Antihypertensive therapy and progression of

nondiabetic chronic kidney disease in adults

Authors: Johannes FE Mann, MD, George L Bakris, MD
Section Editors: Gary C Curhan, MD, ScD, William B White, MD
Deputy Editor: John P Forman, MD, MSc

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: May 2023. | This topic last updated: Dec 16, 2022.

INTRODUCTION

Progression of chronic kidney disease (CKD), as defined by a reduction in the

glomerular filtration rate (GFR), occurs at a variable rate, ranging from less
than 1 to more than 12 mL/min per 1.73 m2 per year, depending upon the
level of blood pressure control, the degree of proteinuria, the previous rate of
GFR decline, and the underlying kidney disease, including diabetes [1-5].

There are two major components to slowing the rate of progression of CKD:
treatment of the underlying disease, if possible; and treatment of secondary
factors that are predictive of progression, such as elevated blood pressure
and proteinuria. (See 'Importance of proteinuria and blood pressure control'
below.)

The clinical trials evaluating antihypertensive therapy in nondiabetic CKD and

our recommendations for choice of therapy as well as treatment goals will be
reviewed here. The animal studies that provided the mechanisms and
rationale for the clinical trials, the treatment of diabetic nephropathy, and
general issues related to the treatment of hypertension in patients with CKD
are discussed separately:

● (See "Antihypertensive therapy and progression of chronic kidney

disease: Experimental studies".)
● (See "Treatment of diabetic kidney disease".)
● (See "Overview of hypertension in acute and chronic kidney disease".)

The approach to slowing the progression of CKD in children is discussed

elsewhere. (See "Chronic kidney disease in children: Overview of
management", section on 'Slow progression of CKD'.)

The timing of administration of antihypertensive therapy (ie, morning versus

evening dosing) in patients with CKD is presented elsewhere. (See "Overview
of hypertension in acute and chronic kidney disease", section on 'Possible
benefit from nocturnal therapy'.)

IMPORTANCE OF PROTEINURIA AND BLOOD PRESSURE

CONTROL

Multiple studies in animals and humans have shown that progression of a

variety of chronic kidney diseases may be largely due to secondary
hemodynamic and metabolic factors, rather than the activity of the
underlying disorder. The major histologic manifestations of these secondary
causes of kidney injury are interstitial fibrosis and focal segmental
glomerulosclerosis (called secondary FSGS), which are superimposed upon
any primary kidney injury that may be present. (See "Focal segmental
glomerulosclerosis: Clinical features and diagnosis".)

Glomerular damage and proteinuria typically occur with progressive chronic

kidney disease (CKD), even in primary tubulointerstitial diseases such as
chronic pyelonephritis due to reflux nephropathy [6]. Conversely, interstitial
fibrosis occurs with progressive CKD, even in the setting of primary
glomerular disease.

Identification of the factors responsible for secondary injury, such as

intraglomerular hypertension, glomerular hypertrophy, and proteinuria
greater than 500 to 1000 mg/day, is clinically important because they can be
treated, slowing disease progression in many patients. (See "Secondary
factors and progression of chronic kidney disease".)

Studies of antihypertensive therapy in proteinuric nondiabetic CKD have

focused on two areas: short-term reduction in protein excretion; and long-
term protection against progressive decline in glomerular filtration rate (GFR).
Data are limited on nonproteinuric CKD, defined as CKD associated with urine
protein excretion less than 500 to 1000 mg/day. Among patients with
proteinuric CKD, the preferred antihypertensive agents are drugs that block
the renin-angiotensin system, such as angiotensin-converting enzyme
inhibitors and, at least in patients with type 2 diabetes, angiotensin II
receptor blockers [2,4,5].

Importance of proteinuria and the proteinuric response — In patients

with CKD, higher degrees of urinary protein excretion are associated with a
more rapid decline in GFR, regardless of the primary cause of the kidney
disease and the initial GFR ( figure 1). In addition to the initial urinary
protein excretion, a number of studies have reported correlations between
reduction in proteinuria with antihypertensive therapy and slower
progression of the kidney disease. (See 'The proteinuric response as a
predictor of outcome' below.)

Importance of blood pressure control — Observational studies show that

patients with CKD and a normal blood pressure have better preservation of
glomerular filtration rate (GFR) than hypertensive patients [7]. Interventional
studies show that lower blood pressure targets (below 130/80 mmHg) are
associated with better kidney outcomes in patients with proteinuric CKD
(defined as urine protein excretion greater than 500 to 1000 mg/day) [8]. (See
'Effect of goal blood pressure on progression of CKD' below.)

EFFECT OF ANTIHYPERTENSIVE DRUGS ON PROTEINURIA

The effect of antihypertensive drugs on proteinuria varies with drug class.

When the blood pressure is controlled, renin-angiotensin system (RAS)
inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs) are more effective than other
antihypertensive drugs in reducing proteinuria and in slowing the rate
progression of proteinuric chronic kidney disease (CKD), regardless of
etiology [3]. These benefits can be demonstrated even in patients who are not
hypertensive and in those with diabetic nephropathy. (See 'Effect of renin-
angiotensin system inhibitors on progression of CKD' below and "Treatment
of diabetic kidney disease".)

The generally greater antiproteinuric effect seen with the ACE inhibitors and
ARBs is compatible with a greater fall in intraglomerular pressure, which has
been demonstrated in animal models of proteinuric CKD [9,10]. This effect is
mediated in part by dilation of both efferent and afferent glomerular
arterioles, rather than only the afferent arterioles as occurs with other classes
of antihypertensive drugs. (See "Antihypertensive therapy and progression of
chronic kidney disease: Experimental studies".)

Renin-angiotensin system inhibitors — A number of trials have identified a

preferential benefit of renin-angiotensin system (RAS) inhibitors in reducing
proteinuria, compared with other antihypertensive drugs. The rationale
behind these studies is the observation that protein excretion varies directly
with the intraglomerular pressure in animals with structural glomerular
disease [11].
In addition to the reduction in intraglomerular pressure, a variety of other
mechanisms may contribute to RAS inhibitor-induced reductions in
proteinuria. These include:

● Direct improvement in the permselective properties of the glomerulus by

ACE inhibitors, independent of changes in glomerular hemodynamics
[12-14]. The following findings support this hypothesis:

• Protein excretion progressively declines over weeks to several months,

whereas the hemodynamic effects of ACE inhibition occur rapidly and
are then stable [15].

• Acute administration of angiotensin II does not reverse the

antiproteinuric effect, despite inducing renal and systemic
vasoconstriction, and increasing intraglomerular pressure [16].

