Established and Emerging Strategies in the Treatment

of Chronic Kidney Disease

*

Julio E. Pena-Polanco, MD, and Linda F. Fried, MD, MPH

Summary: Chronic kidney disease (CKD) is a common condition that has become a significant public health
concern. The mainstay therapeutic approach to CKD is based on renin-angiotensin system blockade as well
as blood pressure and glycemic control. Despite these interventions, the management of CKD remains
suboptimal, with a large proportion of the CKD population progressing to end-stage renal disease. Newer
strategies for the treatment of CKD have emerged over the past years focusing on decreasing
inflammation and delaying the development of fibrosis. Despite promising results in experimental
models and small randomized studies, adequately powered randomized trials are required to evaluate the
benefits and risks of these therapies in the CKD population. In this review, we discuss the evidence
behind, and gaps in our knowledge of, established therapies as well as newer potential strategies for
managing CKD, concentrating on interventions that currently are being evaluated in randomized studies.
Semin Nephrol 36:331-342 C 2016 Elsevier Inc. All rights reserved.
Keywords: Chronic kidney disease, progression, renin-angiotensin system

hronic kidney disease (CKD) is a common condition that has become a signicant public
health concern. The mainstay therapeutic
approach to slow progression of CKD is based on reninangiotensin system (RAS) blockade as well as blood
pressure
and
glycemic
control.
These
interventions slow, but do not stop, the progression of
kidney disease. In addition, the benet of standard
therapies varies across stages of CKD.
Newer strategies for the treatment of CKD have
emerged over the past years focusing on different
factors associated with the progression of renal disease.
Medications that target inammation and delay the
development of brosis are being investigated in CKD
with the purpose of preserving renal function and
delaying the progression of this disease.
In this review, we discuss the evidence in support of
established therapies as well as newer potential strategies for the management of CKD.

Department of Medicine, Renal-Electrolyte Division, University of

Pittsburgh School of Medicine, Pittsburgh, PA.

Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, PA.

Epidemiology and Clinical and Translational Science, University

of Pittsburgh, Pittsburgh, PA.
Financial support: none.
Conict of interest statement: Linda Fried is on the steering
committee for the Chronic Kidney Disease Pilot Study Consortium
(National Institute of Diabetes and Digestive and Kidney Diseases), serves as a consultant to Bayer, and is serving as a site
investigator for the Study of Diabetic Nephropathy with Atrasentan (SONAR) (sponsored by AbbVie) and the Pyridorin in
Diabetic Nephropathy study (sponsored by Nephrogenex).
0270-9295/ - see front matter
& 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.semnephrol.2016.05.009

Seminars in Nephrology, Vol 36, No 4, July 2016, pp 331342

ESTABLISHED THERAPIES IN THE TREATMENT OF

CKD
RAS Blockade
RAS blockade has been the cornerstone of treatment of
CKD. Earlier studies showed that RAS blockade
affects renal hemodynamics by decreasing glomerular
intracapillary pressure and decreasing urine protein
excretion. Its benets on progression of renal disease
are independent of its antihypertensive effects.1,2
However, RAS blockade is not a one-ts-all strategy
for all patients with renal disease. The benet of RAS
blockade with an angiotensin-converting
enzyme
inhibitor (ACE-I) or an angiotensin-receptor blocker
(ARB) has been shown most clearly for individuals
with urinary albumin excretion (UAE) greater than 300
mg/g creatinine. In individuals with high levels of
proteinuria, RAS blockade slows the decrease of
glomerular ltration rate (GFR) and progression to
end-stage renal disease (ESRD) by 16% to 56%. The
benet of RAS blockade in individuals with proteinuria has been shown for diabetic kidney disease, hypertensive kidney disease, and glomerular disease.27
The data in favor of RAS blockade are less strong
for individuals with lower levels of albuminuria (30300 mg/g creatinine), especially for individuals without
diabetes. In the Irbesartan in Patients with Type 2
Diabetes and Microalbuminuria (IRMA) study, 590
hypertensive patients with type 2 diabetes and persistent microalbuminuria were randomized to irbesartan
150 mg, irbesartan 300 mg, or placebo daily. The
patients were followed up for 2 years to assess the
development of overt nephropathy dened by UAE
rate 200 mg/min or greater and at least 30% higher than
baseline. After adjustment for baseline levels of microalbuminuria and blood pressure, irbesartan decreased
the risk for overt proteinuria by 44% and 68% in the

331

332
Iron metabolism and anemia in CKD

150-mg and 300-mg groups, respectively. Moreover,

irbesartan restored normoalbuminuria in more patients
compared with placebo.8 However, there was no
difference in loss of kidney function. The Telmisartan
Randomised Assessment Study in ACEI Intolerant
Subjects with Cardiovascular Disease (TRANSCEND)
study looked at the renal effects of telmisartan in
individuals 55 years or older who could not tolerate
ACE-I and who had either documented cardiovascular
disease or diabetes complicated by end-organ damage.
The incidence of the composite outcome of dialysis or
doubling of serum creatinine level was similar across
the telmisartan and placebo treatment groups. Although
this study was a negative for the primary composite
outcome, telmisartan reduced the risk for new microalbuminuria, macroalbuminuria, or both (relative risk,
0.77; 95% condence interval [CI], 0.67-0.88; P
.001) and the progression to macroalbuminuria in
patients with baseline microalbuminuria (relative risk,
0.58; 95% CI, 0.36-0.92; P .018). In a subgroup
analysis, telmisartan reduced the composite renal outcome of dialysis or doubling of serum creatinine level
in patients with microalbuminuria or an eGFR less than
60 mL/min/1.73 m2.9 These observations suggest a
possible role for RAS blockade in patients with mild
levels of albuminuria and CKD.
RAS Blockade and Prevention of CKD

