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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.
331
332
Iron metabolism and anemia in CKD
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.
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
Effect
Development of albuminuria
Progression of microalbuminuria to overt proteinuria
GFR loss in nonproteinuric diabetic nephropathy
GFR loss in proteinuric diabetic nephropathy
Likely
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
Pentoxifylline
Vitamin-Based Therapies
Pyridoxamine
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
CONCLUSIONS
The main therapeutic approaches to slowing progression of kidney disease are blood pressure control and
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