• In transgenic rats, overexpression of the angiotensin II receptor (type

1) in glomerular podocytes results in significant proteinuria, foot
process effacement, and glomerulosclerosis [17].

• Angiotensin II reduces the expression of nephrin, a major component

of the podocyte slit pore membrane and an important contributor to
the glomerular filtration barrier [18]. By contrast, nephrin expression is
increased by ACE inhibitor therapy [19].

● ACE inhibitors have an antifibrotic effect, which could contribute to the

slowing of kidney disease progression. (See "Secondary factors and
progression of chronic kidney disease", section on 'Tubulointerstitial
fibrosis'.)

● The fall in protein excretion induced by RAS inhibitors (and some other
antihypertensive drugs described below) may be associated with a
reduction in serum lipid levels, which may reduce both the risk of
 systemic atherosclerosis and the rate of kidney disease progression. (See
"Secondary factors and progression of chronic kidney disease".)

ACE inhibitors and ARBs have important side effects in patients with CKD,
including the potential to induce hyperkalemia. The risk is low if the
glomerular filtration rate is greater than 40 mL/min per 1.73 m2 and the initial
serum potassium is in the low to normal range, and risk is even lower if a
diuretic is also given [20]. They can also acutely reduce the glomerular
filtration rate, particularly if the patient is hypovolemic. (See "Major side
effects of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers".)

ACE inhibitors — ACE inhibitors generally reduce protein excretion by

approximately 30 to 35 percent in patients with nondiabetic or diabetic CKD
[21-25]. The antiproteinuric effect is most prominent in patients who are on a
low-sodium diet or who are treated with diuretics since relative volume
depletion results in greater angiotensin II dependence of the glomerular
microcirculation [23,26]. (See 'Importance of salt intake' below.)

It is unclear whether the ACE inhibitor dose associated with a maximal

antihypertensive effect is the same as that required for an optimal
antiproteinuric effect. This issue was addressed in a study of 23 proteinuric
patients with nondiabetic kidney disease who were given increasing doses of
spirapril for maximal antihypertensive effect (median dose of 6 mg/day), as
assessed by ambulatory blood pressure monitoring [27]. This dose reduced
proteinuria from a mean of 2.56 to 1.73 g/day. An additional increase of
spirapril to a supramaximal dose (median dose of 12 mg/day) failed to further
decrease either blood pressure or proteinuria. In contrast to these findings,
other studies have reported a dissociation between the doses required for
optimal antihypertensive and antiproteinuric effects, suggesting that the
amounts necessary for these two benefits are likely to vary among patients
[28].

Angiotensin II receptor blockers — The antiproteinuric effect of

angiotensin II receptor blockers (ARBs) has been demonstrated in patients
with diabetic and nondiabetic CKD. Their effect on slowing progression of GFR
decline has been best demonstrated in diabetic kidney disease. It seems likely
that they will have a similar renoprotective effect as ACE inhibitors in
nondiabetic CKD but supportive data are limited [29]. (See "Treatment of
diabetic kidney disease".)

Studies in humans have found that ARBs are as effective as ACE inhibitors in
reducing protein excretion in patients with CKD [14,21,30,31]. In a 2008 meta-
analysis of 49 randomized trials (mostly small), the reduction in proteinuria at
5 to 12 months was similar with ARBs and ACE inhibitors (ratio of means 1.08,
95% CI 0.96-1.22) [21].

As with ACE inhibition, there appears to be a dose effect, with greater

reduction of proteinuria at higher (even supramaximal) doses in both
nondiabetic and diabetic patients [32-35]. In the SMART trial, for example, 269
patients with proteinuria greater than 1 g/day despite seven weeks of the
maximum approved dose of candesartan (16 mg/day) were randomly
assigned to candesartan at a dose of 16, 64, or 128 mg/day [35]. Patients who
received 128 mg/day had a significantly greater reduction in proteinuria at 30
weeks compared with those who received 16 mg/day (mean difference 33
percent). The blood pressure was not different between groups. Although
hyperkalemia required the withdrawal of 11 patients from the trial, there was
no difference in the incidence of hyperkalemia between groups. Such high-
dose therapy is not typically used in clinical practice.

ACE inhibitor plus ARB — The reduction in proteinuria appears to be

greater when ACE inhibitors are used in combination with ARBs than with
either drug alone, although no study has compared combination therapy with
doubling the dose of a single agent [21]. However, it has not been proven that
combination therapy improves kidney outcomes and adverse effects may be
more common. (See 'Combination of ACE inhibitors and ARBs' below.)

Other antihypertensive drugs — Other antihypertensive drugs have a

variable effect on protein excretion. These drugs may be used in addition to
RAS-inhibitors to further reduce protein excretion but only one trial (AASK)
has evaluated the efficacy of such regimens on the rate of disease
progression in patients with nondiabetic CKD. (See 'AASK trial of
antihypertensive therapy' below.)

Calcium channel blockers — The non-dihydropyridine calcium channel

blockers, such as diltiazem and verapamil, have significant antiproteinuric
effects in patients with proteinuria [22,36,37]. By comparison, the
dihydropyridines, such as amlodipine and nifedipine, have a variable effect on
proteinuria, ranging from an increase to no effect to a fall in protein excretion
[21,36,38].

Differences between non-dihydropyridine and dihydropyridine calcium

channel blockers were illustrated in a systematic review of 23 studies that
adjusted for sample size, study length, and baseline values [36]. Based upon
an analysis of monotherapy in 510 patients, non-dihydropyridines decreased
mean proteinuria by 30 percent and dihydropyridines increased proteinuria
by 2 percent (95% CI 10-54% for the differences between the two drug
classes). Similar observations were noted when these agents were used in
combination with ACE inhibitors or ARBs: despite similar reductions in blood
pressure, the mean change in proteinuria was -39 and +2 percent for non-
dihydropyridines and dihydropyridines, respectively.

The mechanisms underlying this varied effect on proteinuria may include

preferential afferent arteriolar dilatation with dihydropyridines, which allows
more of the aortic pressure to be transmitted to the glomerulus, and
differential abilities of the non-dihydropyridine and dihydropyridine calcium
channel blockers to alter renal autoregulation, the permeability of the
glomerulus, and perhaps other factors [36].

Mineralocorticoid receptor antagonists — Mineralocorticoid receptor

antagonists further reduce protein excretion when added to an ACE inhibitor
and/or ARB [39-44]. The following are findings from a meta-analysis that
included seven trials in which patients were treated with an ACE inhibitor
and/or ARB plus either spironolactone (usually 25 mg/day) or placebo [40]:

● There was a significantly greater reduction in proteinuria in the

spironolactone group (weighted mean difference 800 mg/day, 95% CI
330-1270 mg/day).