The clinical practice recommendations regarding

RAS blockade among individuals with diabetes and
hyper- tension differ across organizations. Many of their
guide- lines do not differentiate the recommendations
by level of albuminuria (Table 1). Kidney Disease
Outcomes Quality Initiative (KDOQI) clinical practice
guideline for diabetes and CKD and the American
Diabetes Association (ADA) standards of medical care
in diabetes
2015 recommend not using ACE-Is or ARBs for the
primary prevention of diabetic kidney disease in normotensive normoalbuminuric patients with diabetes.10,11
Results of randomized studies evaluating the use of
an ACE-I or ARB to prevent the development of
microalbuminuria in individuals with diabetes are

J.E.P. Polanco and L.F. 332

Fried

mixed. The Diabetic Retinopathy Candesartan Trials

(DIRECT) program evaluated the use of candesartan
versus placebo for the prevention of microalbuminuria
in normotensive, normoalbuminuric individuals with
type 1 diabetes and in normoalbuminuric individuals
with type 2 diabetes regardless of hypertension. The
study found that candesartan had no effect on the
incidence of microalbuminuria over a median followup period of 4.7 years.12 Mauer et al13 evaluated the
effects of RAS blockade on early renal structural
changes from diabetic nephropathy (mesangial fractional volume on renal biopsy) in 285 normotensive
patients with type 1 diabetes and normoalbuminuria.
In this study, patients were randomized to receive
enalapril 20 mg daily, losartan 100 mg daily, or placebo.
The study showed no differences in structural
changes and similar reductions in GFR in all three
groups over a median follow-up period of 5 years.
In contrast, the Bergamo Nephrologic Diabetes
Complications Trial (BENEDICT) compared the
effects of trandolapril in combination with verapamil,
trandolapril alone, verapamil alone, and placebo on the
incidence of microalbuminuria in 1,204 patients with
type 2 diabetes, hypertension, and normoalbuminuria.
This study found that trandolapril plus verapamil and
trandolapril alone reduced the risk of microalbuminuria
compared with placebo (5.7% and 6% versus 10%,
respectively) independent of blood pressure and diabetes control. Verapamil was no different than placebo
(11.9%% versus 10%).14 Similarly, the Randomized
Olmesartan and Diabetes Microalbumin Prevention
(ROADMAP) trial found that olmesartan was associated with a delayed onset of microalbuminuria compared with placebo.15 Olmesartan was more likely to
be effective in patients with higher blood pressure,
lower hemoglobin A1c (HbA1c) levels, lower levels of
renal function, or higher UAE at baseline. However, it
was associated with a higher number of cardiovascular
deaths, particularly in patients with pre-existing coronary heart disease. In the Heart Outcomes and Prevention Evaluation (HOPE) study, patients with
vascular disease or diabetes with at least one other
cardiovascular risk factor or evidence of vascular

Table 1. Recommendations for Treatment of Hypertension in Patients With CKD but Without Albuminuria
Guideline
KDIGO hypertension
KDOQI diabetes
ADA
JNC 8
ACP

Recommendations
No specific recommendation regarding use of ACE-I or ARB if UAE o30 mg/g creatinine
Should be treated with an ACE-I or ARB, usually in combination with a diuretic (CKD stages 1-4,
no differentiation by level of albuminuria)
Use an ACE-I or ARB as first line in all patients with diabetes and hypertension
2
ACE-I or ARB, regardless of race or diabetes status (CKD defined as eGFR o60 mL/min/1.73 m
or by albuminuria 4 30 mg/g creatinine)
Recommend ACE-I or ARB (CKD stages 1-3, do not differentiate by level of albuminuria)

ACP, American College of Physicians; JNC, Joint National Committee; KDIGO, Kidney Disease Improving Global Outcomes.

disease were randomized to ramipril or placebo. In the

subgroup of patients without microalbuminuria at
baseline, ramipril reduced the risk of progression of
proteinuria (dened as new microalbuminuria and new
clinical proteinuria) independently of diabetes (overall
odds ratio, 0.85; 95% CI, 0.75-0.97; P o .05).16 It
may be that the HOPE,
BENEDICT,
and
ROADMAP studies observed benecial effects on the
incidence of proteinuria whereas the DIRECT and the
Mauer et al13 studies did not because of differences in
study partici- pant characteristics. In the studies in
which ACE-I or ARB decreased the incidence of
albuminuria, the subjects had higher blood pressure
and a higher prevalence of vascular disease at baseline.
These differences may indicate greater vascular RAS
activity and, hence, a greater response to RAS
blockade.12
Additional studies of patients without kidney disease
are needed to determine whether RAS blockade can
prevent CKD and who is most likely to benet.

