.
125. Rosario RF, Prabhakar S. Lipids and diabetic nephropa-
thy. Curr Diab Rep. 2006;6(6):455-462.
126. Stojceva-Taneva O, Polenakovic M, Grozdanovski R,
Sikole A. Lipids, protein intake, and progression of diabetic
nephropathy. Nephrol Dial Transplant. 2001;16(suppl 6):90-91.
127. Trevisan R, Dodesini AR, Lepore G. Lipids and renal
disease. J Am Soc Nephrol. 2006;17(4)(suppl 2):S145-S147.
128. Davis TM, Ting R, Best JD, et al. Effects of fenobrate on
renal function in patients with type 2 diabetes mellitus: the
Fenobrate Intervention and Event Lowering in Diabetes (FIELD)
Study. Diabetologia. 2011;54(2):280-290.
129. Ting RD, Keech AC, Drury PL, et al. Benets and safety
of long-term fenobrate therapy in people with type 2 diabetes and
renal impairment: the FIELD Study. Diabetes Care. 2012;35(2):
218-225.
130. Bonds DE, Craven TE, Buse J, et al. Fenobrate-associ-
ated changes in renal function and relationship to clinical out-
comes among individuals with type 2 diabetes: the Action to
Control Cardiovascular Risk in Diabetes (ACCORD) experience.
Diabetologia. 2012;55(6):1641-1650.
131. Gaede P, Lund-Andersen H, Parving HH, Pedersen O.
Effect of a multifactorial intervention on mortality in type 2 dia-
betes. N Engl J Med. 2008;358(6):580-591.
132. Maric C, Hall JE. Obesity, metabolic syndrome and dia-
betic nephropathy. Contrib Nephrol. 2011;170:28-35.
133. Perez G, Devaud N, Escalona A, Downey P. Resolution of
early stage diabetic nephropathy in an obese diabetic patient after
gastric bypass. Obes Surg. 2006;16(10):1388-1391.
134. Amann K, Benz K. Structural renal changes in obesity and
diabetes. Semin Nephrol. 2013;33(1):23-33.
S21