● The patients treated with spironolactone also had a modestly but

significantly lower systolic pressure (3.4 mmHg).

● Short-term changes in estimated GFR (less than one year of follow-up)

were similar with spironolactone and placebo.

However, most of these studies did not first maximize the dose of the ACE
inhibitor or ARB, and the mineralocorticoid receptor antagonist was
associated with an increased risk of hyperkalemia in this meta-analysis (7.0
versus 2.6 percent) [40]. Long-term trials are required to determine whether
spironolactone or eplerenone slows the rate of progression of the kidney
disease.

The nonsteroidal mineralocorticoid receptor antagonist finerenone slows the

progression of kidney disease in patients with diabetes and causes less
hyperkalemia than steroidal agents (ie, spironolactone, eplerenone). The use
of finerenone in patients with diabetic kidney disease is presented in detail
elsewhere. (See "Treatment of diabetic kidney disease".)
Direct renin inhibitors — Direct renin inhibitors further reduce proteinuria
when added to an ACE inhibitor or ARB. However, this does not appear to
translate into clinical benefit. These issues are discussed in detail elsewhere.
(See "Renin-angiotensin system inhibition in the treatment of hypertension",
section on 'Direct renin inhibitors'.)

Drugs with little or no effect — Other antihypertensive drugs have little or

no effect on protein excretion [22,24,25]. As an example, beta blockers,
diuretics, and the alpha-1-blockers (prazosin, terazosin, doxazosin) typically
have a lesser antiproteinuric effect than RAS inhibitors [22,24,25]. In a 1995
meta-analysis, ACE inhibitors lowered protein excretion by 40 percent
compared with 16 percent for beta blockers and 14 percent for other, non-
calcium channel blocker antihypertensive drugs [22]. Sympathetic blockers,
such as methyldopa and guanfacine, had little effect on protein excretion.

Importance of salt intake — In patients with CKD, a high sodium intake

(above approximately 5.5 g/day [14 g of sodium chloride]) is associated with a
higher risk of having a cardiovascular event, including heart failure,
myocardial infarction, and stroke [45]. The effect of sodium reduction on
cardiovascular disease is presented in detail separately. (See "Salt intake, salt
restriction, and primary (essential) hypertension".)

In addition, in patients with proteinuric CKD, the antiproteinuric effect of RAS

inhibitors and non-dihydropyridine calcium channel blockers is greatly
impaired with a high salt intake, even when blood pressure control seems
reasonable, and is enhanced with salt restriction [23,46-53]. The benefits of
RAS inhibitors on prevention of end-stage kidney disease (ESKD) in patients
with proteinuric CKD may also be enhanced by a low-salt diet and/or
mitigated by a high-salt diet [51-53]. Similar findings are seen in diabetic
nephropathy. (See "Treatment of diabetic kidney disease".)

The following examples illustrate the range of findings:

● A crossover trial (HONEST) included 52 patients with proteinuric CKD
(mean protein excretion 1.6 g/day, mean creatinine clearance 70
mL/min), all of whom were treated with lisinopril [46]. Four treatments
were given in random order, each for six weeks: a low-sodium diet with
placebo; a low-sodium diet with valsartan; a regular-sodium diet with
placebo; and a regular-sodium diet with valsartan. Compared with a
regular-sodium diet (mean urinary sodium excretion 184 mEq/day), a
low-sodium diet (mean 106 mEq/day) decreased mean daily protein
excretion to a significantly greater degree than the addition of valsartan
(51 versus 21 percent). Addition of valsartan produced a minimal
additional reduction in protein excretion beyond a low-sodium diet.

A similar difference was noted with blood pressure control. A low-sodium

diet reduced the mean systolic pressure from 134 at baseline to 123
mmHg, while the addition of valsartan to either a regular or low-sodium
diet reduced blood pressure by only 2 to 3 mmHg.

● A high-sodium diet was associated with both a blunting of the proteinuria

reduction induced by the ACE inhibitor ramipril and a higher incidence of
ESKD in 500 proteinuric CKD patients enrolled in the REIN and REIN-2
trials [51]. Patients on a high-sodium diet (defined as a 24-hour urinary
sodium excretion greater than 250 mmol of sodium [14 grams of salt] per
day) had the following adverse outcomes compared with patients on a
low-sodium diet (defined as a 24-hour urinary sodium excretion less than
125 mmol of sodium [7 grams of salt] per day):

• A significantly smaller reduction in proteinuria in response to ramipril

therapy at three months (20 versus 31 percent). In patients on a lower-
sodium diet, this initial three-month reduction in proteinuria persisted
over the entire four-year study period. However, the initial reduction in
 proteinuria waned in patients on a high-sodium diet, and returned to
pre-ramipril levels by the end of the study.

• A significantly higher incidence of ESKD (32 versus 16 percent). This

higher risk of ESKD with a high-sodium diet was independent of age,
sex, cause of kidney disease, and blood pressure. However, the
association was attenuated after controlling for changes in
proteinuria, suggesting that a high-sodium diet mitigated the
beneficial effects of the ACE inhibitor.

Thus, patients treated with ACE inhibitors or ARBs who do not have a
sufficient reduction in protein excretion despite reaching goal blood pressure
should be instructed to follow a low-salt diet. An assessment of baseline
sodium intake can be achieved by obtaining a 24-hour urine collection for
sodium and creatinine (creatinine excretion is used to assess the
completeness of the collection; the expected normal values are discussed
elsewhere). If, after several months, the reduction in protein excretion is less
than desired, the 24-hour urine collection can be repeated to determine
whether a low-salt diet has been attained. Measuring 24-hour urine sodium
several times increases precision of estimating intake. (See "Patient
education: Collection of a 24-hour urine specimen (Beyond the Basics)" and
"Assessment of kidney function".)

If a low-salt diet is not achieved, administration of a diuretic can enhance the

antiproteinuric effect of RAS inhibitors [54,55]. Among patients treated with
an ACE inhibitor or ARB, the combination of salt restriction and a diuretic may
provide a greater antiproteinuric effect and more blood pressure reduction
than either intervention alone [56].

The effects of salt intake and salt restriction on blood pressure and the
efficacy of antihypertensive medications are discussed separately. (See "Salt
intake, salt restriction, and primary (essential) hypertension".)
EFFECT OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS ON
PROGRESSION OF CKD

Clinical trials have demonstrated a benefit of antihypertensive therapy with

renin-angiotensin system (RAS) inhibitors, mostly angiotensin-converting
enzyme (ACE) inhibitors, in patients with proteinuric nondiabetic chronic
kidney disease (CKD). The renoprotective effect of angiotensin II receptor
blockers (ARBs) has been best demonstrated in patients with diabetic
nephropathy. It seems likely that they have a similar renoprotective effect as
ACE inhibitors in nondiabetic CKD but supportive data are limited [29]. (See
"Treatment of diabetic kidney disease".)