plus lisinopril in type 2 diabetic patients with macroalbuminuria. It showed that combination therapy did
not signicantly decrease cardiovascular, renal, or
mortality events and increased the risk of acute kidney
injury and hyperkalemia.20 Based on these ndings,
dual RAS blockade is not recommended by KDOQI or
the ADA.10,11 Table 2 summarizes the renal effects of
RAS blockade on proteinuria and the progression of
renal disease.
Mineralocorticoid-Receptor Antagonists
Another approach to blocking the renin-angiotensinaldosterone system is to use mineralocorticoid receptor
antagonists (MRAs). Aldosterone has been linked to
the progression of renal disease not only by its effects
on systemic hypertension, but also through its stimulation of cell proliferation and hypertrophy resulting
in brosis and inammation.21 Several studies of
patients with CKD have shown that aldosterone blockade added to standard therapy with ACE-I or ARB
22

Dual RAS Blockade

Recognizing that combination therapy with ACE-I plus

ARB is more effective in reducing proteinuria than
either drug alone,17 investigators assessed the effects of
dual RAS blockade on the progression of kidney
disease.1820 In these studies, dual blockade was not
benecial and was associated with an increased risk of
adverse events. The Ongoing Telmisartan Alone and in
Combination with Ramipril Global Endpoint Trial
(ONTARGET) showed an increase in the composite
primary renal outcome of dialysis, doubling of serum
creatinine level, or death in the combination treatment
group despite improvement in albuminuria.18 The
Aliskiren Trial in Type 2 Diabetes Using Cardiorenal
Endpoints (ALTITUDE) study assessed the effectiveness and safety of aliskiren (direct renin inhibitor)
versus placebo in patients already taking ACE-I or
ARB therapy with respect to cardiovascular and renal
events. The study was terminated early because the
addition of aliskiren did not reduce cardiovascular or
renal outcomes and resulted in an increased number of
adverse events such as hyperkalemia and stroke.19
The Veterans Affairs Nephropathy in Diabetes Study
(VA NEPHRON D) looked at the efcacy of losartan

Table 2. Summary of the Effects of Angiotensin-Converting

Enzyme Inhibitors and Angiotensin-Receptor Blockers on Renal
Disease
Event

Effect

Development of albuminuria
Progression of microalbuminuria to overt proteinuria
GFR loss in nonproteinuric diabetic nephropathy
GFR loss in proteinuric diabetic nephropathy

Likely

further reduces albuminuria. Mehdi et al found that

the addition of spironolactone to maximal doses of
ACE-I in the setting of type 1 or type 2 diabetes with
persistent albuminuria (4300 mg/24 h) was more
effective in reducing albuminuria than the combination
of ACE-I and ARB. The Eplerenone Combination
versus Conventional Agents to Lower Blood Pressure
on Urinary Anti-Albuminuric Treatment Effect
(EVALUATE) trial studied the long-term effects of
low-dose eplerenone (50 mg/day) added to standard
therapy in hypertensive patients with nondiabetic
CKD. Eplerenone was associated with a signicant
reduction in the early morning urinary albumin to
creatinine ratio (UACR).23
However, treatment with MRA often is limited by
the occurrence of hyperkalemia. In the Mehdi et al 22
study, 50% of participants in the spironolactone plus
ACE-I arm had an episode of hyperkalemia (potassium
level, 46.0 mEq/L). Whether the risk-benet ratio can
be changed by the use of patiromer, the recently
approved potassium binder, deserves further study.
The phase 2 Mineralocorticoid Receptor Antagonist
Tolerability Study-Diabetic Nephropathy (ARTS-DN)
study evaluated nerenone, a nonsteroidal MRA,
added to standard RAS blockade in 821 type 2 diabetic
patients with UACR of 30 mg/g creatinine or greater.
The study showed a dose-dependent reduction in
UACR.24 In an earlier study of patients with heart
failure and CKD, the risk of hyperkalemia was less
with nerenone compared with spironolactone.25 Phase
3 studies of nerenone in patients with diabetic kidney
disease are under way. Efcacy and Safety of
Finerenone in Subjects with Type 2 Diabetes Mellitys
and Diabetic Kidney Disease (FIDELIO-DKD)
(NCT02540993) and Efcay and Safety of Finerenone

in Subjects with Type 2 Diabetes Mellitus and

the Clinical Diagnosis of Diabetic Kidney Disease
(FIGARO-DKD) (NCT02545049) will evaluate the
effect of nerenone on the progression of kidney
disease and cardiovascular events.
Despite the improvement of proteinuria with
mineralocorticoid-receptor antagonists, they have not
become a routine part of clinical practice because there
are not enough data on outcomes such as mortality,
development of ESRD, and safety end points,
especially in patients with more severe CKD. The
FIGARO-DKD and FIDELIO-DKD studies promise to
help us to discern whether MRAs are benecial in
diabetic kidney disease.
Blood Pressure Control
Hypertension is one of the most important risk factors
for CKD, however, the target blood pressure remains
controversial. The Joint National Committee 8 recommends a blood pressure goal of less than 140/90 mm
Hg in patients with CKD with or without diabetes or
HTN.26 KDIGO recommends a blood pressure of less
than 140/90 mm Hg in individuals without albuminuria,
but a blood pressure goal of less than 130/80 mm Hg in
individuals with albuminuria greater than 30 mg/g
creatinine.27 Most studies evaluating the association
of blood pressure with progression have been observational. Trial data suggest that a lower blood pressure
goal may be benecial in individuals with overt
proteinuria, but are lacking for individuals with lower
levels of proteinuria.
The Modication of Diet in Renal Disease (MDRD)
study evaluated the effects of protein/phosphorus
intake and blood pressure control on the progression
of CKD. The study showed no overall relationship
between blood pressure and rate of decrease of GFR.
However, individuals with more than 1 g/day of
proteinuria had a slower rate of GFR decrease with
lower blood pressure.28 In the African American Study
of Kidney Disease and Hypertension (AASK), patients
were randomized to a mean arterial pressure goal of
102 to 107 mm Hg or to a lower mean arterial pressure
goal of 92 mm Hg or less. There were no signicant
differences in the mean decrease in GFR and the main
clinical composite outcome of decreasing GFR, ESRD,
or death. Similar to the MDRD study, there was a
benet of lower blood pressure in individuals with
proteinuria, dened as a urine protein to creatinine ratio
greater than 0.22, which corresponds to a urine protein
excretion of approximately 300 mg/day.29
In contrast, the Ramipril Efcacy in Nephropathy-2
(REIN-2) study included patients aged 18 to 70 years
with nondiabetic nephropathy and persistent proteinuria (41 g/day). The cumulative incidence of ESRD,
rate of GFR decline, and residual proteinuria were