This section will review the trials, and meta-analyses of such trials, that
evaluated the efficacy of RAS inhibitors compared with other antihypertensive
drugs on the progression of nondiabetic CKD. The trials that evaluated the
importance of goal blood pressure in such patients are discussed below. (See
'Effect of goal blood pressure on progression of CKD' below.)

Meta-analyses — Meta-analyses of randomized trials, including those trials

presented below, provide evidence in support of a preferential benefit with
ACE inhibitors in proteinuric patients [8,57-62]. In a representative meta-
analysis, patient-level data were analyzed from 11 randomized, controlled
trials that enrolled 1860 nondiabetic patients with CKD; the alternative
treatments were other antihypertensive drugs and placebo [58]. After
statistical adjustments, ACE inhibitor therapy compared with the alternative
treatments was associated with significant reductions in the rate of
progression to end-stage kidney disease (ESKD) (7.4 versus 11.6 percent,
relative risk 0.69, 95% CI 0.51-0.94), while that for doubling of the baseline
serum creatinine concentration or ESKD was 13.2 versus 20.5 percent (relative
risk 0.70, 95% CI 0.55-0.88). The benefits of ACE inhibitors increased with
increasing baseline proteinuria and were insignificant in patients with
proteinuria below 500 to 1000 mg/day [60]. ACE inhibitors were also
associated with a significantly larger reduction in blood pressure (4.5 versus
2.3 mmHg), although this may be due to the fact that ACE inhibitors were
compared with placebo in 5 of the 11 trials.

The benefits of ACE inhibitors and ARBs on CKD progression in proteinuric

patients was confirmed in a meta-analysis of 12 trials that included patients
with severely increased albuminuria (formerly called "macroalbuminuria") or
a combination of severely increased albuminuria and moderately increased
albuminuria (formerly called "microalbuminuria") [63]. Compared with other
antihypertensive drugs, therapy with ACE inhibitors resulted in a significantly
lower incidence of ESKD (2.6 versus 3.8 percent; relative risk 0.67, 95% CI 0.54-
0.84). ARB therapy also reduced the incidence of ESKD compared with other
drugs (14 versus 18 percent; relative risk 0.78, 95% CI 0.66-0.90).

Additional analyses of these trials from the same research group found that
the risk of progression increased with higher baseline systolic pressures
above 120 mmHg and increasing proteinuria above 1000 mg/day [8,60].
There was no evidence of benefit on kidney function preservation from ACE
inhibitors or ARBs, or with systolic pressures below 120 mmHg, in patients
with proteinuria less than 500 mg/day [60]. (See 'Proteinuria goal' below and
'Blood pressure goal' below.)

Benazepril trial — The Benazepril trial included 583 patients with a variety of
chronic nondiabetic kidney diseases [64]. The patients were already in
reasonable blood pressure control on a variety of different medications and
were then randomly assigned to benazepril or placebo in addition to their
usual antihypertensive regimen. At baseline, the mean serum creatinine was
2.1 mg/dL (186 micromol/L) and mean protein excretion was 1.8 g/day.

The following results were noted:

● The mean attained blood pressure during the trial was significantly lower
with benazepril than with placebo (135/84 versus 144/88 mmHg).

● Benazepril therapy reduced protein excretion by 25 percent compared

with placebo.

● Progression to the primary endpoint (defined as doubling of the serum

creatinine concentration or progression to dialysis) occurred in 31 of 300
patients treated with benazepril versus 57 of 283 in the placebo group.
The relative risk reduction was 53 percent in the entire group, 71 percent
in those with a baseline creatinine clearance above 45 mL/min, and 46
percent in those with a baseline creatinine clearance ≤45 mL/min.

● There was benefit in patients with chronic glomerular diseases and in the
few patients with diabetic nephropathy who were enrolled; the findings
were inconclusive in hypertensive nephrosclerosis because too few
events occurred. Subsequent trials have shown that ACE inhibitors are
associated with a slower rate of decline in glomerular filtration rate in
proteinuric patients with primary hypertension (formerly called
"essential" hypertension) and in proteinuric Black patients with benign
hypertensive nephrosclerosis compared with a beta blocker or calcium
channel blocker therapy, despite equivalent degrees of blood pressure
control. (See 'AASK trial of antihypertensive therapy' below.)

● Benazepril had no benefit in the 64 patients with polycystic kidney

disease or in patients with protein excretion below 1000 mg/day, two
settings in which hemodynamically-mediated glomerular disease does
not appear to be prominent. (See "Autosomal dominant polycystic kidney
disease (ADPKD): Treatment", section on 'Management of blood
pressure'.)
REIN trial — A benefit was also noted in a report from the Ramipril Efficacy In
Nephropathy (REIN) trial in which patients with nondiabetic CKD were
randomly assigned to ramipril or placebo plus other antihypertensive therapy
to attain a diastolic pressure below 90 mmHg [65]. At baseline, the mean
serum creatinine was 2.4 mg/dL (212 micromol/L) and mean protein excretion
was 5.3 g/day.

The degree of blood pressure control was the same in both groups. The trial
was terminated prematurely in patients excreting more than 3 grams of
protein per day because of a significant benefit with ACE inhibition in
ameliorating the rate of decline of kidney function (0.53 versus 0.88 mL/min
per month for placebo).

Whether these benefits with ramipril continued over time in patients

excreting more than 3 grams of protein per day was addressed in an
observational follow-up study of those initially enrolled in the trial phase [66].
The rate of decline of kidney function and the need for dialysis were the
principal outcomes assessed in patients who continued to receive ramipril (51
patients) and in those originally randomized to conventional antihypertensive
therapy plus placebo who were switched to ramipril at the beginning of the
observational follow-up (46 patients) [66]. At 20 months (and at 44 months for
the trial phase and observational follow-up combined), the following benefits
were noted:

● The mean rate of decline of the glomerular filtration rate (GFR) decreased
from 0.44 to 0.10 mL/min per 1.73 m2 for patients originally randomized
to ramipril, and from 0.81 to 0.14 mL/min per 1.73 m2 for those not
originally given ramipril.

● At the end of the observational follow-up, the group originally

randomized to ramipril had a significantly higher GFR (35.5 versus 23.8
mL/min per 1.73 m2).
 ● During the entire 44 month period of follow-up (including the trial and
observational phases), the incidence of ESKD was significantly lower in
those patients originally assigned to ramipril compared with those
originally assigned to other antihypertensive drugs and then switched to
ramipril (19 versus 35 percent).

Additional follow-up at 60 months found that some patients on continued

ramipril therapy even had increased GFR compared with baseline values [67].

Post-hoc analyses of the REIN trial evaluated the benefits of ramipril in

patients with varying degrees of proteinuria and reductions in GFR [68,69]:

● The administration of ramipril to patients with a GFR less than 45 mL/min

and proteinuria between 1.5 and 3 g/day resulted in a significantly lower
rate of decline in GFR (-0.31 versus -0.40 mL/min/1.73 m2 per month for
other therapy) and a decreased incidence of ESKD (18 versus 52 percent)
[68].

● Kidney benefits of ramipril were observed whether the initial (baseline)

GFR was within the lowest (11 to 33 mL/min/1.73 m2), middle (33 to 51
mL/min/1.73 m2), or highest tertile (51 to 101 mL/min/1.73 m2).
Compared with other drugs, ramipril therapy decreased the rate of GFR
decline by 20, 22, and 35 percent, respectively, and the incidence of ESKD
by 33, 37, and 100 percent, respectively [69]. The incidence of adverse
events was similar across the tertiles and within each tertile for the
ramipril and other treatment groups.

Thus, the original and follow-up ramipril studies strongly suggest that
patients who particularly benefit are those with prominent proteinuria, a
finding similar to that noted in other trials [65-68,70,71]. Significant benefit
was also seen in patients with non-nephrotic proteinuria (1.0 to 2.9 g/day)
[68].
Relative benefits from ramipril also appear to be independent of the initial
GFR, but absolute benefits are greater when initiated earlier in the course of
kidney disease. Given that many patients had significant kidney function
impairment (eg, the lowest tertile had a GFR between 11 to 33 mL/min/1.73
m2), the low incidence of adverse effects with ramipril reflects the exclusion of
patients with evidence of hypovolemia and renal artery stenosis, as well as
the discontinuation of diuretics prior to initiating ACE inhibitor therapy.

REIN-2 trial — A lack of renoprotection with a dihydropyridine calcium

channel blocker, even when used as add-on therapy to an ACE inhibitor to
attain aggressive blood pressure control, was found in the REIN-2 trial of
patients with nondiabetic proteinuric CKD (mean baseline GFR 35 mL/min and
mean proteinuria 2.9 g/day) [72]. In this trial, 335 patients receiving ramipril
(2.5 to 5 mg/day) were randomly assigned to conventional (diastolic pressure
less than 90 mmHg) or intensified (<130/80 mmHg) blood pressure control,
with felodipine added to attain the lower blood pressure target level.
Achieved mean arterial blood pressures were 96.2 and 99.5 mmHg,
respectively (corresponding to 130/80 and 134/82 mmHg, respectively).

At a median follow-up of 19 months, no significant differences were noted in

the proportion of patients who progressed to ESKD (23 and 20 percent),
decline in glomerular filtration rate, and effects on proteinuria.

These findings are consistent with previous observations showing that

dihydropyridine calcium channel blockers fail to provide renoprotection in
patients with nondiabetic proteinuric kidney disease, even with further blood
pressure reduction from that obtained with fixed doses of ACE inhibitors.

AASK trial of antihypertensive therapy — The African American Study of

Kidney Disease and Hypertension (AASK) trial included 1094 African American
patients with hypertensive kidney disease. The mean glomerular filtration
rate was 46 (range 20 to 65) mL/min per 1.73 m2 and mean protein excretion
was approximately 600 mg/day in males and 400 mg/day in females. In
African Americans with long-standing hypertension, otherwise unexplained
progressive CKD with mild proteinuria is almost always associated with
histologic changes compatible with hypertensive nephrosclerosis as the sole
disease [73].

The patients were randomly assigned to three different antihypertensive

drugs and to two different blood pressure goals. The data on goal blood
pressure are presented below. (See 'AASK trial of goal blood pressure' below.)

Patients were randomly assigned to treatment with an ACE inhibitor (ramipril,

2.5 to 10 mg/day), a calcium channel blocker (amlodipine, 5 to 10 mg/day), or
a beta blocker (metoprolol, 50 to 200 mg day); other antihypertensive drugs
were added to initial monotherapy to achieve the blood pressure goals [38].
The primary outcome was the rate of change in glomerular filtration rate
(GFR); the main secondary outcome was a composite endpoint of: reduction
in GFR of more than 50 percent or more than 25 mL/min per 1.73 m2; ESKD;
or death.

The three-year rate of decline in GFR was similar with ramipril and amlodipine
therapy. However, compared with amlodipine, and after adjustment for
baseline covariates, ramipril significantly reduced the relative risk of the
composite endpoint by 38 percent.

Importantly, the relative efficacy of ramipril compared with amlodipine at

three years varied with the degree of proteinuria at baseline:

● Approximately one-third of patients had a urine protein-to-creatinine

ratio of >0.22 (this protein-to-creatinine ratio is approximately equivalent
to 300 mg protein in 24 hours); the mean protein excretion in this
subgroup was 1.5 g/day in males and 1.2 g/day in females. In these
proteinuric patients, ramipril led to a significant 36 percent reduction in
 the rate of decline in GFR (2.0 mL/min per year) and a significant 48
percent reduction in the composite endpoint.

● In those patients who had a urine protein-to-creatinine ratio of 0.22 or

less, there was no significant difference in mean decline in GFR or the
composite clinical endpoint among the treatment groups.

The final results at four years of follow-up showed no difference among the
drug groups in reducing the rate of decline of GFR. However, the incidence of
the composite endpoint was significantly lower in those treated with ramipril
than with amlodipine (6.9 versus 8.2 percent per year) or metoprolol (6.9
versus 8.7 percent per year) [74]. (See "Clinical features, diagnosis, and
treatment of hypertensive nephrosclerosis", section on 'Choice of
antihypertensive agent'.)

After completion of the AASK trial, all of the participants were invited to enroll
in a cohort phase during which ramipril was prescribed to everyone. After five
years of additional follow-up during the cohort phase, progression of
nephropathy was significantly slowed but not stopped [75,76]. Compared
with patients with controlled clinic blood pressure or white coat hypertension
(ie, hypertension in the doctor's office but not at home), target organ damage
(proteinuria, left ventricular hypertrophy) was more likely in patients with
elevated blood pressure at night despite good blood pressure control in the
office, masked hypertension (which refers to patients with normal office
blood pressure who are hypertensive during the day on ambulatory
monitoring), isolated ambulatory hypertension, or sustained hypertension
[76]. (See "Out-of-office blood pressure measurement: Ambulatory and self-
measured blood pressure monitoring".)