similar in the conventional blood pressure control

group (diastolic blood pressure o90 mm Hg, irrespective of systolic blood pressure) versus the intensied
blood pressure control group (o130/80 mm Hg).30
The Systolic Blood Pressure Intervention Trial
(SPRINT) compared two different systolic blood pressure targets of less than 140 mm Hg versus a more
intensive target of less than 120 mm Hg in 9,361
individuals older than age 50 years and an increased
risk of cardiovascular events. There was a 25%
reduction of the primary end point (myocardial infarction, other acute coronary syndromes, stroke, heart
failure, and cardiovascular death) and a lower risk of
all-cause mortality (hazard ratio [HR], 0.73; 95% CI,
0.60-0.90; P .003). In individuals with an eGFR less
than 60 mL/min/1.73 m2, there was no difference in the
composite renal outcome with lower blood pressure,
although the total number of events was small (HR,
0.89; 95% CI, 0.42-1.87; P .76). In contrast, there
was a higher risk of the renal end point in individuals
with an eGFR of 60 mL/min/1.73 m2 or greater
(HR, 3.49; 95% CI, 2.44-5.10; P o .001). Results
by baseline proteinuria level have not yet been
published.31
There are some nuances of the Systolic Blood
Pressure Intervention Trial study that complicate its
interpretation. The disparate ndings in the low and
normal eGFR subgroups deserve comment. In individuals with an eGFR less than 60 mL/min/1.73 m2, the
denition of progression was a conrmed 50%
decrease in eGFR or ESRD; whereas in patients with
an eGFR of 60 mL/min/1.73 m2 or greater it was a
conrmed 30% decrease in eGFR with a decrease to
less than 60 mL/min/1.73 m2. Because more intensive
blood pressure control can have hemodynamic effects
on eGFR, the 30% decrease in eGFR may not have
been large enough. It has been recommended that if
there is a hemodynamic effect on eGFR a 40% rather
than a 30% decrease in eGFR be used.32 Perhaps not
surprisingly, given the hemodynamic effects, there was
also a higher risk of acute kidney injury in the intensive
treatment group (4.4% versus 2.6%; HR, 1.71;
P o .001).
There is a noticeable lack of trial data for lower
blood pressure targets in individuals with diabetic
kidney disease. The Action to Control Cardiovascular
Disease in Diabetes (ACCORD) blood pressure trial
tested the effect of a target systolic blood pressure of
less than 120 mm Hg (intensive treatment group)
versus a systolic blood pressure of less than 140 mm Hg
(standard therapy group) on major cardiovascular
events among patients with diabetes. The intensive
therapy group achieved an average blood pressure of
119.3/64.4 mm Hg compared with 133.5/70.5 mm
Hg in the standard therapy group, but failed to
signicantly
reduce
the rate of the primary
cardiovascular outcome or death from

any cause.33 A subsequent analysis of the ACCORD

blood pressure trial showed no difference in the primary
composite outcome of development of renal failure or
needing retinal photocoagulation or vitrectomy to treat
retinopathy. This analysis also showed a 16%
reduction
in the development of incident microalbuminuria.34
In light of these disparate trial ndings, it is clear
that
the practice of pursuing lower blood pressure
control in
individuals
with
diabetes
and
proteinuria is
based
principally
on
extrapolation
and
observational
studies.
In summary, these studies suggest that lower
blood pressure control is benecial, especially in
individuals with proteinuria. However, there remain
important gaps in our understanding of the relationship
between blood pressure control and renal disease
outcomes.
Glycemic Control
Glycemic control is essential to diabetes management
and has been shown to reduce microvascular complications including diabetic kidney disease. KDOQI
and the ADA recommend decreasing HbA1c to
approximately 7% to reduce the development of these
complications.10,11 However, once advanced complications are present, the guidelines recommend less
stringent glucose control.
The Diabetes Control and Complications Trial
(DCCT) compared the effect of intensive (HbA1c o
6.05%) with conventional diabetes therapy on the
development and progression of early vascular and
neurologic complications among patients with type
1 diabetes for 1 to 5 years. This study showed that
intensive therapy decreases the risk of proteinuria with
a risk reduction of 39% for microalbuminuria and 54%
for clinical albuminuria, dened as UAE of 300 mg/
day or greater.35,36 The benecial effects of intensive
therapy were persistent 7 to 8 years after the end of
DCCT with a reduction of the odds of microalbuminuria by 59% and clinical albuminuria by 84%, even
though the difference in mean HbA1c was only 0.2%
(P .002) between the two treatment groups during
follow-up evaluation (8.0% in intensive treatment
versus 8.2% in conventional treatment).37 A followup analysis of the DCCT study showed a long-term
benet of intensive glucose control on eGFR loss, but
the benet was not seen until after 10 years of followup.38 In newly diagnosed type 2 diabetic patients, the
United Kingdom Prospective Diabetes Study 33
showed a 25% reduction risk of microvascular end
points in the intensive treatment group. The positive
effects of intensive therapy on microalbuminuria and
doubling of the serum creatinine level were evident
only after 9 to 12 years and 12 years of follow-up,
respectively.39