Use in advanced disease — A question that is often asked is whether the

benefit from ACE inhibitors or ARBs extends to patients with advanced CKD,
particularly given the increased risk of hyperkalemia. Stated differently, is
there a serum creatinine concentration above which one would not use such
therapy? The answer to this question appears to be no, except for truly end-
stage disease.

The potential value of RAS inhibition in advanced disease was best shown in a
Chinese study in which 422 patients with nondiabetic CKD were randomly
assigned to benazepril or placebo plus other antihypertensive therapy to
attain a systolic and diastolic pressure below 130 and 80 mmHg, respectively
[77]. Based upon the baseline serum creatinine concentration, patients were
divided into two groups:

● Group 1 consisted of 141 patients with a serum creatinine concentration

between 1.5 to 3.0 mg/dL (133 to 265 micromol/L). The mean estimated
glomerular filtration rate (GFR) and level of proteinuria were 37 mL/min
per 1.73 m2 and 1.6 g/day, respectively.

● Group 2 consisted of 281 patients with a serum creatinine concentration

between 3.1 to 5.0 mg/dL (274 to 442 micromol/L). The mean estimated
GFR and proteinuria were approximately 26 mL/min per 1.73 m2 and 1.6
g/day.

All patients had an eight-week run-in period in which they received benazepril
at 10 mg/day for four weeks; they were closely monitored with weekly
measurements of serum creatinine and potassium levels and blood pressure;
the dose was increased to 10 mg twice daily if the serum creatinine
concentration increased less than 30 percent, the serum potassium remained
below 5.6 mEq/L, and no adverse effects occurred. During this period, 94
patients were excluded from further study because of dry cough, marked
changes in kidney function, severe hyperkalemia, or poor adherence. Thus,
the study group was highly selected.
All 104 remaining patients in group 1 received benazepril (at 10 mg twice
daily, since it was deemed unethical to administer placebo), while the 224
patients remaining in group 2 were randomly assigned to benazepril (10 mg
twice daily) or placebo. Additional antihypertensive therapy was administered
to attain blood pressure goals. The primary endpoint was the composite of
doubling of the serum creatinine level, ESKD, or death, while secondary
endpoints were change in proteinuria and rate of progression of the kidney
disease.

The following results were noted at a mean follow-up of 3.4 years:

● Significantly fewer group 2 patients (mean GFR of 26 mL/min per 1.73 m2)
treated with benazepril reached the primary endpoint (41 versus 60
percent with placebo), resulting in an overall relative risk reduction of 43
percent with active therapy. The primary endpoint was reached less often
in group 1 patients (22 percent), who had less severe disease and were all
treated with benazepril.

● In group 2 patients, benazepril was associated with the following

significant benefits: a lower rate of doubling of the serum creatinine
concentration and of reaching ESKD by 51 and 40 percent, respectively; a
greater reduction of proteinuria (52 versus 20 percent); and a lower rate
of decline in GFR (6.8 versus 8.8 mL/min per 1.73 m2 per year).

● The extent of proteinuria reduction in patients with protein excretion

above 1 g/day correlated significantly with the rate of decline in
estimated GFR.

● The benefits with benazepril were independent of blood pressure

lowering since the attained blood pressures were comparable in all
groups.
 ● The incidence of major adverse effects was similar with benazepril and
placebo.

The absence of serious hyperkalemia may have resulted from one or more of
the following factors: approximately 5 percent of patients in group 2 were
excluded from the study because of hyperkalemia during the eight-week run-
in period; dietary intake of potassium was likely to be lower than in Western
patients; and diuretics were used in more than 80 percent of patients,
possibly resulting in increased renal potassium excretion [78]. The exclusion
of patients with diabetes, which is associated with an increased risk of
hypoaldosteronism, may also have contributed to the low incidence of
hyperkalemia. (See "Etiology, diagnosis, and treatment of hypoaldosteronism
(type 4 RTA)", section on 'Diabetes and kidney function impairment'.)

Further evidence in support of benefit from ACE inhibitors in patients with

advanced kidney failure was found in the REIN trial. As previously mentioned,
patients with an initial GFR within the lowest group (11 to 33 mL/min/1.73 m2)
had a 20 percent decrease in the rate of decline in GFR and a 33 percent
reduction in the incidence of ESKD [69] (see 'REIN trial' above). In addition, the
use of ACE inhibitors or ARBs in patients with very advanced disease (serum
creatinine concentration greater than 6.0 mg/dL [530 micromol/L]) does not
appear to hasten the need for long-term dialysis, although the risk of
hyperkalemia is increased [79]. ACE inhibitors also appear to slow the rate of
loss of residual kidney function being treated with peritoneal dialysis [80].

Use in older adult patients — It is not known whether the benefits from
renin-angiotensin system (RAS) inhibition in proteinuric CKD extend to
patients older than 70 years because most of the above trials did not include
such individuals [71]. This is an important issue since older patients are more
likely to have adverse effects from therapy, including acute kidney injury and
hyperkalemia. (See "Major side effects of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers", section on 'Reduction in GFR'
and "Major side effects of angiotensin-converting enzyme inhibitors and
angiotensin II receptor blockers", section on 'Hyperkalemia'.)

Older patients with CKD are also less likely to have proteinuria, which was
required in most of the RAS inhibition trials cited above. This was
demonstrated in an analysis of 1190 National Health and Nutrition
Examination Survey (NHANES) participants who were over age 70 years and
had CKD, which was defined as an estimated GFR <60 mL/min per 1.73 m2 or
an albumin-to-creatinine ratio of >200 mg/g of creatinine (approximately 300
mg/day) [71]. This level of proteinuria was present in only 13 percent. There is
no evidence of benefit from RAS inhibition in patients with protein excretion
below 500 mg/day [60].

In addition, older patients are less likely to live long enough to derive the
benefits of RAS inhibition. As an example, in a study of 790,342 military
veterans aged 70 years or older, the number-needed-to-treat (NNT) with RAS
inhibition to prevent one ESKD event was calculated, assuming that such
medications result in a 30 percent lower relative risk (similar to the effect in
younger populations) [81]. The NNT ranged from 2500 among patients with
an estimated GFR 45 to 59 mL/min per 1.73 m2 and no dipstick proteinuria to
16 among those with an estimated GFR 15 to 29 mL/min per 1.73 m2 and 2+
or greater dipstick proteinuria. More than 90 percent of the cohort had a NNT
greater than 100, comparing unfavorably to the NNT calculated from trials of
younger patients (which were usually less than 25).