Table 3. Summary of the Effects of Glycemic Control on Renal

Disease
Event

Effect

Development of albuminuria

Progression of microalbuminuria to
overt proteinuria
GFR loss in type 2 diabetes
GFR loss in type 1 diabetes

, long-term effect

Three studies evaluated intensive control in

advanced type 2 diabetes, the Action in Diabetes and
Vascular Disease: Preteraz and Diamicron Modied
Release Controlled Evaluation (ADVANCE)40 (type
2 diabetic patients, target HbA1c level r6.5%),
VA Diabetes Trial (VADT)41 (type 2 diabetic patients,
target HbA1c level o6%), and ACCORD42 (type
2 diabetic patients, target HbA1c level o6%). Each
trial showed a decrease in the risk of development of
albuminuria with intensive glucose control. However,
intensive glycemic control was associated with a
higher incidence of hypoglycemic events, and
increased cardiovascular mortality in the ACCORD
trial. There was no benet with respect to loss of
eGFR, but the studies may have been too short in
duration to see such a benet.
Therefore, in consideration of HbA1c goals and
CKD progression, one needs to consider life expectancy, associated comorbidities, and time course of
kidney disease because the benecial effects of tight
glycemic control on progression of renal disease are
not seen for many years and risk of hypoglycemia in
CKD is higher. Table 3 summarizes the renal effects of
glycemic control on proteinuria and progression of
renal disease.

EMERGING STRATEGIES IN THE TREATMENT OF

CKD
Uric AcidLowering Therapy
Hyperuricemia is highly prevalent in the CKD population. Uric acid is produced as an end-product of
purine catabolism by xanthine oxidase and approximately 70% is excreted in the urine through the
kidneys.43,44 An elevated uric acid level occurs as a
result of increased production or decreased renal
excretion, which is exacerbated further by the use of
diuretics.44,45 There is uncertainty whether hyperuricemia is an important risk factor for CKD progression or
just an indicator of renal dysfunction. Animal studies
have shown that hyperuricemia induces hypertension
and severe preglomerular vascular disease owing
to increased expression of renin and cyclooxygenase
2.46 Xanthine oxidase is known to generate free

oxygen radicals and cause inammation and oxidative

stress.43
Small randomized studies have found that allopurinol slows the progression of renal disease. Siu et al47
evaluated the renal effects of allopurinol (100 or 200
mg, depending on renal function) in 54 hyperuricemic
patients with CKD. More patients in the control group
showed deterioration in kidney function at the end of
the study (P o .015). Goicoechea et al48 randomized
113 patients with CKD (eGFR o60 mL/min/1.73 m2)
to allopurinol or control and followed up these patients
for 24 months. After adjustment for age, sex, diabetes,
uric acid, C-reactive protein levels, RAS blockers,
CKD etiology, and albuminuria, allopurinol slowed
the progression of renal disease (dened as a decrease
40.2 mL/min/1.73 m2 per month) by 47% (HR, 0.53;
95% CI, 0.28-0.99; P .048). A follow-up study of
Goicoechea et al49 showed that at 84 months, allopurinol reduced the rate of renal events (dened as
progression to dialysis therapy or a 50% increase in
creatinine levels) by 68% compared with the control
group (HR, 0.32; 95% CI, 0.15-0.69; P .004). One
trial in progress is the Preventing Early Renal Loss in
Diabetes (PERL) study (NCT02017171). PERL is a
randomized controlled study of the efcacy of allopurinol versus placebo on change in measured GFR in 480
individuals with type 1 diabetes and kidney disease.
Although this study would be a large randomized
study, it is not an end point trial.50 Adequately
powered randomized trials are required to evaluate
the benets and risks of uric acidlowering therapy in
this patient population.
Bicarbonate Therapy
Metabolic acidosis is a well-known complication of
CKD, with an inverse association between the severity
of acidosis and the degree of renal function.51 Acidosis
has been implicated in the progression of renal failure
possibly owing to activation of the alternative complement pathway causing tubulointerstitial inammation
and injury, as a result of increased ammonia production
from compensatory single-nephron ammoniagenesis.51,52 A retrospective study followed up 5,422
participants for a median of 3.4 years and observed
that patients with bicarbonate levels of 22 mEq/L or
less had a 54% increased risk of renal disease progression dened as either a decrease in eGFR by 50%
or reaching an eGFR less than 15 mL/min/1.73 m2,
compared with those in the reference group (25-26
mEq/L).52 Small experimental studies have shown that
correction of acidosis in CKD slows the progression of
chronic renal injury in the 5/6 nephrectomy model53
and that oral sodium bicarbonate reduces protein
catabolism, ammonia production, and tubular damage
in patients with moderate renal failure.54 In one study,