The findings above suggest that the great majority of patients over age 70
years with CKD would not benefit from RAS inhibition for renoprotection and
may have harm from a higher rate of side effects [82]. However, this
conclusion does not necessarily apply to patients excreting more than 1 g/day
of protein in whom RAS inhibition may slow disease progression, a benefit
that is likely to be greater than any risks. Careful monitoring is warranted.
(See 'Lack of benefit in nonproteinuric CKD' below.)

The proteinuric response as a predictor of outcome — In nondiabetic CKD,

a number of studies, primarily observational post-hoc analyses, and meta-
analyses, have reported correlations among the initial degree of urinary
protein excretion, reduction in proteinuria with therapy, and decreased
progression of kidney disease [8,58,65,68,70,83-88]. As examples:

● In the MDRD study, for each 1 g/day reduction in protein excretion during
the first four months, the rate of decline in GFR fell by 0.9 to 1.3 mL/min
per year [86]. The fall in proteinuria was related to the blood pressure,
being more prominent in those with more aggressive blood pressure
control.

● Among patients with protein excretion ≥3 g/day in the REIN trial, the rate
of decline in GFR correlated inversely with the degree of proteinuria
reduction and the magnitude of benefit seemed to exceed that expected
for the degree of blood pressure lowering [65].

In addition to the benefit associated with proteinuria reduction in patients

with CKD, the loss of an initial antiproteinuric response to antihypertensive
therapy correlates with an exacerbation of kidney dysfunction. This was
illustrated in a report of 33 patients with nondiabetic kidney disease and an
initial antiproteinuric response to ACE inhibition, 14 of whom escaped from
this benefit after approximately 19 months [87]. These patients had a
significant increase in the rate of loss of creatinine clearance (+0.05 versus
-0.70 mL/min per month during the periods of response and escape,
respectively).

Most studies have found that better kidney outcomes are associated with
agents that lower both proteinuria and blood pressure. However, no trials
have examined "goal proteinuria" in which different levels of proteinuria
reduction were compared.

With respect to monitoring proteinuria, we generally monitor protein

excretion by repeated measurement of the urine protein-to-creatinine ratio or
albumin-to-creatinine ratio in a random urine specimen. These tests are
reasonably accurate in detecting changes in protein excretion. (See
'Proteinuria goal' below and "Assessment of urinary protein excretion and
evaluation of isolated non-nephrotic proteinuria in adults".)

Adverse effects — Renin-angiotensin system (RAS) inhibition can be

associated with a variety of adverse effects. (See "Major side effects of
angiotensin-converting enzyme inhibitors and angiotensin II receptor
blockers".)

With respect to progression of the kidney disease, ACE inhibitors and ARBs
can cause an acute decline in kidney function and a rise in serum potassium
that typically occur one to two weeks after the onset of therapy. Thus, repeat
measurement of the serum creatinine and potassium should be obtained
during this time frame after the initiation or intensification of therapy.

The long-term clinical significance of a modest and stable rise in serum

creatinine after the initiation or intensification of RAS inhibitor therapy is
debated since it is due in part to a reduction in intraglomerular pressure,
which is thought to contribute to the slowing of disease progression. An
initial elevation in serum creatinine of as much as 30 to 35 percent above
baseline that stabilizes within the first two months of therapy is considered
acceptable and not a reason to discontinue therapy as long as there is not an
excessive fall in blood pressure; the latter is most likely to occur in patients
who are volume depleted at the initiation of therapy due, for example, to
diuretic therapy [89,90]. The prognostic implications of an acute and stable
rise in serum creatinine of up to 30 percent are uncertain. Several studies
suggest that such reductions in GFR are associated with adverse
consequences [91,92]. By contrast, a review of 12 randomized trials found
that patients with an acute and stable rise in serum creatinine of up to 30
percent were more likely to have long-term preservation of kidney function
[89].

A separate question is whether or not ACE inhibitors and ARBs should be

discontinued among patients who take these agents chronically if they
progress to advanced CKD (ie, eGFR <30 mL/min per 1.73 m2). Theoretically,
the acute decline in eGFR occurring after initiation of therapy with an ACE
inhibitor or ARB could be regained when these drugs are stopped, thereby
delaying the onset of ESKD. However, rigorous studies indicate that there is
no benefit from discontinuing these agents [93-95]. The best data come from
a trial of 411 patients with advanced CKD (median eGFR 18 mL/min per 1.73
m2) who were treated with an ACE inhibitor or ARB for at least six months;
patients were randomly assigned to continue or discontinue therapy with
these drugs [93]. At three years, patients who discontinued therapy were
more likely to develop ESKD, although this was not statistically significant (62
versus 56 percent; hazard ratio 1.28, 95% CI 0.99-1.65). Rates of death and
cardiovascular events were similar between the groups. These data support
continuing these agents in patients with stage 4 CKD.

Combination of ACE inhibitors and ARBs — A number of trials and meta-

analyses have demonstrated that combination ACE inhibitor/ARB therapy has
a greater antiproteinuric effect than either agent alone [21,96-101]. A 2013
meta-analysis of 59 trials with 1 to 49 months of follow-up found that
combination therapy significantly reduced protein excretion compared with
monotherapy (by almost 400 mg/day) and also increased the likelihood of
achieving a normal level of albumin excretion (by 9.4 percent) [96]. Lowering
of proteinuria has been a marker for better outcomes in other studies. (See
'The proteinuric response as a predictor of outcome' above.)
In addition to lack of proven benefit in proteinuric CKD, combination therapy
may have adverse effects as demonstrated in the ONTARGET trial of 25,620
patients with preexisting vascular disease or diabetes. ONTARGET was
designed to evaluate the effects of ramipril, telmisartan, or the combination
of both drugs on cardiovascular and kidney endpoints during approximately
4.5 years of follow-up [102]. A later report from ONTARGET evaluated the
effects of combination therapy versus monotherapy in the subset of 5623
patients who, at baseline, had reduced kidney function (defined as an
estimated glomerular filtration rate less than 60 mL/min per 1.73 m2) and/or
proteinuria (defined as a urine albumin-to-creatinine ratio greater than 177
mg/g for males and 248 mg/g for females, thresholds that roughly correlate
with more than 300 mg of albumin on a 24-hour urine collection) [103].

The following observations were made among the patients with reduced
kidney function:

● Combination therapy resulted in a small but significant increase in the

incidence of ESKD (defined as the need for chronic dialysis) or doubling of
the serum creatinine (0.79 versus 0.56 percent per year), but a
nonsignificant increase in ESKD alone (0.34 versus 0.27 percent per year).