134 patients with CKD and acidosis (bicarbonate levels

416 and o20 mmol/L) were assigned randomly to
receive either oral sodium bicarbonate to achieve and
maintain a level of 23 mmol/L or greater versus routine
care.55 It showed that fewer patients supplemented
with bicarbonate experienced rapid progression
(dened as 43 mL/min/1.73 m2/year) or developed
ESRD. Mahajan et al56 showed that daily oral bicarbonate signicantly reduced the rate of eGFR decrease
compared with sodium chloride or placebo (-1.47
0.19 versus -2.05 0.19 versus -2.13 0.19 mL/min/
1.73 m2/year, respectively) in a cohort of patients with
hypertensive nephropathy, macroalbuminuria (UAE
4200 but o2,000 mg/g creatinine), and CKD
stage 2. In addition, alkali therapy decreases urine
endothelin-1 (ET-1) excretion and urine N-acetyl--Dglucosaminidase, which is a marker of kidney tubulointerstitial injury.56,57 However, alkali therapy and
higher bicarbonate levels were associated with greater
mortality and heart failure in observational studies.58,59
Therefore, larger trials are needed to evaluate the role
bicarbonate supplementation should play in the care of
patients with CKD.
In recognition of the unanswered questions regarding the optimal dose of bicarbonate, the Bicarbonate
Administration to Stabilize Estimated Glomerular
Filtration Rate (BASE) study is evaluating the safety
and tolerability of high and low doses of bicarbonate
supplementation in individuals with CKD and serum
bicarbonate levels of 20 to 28 mEq/L (NCT02521181).
Further information on the reduction of net acid
excretion will be collected. This information will
inform future phase 3 studies of bicarbonate dosing
and its effect on CKD progression.
Endothelin Antagonists
Endothelin is a peptide synthesized by endothelial cells
that acts as a potent vasoconstrictor and modulates
renal blood ow and GFR. It affects mesangial cells,
causing cell contraction, proliferation, and matrix
formation. It also inhibits water reabsorption and
promotes sodium excretion in tubular cells.60 Because
of these vasoconstrictive and probrotic effects,
endothelins could contribute to the pathogenesis and
progression of renal failure. Multiple animal models
of progressive kidney disease have shown an
up-regulation of renal ET-1 gene expression and an
increase in urinary ET-1 excretion. In addition, they
have observed a delay in the progression of renal
disease and a reduction in proteinuria with the use of
endothelin antagonists.6165
Wenzel et al66 investigated the effects of different
doses of avosentan (5, 10, 25, and 50 mg) versus
placebo on the UAE rate in 286 diabetic patients with
macroalbuminuria. Avosentan decreased the median

relative UAE rates by 28.7%, 42.2%, 44.8%, and

40.2%, respectively, versus a 12.1% increase with
placebo. The Avosentan on Time to Doubling of
Serum Creatinine, End-Stage Renal Disease or Death
in Patients with Type 2 Diabetes Mellitus and Diabetic
Nephropathy (ASCEND) study compared avosentan
25 and 50 mg with placebo in type 2 diabetic patients
with overt nephropathy. The study showed a decrease
in proteinuria by 40% to 50% in both avosentan
treatment groups; however, the study was stopped
early owing to a higher rate of cardiovascular events,
mainly congestive heart failure and uid overload,
associated with avosentan treatment.67
Atrasentan is a more selective endothelin Areceptor antagonist that has been shown in phase 2 studies to
decrease UACR signicantly in patients with diabetic
nephropathy treated with RAS blockade therapy.68,69
Atrasentan therapy has been associated with uid
overload in a dose-dependent manner.68,69 Baseline
predictors of weight gain after 2 weeks of atrasentan
treatment included higher doses, lower eGFR, higher
HbA1c level, higher systolic blood pressure, and lower
homeostatic metabolic assessment product, which
measures insulin resistance.70 These ndings suggest
that one may be able to identify a population with
a benecial risk/benet ratio for use of endothelin
antagonists.
Trials with harder clinical outcomes and longer
follow-up evaluations still are needed before this class
of medications can be approved for the management
of proteinuric CKD. The ongoing SONAR study
(NCT01858532) is evaluating the effect of atrasentan
compared with placebo on time to doubling of serum
creatinine level or the onset of ESRD in subjects with
type 2 diabetes and nephropathy on maximum RAS
blockade. The study will exclude individuals with
signicant edema, history of heart failure, or increased
brain natriuretic peptide. It also will study the effects
on cardiovascular morbidity and mortality, urine albumin excretion, and changes in eGFR. This trial will
help us answer whether endothelin blockade slows
progression of kidney disease without the adverse
effect of heart failure.
Newer Glucose-Lowering Agents
The incretin hormones include the glucagon-like peptide-1 (GLP-1) and the gastrointestinal peptide, which
are released from the gut in response to meals. They
play an important role in the regulation of glucose
homeostasis by increasing insulin biosynthesis and
stimulating insulin secretion. In addition, GLP-1 suppresses glucagon secretion, decreases gastric emptying,
and reduces appetite, leading to a reduction in food
intake and weight loss. These hormones have a very
short half-life because they are degraded rapidly by the

dipeptidyl peptidase-4 (DPP-4) enzyme.71,72 In animal

studies, GLP-1receptor agonists and DPP-4 inhibitors
have been shown to ameliorate renal dysfunction and
improve proteinuria by decreasing glomerular hyperltration, extracellular matrix formation, inammation,
and apoptosis.7377 The combination of linagliptin, a
DPP-4 inhibitor, with telmisartan was studied in a
diabetic endothelial nitric oxide synthase knockout
model. The treatment with linagliptin plus telmisartan
signicantly reduced UAE independent of blood pressure control.78
The Saxagliptin Assessment of Vascular Outcomes
Recorded in Patients with Diabetes Mellitus (SAVOR)
Thrombolysis in Myocardial Infarction (TIMI) 53
study evaluated saxagliptin versus placebo in 16,492
individuals
with type 2 diabetes and either
cardiovascular disease or increased risk for vascular
disease. The study excluded individuals with ESRD or
creatinine levels greater than 6.0 mg/dL. However,
only 2% of individuals had a creatinine clearance less
than 30 mL/min. Saxagliptin did not reduce the risk of
doubling of serum creatinine level or ESRD, although
fewer individuals in the saxagliptin arm had worsening
of albuminuria.79
A retrospective analysis using data from the global
linagliptin development program studied the effects on
proteinuria in type 2 diabetic patients with a baseline
UACR between 30 and 3,000 mg/g creatinine, with an
eGFR of 30 mL/min/1.73 m2 or less, and who were
receiving stable doses of an ACE-I or ARB. The study
found a 32% reduction in UACR compared with 6%
with placebo (between-group difference, 28%; 95%
CI, -47 to -2; P .0357). The effect in proteinuria was
independent of changes in HbA1c level and systolic
blood pressure.80 To date, the studies of DPP-4
inhibitors have not shown safety concerns in CKD,
but also have not shown a reduction in CKD
progression. Currently, there are three clinical trials
evaluating the long-term effects of linagliptin on
cardiovascular and renal outcomes in diabetic patients
at increased risk of cardiovascular disease or albuminuria: Cardiovascular and Renal Microvascular
Outcome Study with Linagliptin in Patients with Type
2 Diabetes Mellitus (CARMELINA) (NCT01897532),
Cardiovascular Outcome Study of Linagliptin Versus
Glimepiride in Patients with Type 2 Diabetes (CAROLINA) (NCT01243424), and Efcacy, Safety &
Modication of Albuminuria in Type 2 Diabetes
Subjects with Renal Disease with Linagliptin (MARLINA) (NCT01792518).
The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of medications that work in the
proximal renal tubule by competitively inhibiting
sodium-glucose cotransport. They not only improve
glycemic control by increasing urinary glucose excretion, but also promote weight loss and reduce
blood

pressure.81 Furthermore, SGLT2 inhibitors appear to

slow the progression of kidney disease. Renal effects
may relate to hemodynamic changes caused by modulation of tubuloglomerular
feedback.82
The
Empaglio- zin, Cardiovascular Outcomes, and
Mortality in Type 2
Diabetes (EMPA-REG) study evaluated empagliozin
in individuals with type 2 diabetes with an HbA1c level
greater than 7.0%. Empagliozin reduced the risk of
cardiovascular death and the risk of heart failure.83 The
renal outcomes were presented at the American
Society of Nephrology meeting in 2015, although they
have not been published yet. Empaglifozin reduced
the risk of doubling of serum creatinine level,
ESRD, or renal death by 46%. This agent has shown
to slow progres- sion of kidney disease when added to
standard therapy including an ACE-I or ARB. The
Evaluation of the Effects of Canagliozin on Renal
and Cardiovascular Outcomes in Participants with
Diabetic Nephropathy (CREDENCE) study will
evaluate canagliozin on renal and cardiovascular
outcomes in individuals with protei- nuric diabetic
kidney disease (NCT02065791) and will help assess
whether the renal benet is a class effect of the SGLT2
inhibitors.

which resulted in a signicant mean difference of

4.3 mL/min/1.73 m2 (95% CI, 3.1-5.5 mL/min/
1.73 m2; P o .001). In addition, the UAE increased
by 5.7% (95% CI, -0.3% to 11.1%) in the control
group versus a mean percentage reduction of 14.9%
(95% CI, -20.4% to -9.4%) in patients treated with
PTF, for an overall mean difference of 20.6% (95%
CI, 28.3%-12.9%; P o .001) between groups in favor
of PTF.88 However the trial had some weaknesses. Its
generalizability was limited owing to the fact that it
was an open-label, single-center study with an
all-white study population. The Renoprotection by
Pentoxifylline and Angiotensin Receptor Blocker in
Chronic Kidney Disease Study (NCT01377285) will
be a multicenter, randomized, double-blind, placebocontrolled, clinical trial that will investigate the renoprotective efcacy of combined PTF and valsartan,
compared with placebo and valsartan in diabetic and
nondiabetic patients with stage 3 or 4 CKD. The
primary outcomes will be doubling of serum creatinine
level, ESRD, and death from any cause, as well
as important secondary outcomes such as changes
in microalbuminuria or proteinuria, inammatory
markers, and cardiovascular disease.

Pentoxifylline

Vitamin-Based Therapies

Pentoxifylline (PTF) is a methylxanthine derivate used

for the management of chronic peripheral arterial
disease that increases blood ow to the microcirculation and enhances tissue oxygenation. In addition,
pentoxifylline has antibrotic, antiproliferative, and
anti-inammatory effects. Pentoxifylline decreases
albuminuria in diabetic patients irrespective RAS
blockade.8486 Goicoechea et al87 studied the effects
of PTF on inammatory markers and renal disease
progression in patients with diabetic and nondiabetic
CKD. PTF stabilized renal function and signicantly
decreased inammatory markers such as highsensitivity C-reactive protein, serum brinogen, and
tumor necrosis factor-. Although there was no difference in UAE between groups, in the subset of patients
with diabetic nephropathy there was a reduction in
albuminuria from 1,238 mg/day (range, 935-2,308 mg/
day) to 778 mg/day (range, 50-1723 mg/day) by the
end of the study.87 The Penotxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial was a
randomized prospective study that evaluated the effects
of PTF as an add-on therapy to RAS blockade on renal
disease progression in patients with type 2 diabetes and
stage 3 or 4 CKD. The mean duration of the follow-up
period was 23.6
1.7 months and the primary
outcome was progression of diabetic kidney disease
dened as the change from baseline in eGFR between
groups. The eGFR decreased by a mean
SEM of 2.1
2
0.4 mL/min/1.73 m in patients treated with PTF
versus 6.5 0.4 mL/min/1.73 m2 in the control group,

Pyridoxamine

Diabetes and other chronic conditions are characterized

by an increase in oxidative chemical modication of
tissue proteins and production of advanced glycoxidation and lipoxidation end-products. Pyridoxamine (Pyridorin, Nephrogenex Raleigh, NC) inhibits the
formation of these end-products, limiting the increased
chemical modication of tissue proteins and associated
pathology in aging and chronic diseases including
diabetes and atherosclerosis.89 Phase 2 studies have
looked at the safety and tolerability of pyridoxamine
for 6 months in diabetic patients with overt nephropathy. A combined study found a 48% smaller change
from baseline in serum creatinine level with pyridoxamine compared with placebo (P .0283), with a
greater effect in patients with the most severe renal
impairment and type 2 diabetes (-73%; P .0033).90
Another study was performed to evaluate the effects of
Pyridorin in type 2 diabetic nephropathy while receiving maximum RAS blockade. The study failed to show
any difference in serum creatinine between treatment
groups.91 The Pyridorin in Diabetic Nephropathy study
(NCT02156843) was a multicenter, double-blind,
placebo-control trial designed to evaluate the safety
and efcacy of Pyridorin 300 mg twice daily in
reducing the rate of progression of nephropathy caused
by type 2 diabetes mellitus, but was recently stopped
for nancial reasons.

Table 4. Phases of Clinical Trials

Phase
Phase 1
Phase 2

Phase 3
Phase 4

Purpose
Dose ranging, to determine pharmacokinetics, pharmacodynamics, and determine whether intervention is safe
to continue study
To determine whether study has efficacy, often using surrogate outcomes; also may be dose ranging to
determine which dose to study in phase 3
Determine preliminary safety
To determine therapeutic effect, uses clinical outcome to determine risk/benefit ratio
Postmarketing study

Vitamin Dreceptor agonists

There is a high prevalence of vitamin D deciency in

the CKD population. This is likely multifactorial in
origin owing to poor sunlight exposure with decreased
skin synthesis, dietary restriction of vitamin Drich
food, and urine loss of 25-hydroxycholecalciferol and
vitamin D binding protein in proteinuric nephropathies.
Experimental studies have shown that vitamin D
receptor activation might be renoprotective through
anti-inammatory, antiproliferative, and antibrotic
actions, as well as have antihypertensive effects owing
to decreased renin expression.92 Small, prospective,
randomized, placebo-control trials have shown that
paricalcitol reduces inammation and albuminuria.93,94
The Selective Vitamin D Receptor Activator for
Albuminuria Lowering (VITAL) study was a randomized prospective trial that assessed the efcacy of
paricalcitol in reducing albuminuria among patients
with type 2 diabetes and nephropathy on stable treatment with an ACE-I or ARB. The study showed that
higher doses of paricalcitol, 2 g/day, reduce residual
albuminuria, particularly in patients with high dietary
sodium intake (n 29; P .005). In addition to
decreasing albuminuria, 2 g paricalcitol also
decreased systolic blood pressure and reduced eGFR
(range, -3 to -5 mL/min/1.73 m2; P .001 versus
placebo).95 The forthcoming Salt Intake and Antiproteinuric Effect of Paricalcitol in Type 2 Diabetes
(PROCEED) study (NCT01393808) will evaluate the
interaction between paricalcitol therapy and sodium
intake in patients with type 2 diabetes and proteinuric
kidney disease on stable RAS blockade therapy. The
primary outcome will be the change in urinary albumin
excretion from baseline. Further studies are needed to
show the renoprotective effects of vitamin Dreceptor
agonists.
Evaluation
of harder renal and
cardiovascular outcomes is needed before this class of
medications becomes a mainstay therapy for the
progression of CKD.

CONCLUSIONS
The main therapeutic approaches to slowing progression of kidney disease are blood pressure control and

RAS blockade, which are most effective in individuals

with proteinuria. The benets of glycemic control
accrue over a longer time frame; tight control decreases
the risk of developing CKD, but the benet of a slower
rate of loss of GFR is not observed until after many
years of treatment.
Therapies that target inammation and brosis are
being investigated, although many of the interventions
proposed have not undergone the standard evaluation
including phase 1, phase 2, or phase 3 studies
(Table 4). We need further research focused on
dening the therapeutic agents, study populations,
and dosing regimens to design appropriate phase 3
studies. Despite promising results in experimental
mod- els and small randomized studies, adequately
powered randomized trials will be required to evaluate
the benets and risks of these therapies in the CKD
population.

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