● In the group of patients who had both reduced kidney function and
proteinuria, combination therapy significantly increased the risk of ESKD
or doubling of the serum creatinine (4.8 versus 2.8 percent per year), as
well as ESKD alone (2.7 versus 1.6 percent per year).

● Combination therapy did not reduce the risk of cardiovascular disease or

death.

Combination therapy with an ACE inhibitor and ARB compared with

monotherapy also increases the incidence of hyperkalemia and hypotension
(by 3.4 and 4.6 percent, respectively, in a systematic review of 59 trials) [96].
(See "Major side effects of angiotensin-converting enzyme inhibitors and
angiotensin II receptor blockers", section on 'Combination of ACE inhibitors
and ARBs'.)

Given the lack of proven benefit and the potential harms demonstrated in
various large trials (ie, ONTARGET, ALTITUDE, VA NEPHRON-D), we
recommend not using combination therapy with ACE inhibitors and ARBs in
patients with nondiabetic CKD with the possible exception of IgA
nephropathy. Similarly, the European Drug Agency states that combined
blockade of the renin-angiotensin system should not be used in any patient.
(See 'Proteinuria goal' below and "IgA nephropathy: Treatment and
prognosis", section on 'Angiotensin inhibition'.)

Lack of benefit in nonproteinuric CKD — The data presented in the

preceding section consistently demonstrate the preferential benefits of renin-
angiotensin system (RAS) inhibitors in patients with proteinuric chronic kidney
disease (CKD). Thus, when trying to slow the progression of nondiabetic CKD,
protein excretion above 1000 mg/day identifies patients who are likely to
benefit from antihypertensive therapy with RAS inhibitors [8,60,64,68,104].
However, some experts would set the threshold at 500 to 1000 mg/day
[3,105].

By contrast, there appears to be no preferential benefit of RAS inhibitors in

patients excreting less than 500 mg/day, as occurs in most patients with
nephrosclerosis and polycystic kidney disease [60]. (See "Clinical features,
diagnosis, and treatment of hypertensive nephrosclerosis", section on 'Choice
of antihypertensive agent' and "Autosomal dominant polycystic kidney
disease (ADPKD): Evaluation and management of hypertension", section on
'Choice of agent'.)

EFFECT OF GOAL BLOOD PRESSURE ON PROGRESSION OF CKD

Overall, the best evidence supports the following points:

● More intensive versus less intensive blood pressuring lowering reduces

the risk of end-stage kidney disease (ESKD) in patients with proteinuric
chronic kidney disease (CKD), but not in patients with nonproteinuric
CKD.

● However, more intensive blood pressure lowering may reduce mortality

in patients with CKD (whether they have proteinuria or not), even though
there is no benefit on kidney endpoints among patients without
proteinuria. The mortality benefit from aggressive blood pressure
lowering is most evident when patients are followed over the long term
(ie, during post-trial follow-up), although an early reduction in mortality
was noted in the Systolic Pressure Intervention Trial (SPRINT). (See "Goal
blood pressure in adults with hypertension", section on 'Patients with
chronic kidney disease'.)

The possibility that a lower blood pressure goal could slow the loss of kidney
function in proteinuric patients was noted in a 2003 observational study that
found a systolic pressure below 130 mmHg was associated with a lower risk
of kidney disease progression in patients with a spot urine total protein-to-
creatinine ratio of ≥1000 mg/g (which approximately represents protein
excretion of greater than 1000 mg/day) [8]. By contrast, there was no
evidence of benefit (adjusted relative risk 1.0) in patients with protein
excretion less than 1000 mg/day. Although these observational data could
not exclude the possibility that patients with normal blood pressure or more
easily controlled hypertension have less severe underlying disease, several
trials and meta-analyses have reached similar conclusions [106].

This section will review the trials and meta-analyses that evaluated the
importance of goal blood pressure on the progression of nondiabetic CKD.
The trials that evaluated the efficacy of renin-angiotensin system (RAS)
inhibitors compared with other antihypertensive drugs on both proteinuria
and disease progression are discussed above. (See 'Effect of antihypertensive
drugs on proteinuria' above and 'Effect of renin-angiotensin system inhibitors
on progression of CKD' above.)

Meta-analyses — Several meta-analyses have synthesized the effects of

more intensive blood pressure lowering on the progression of CKD, as well as
the risk of death [107-111]. Overall, more aggressive blood pressure lowering
reduces the risk of CKD progression among patients with proteinuric kidney
disease, but not among those without proteinuria. Proteinuria was variably
defined in these studies as a protein-to-creatinine ratio greater than 0.22 g/g
or a 24-hour protein excretion greater than 300 mg. In addition, more
aggressive blood pressure lowering reduces all-cause mortality both in
patients with proteinuric CKD and in those with nonproteinuric CKD. The
benefit on mortality was not appreciated in analyses with relatively short-
term follow-up but became evident when patients were followed for more
than one decade.

The following examples are illustrative:

● The most informative study was a meta-analysis that combined patient-

level data on long-term follow-up from the two largest trials (AASK and
MDRD, with 14 to 19 years of follow-up during and after randomized trial
phases) [109]. More intensive blood pressure control was associated with
reduced overall mortality (hazard ratio 0.87, 95% CI 0.76-0.90), and the
reduction in death was similar in patients with and without proteinuria.
Aggressive blood pressure lowering also reduced the progression to
ESKD (hazard ratio 0.88, 95% CI 0.78-1.00), but the benefit was confined
to those with proteinuric CKD.

● A larger meta-analysis of nine goal blood pressure trials and 8127

patients reported no effect of intensive blood pressure lowering on CKD
 progression, cardiovascular events, or mortality at 3.3 years of follow-up
[110]. However, long-term (post-trial) follow-up of those patients with
proteinuria revealed a benefit on the incidence of ESKD (relative risk 0.91,
95% CI 0.85-0.99). The investigators did not report the risk of death
during long-term follow-up.

MDRD study — Results from the multicenter Modification of Diet in Renal

Disease (MDRD) trial suggest that both the rate of progression and the
efficacy of antihypertensive therapy are related to baseline protein excretion,
which in turn is a reflection of the severity of glomerular injury [104]. Two
groups were compared: one with usual blood pressure control (target mean
arterial pressure less than 107 mmHg, which is equivalent to 140/90 mmHg)
and one with more aggressive control (target mean arterial pressure less
than 92 mmHg, which is equivalent to 125/75 mmHg) over a three-year
period. The achieved mean arterial pressures were 96 and 91 mmHg
(equivalent to 130/80 and 125/75 mmHg, respectively). Almost one-half of the
patients were treated with an ACE inhibitor, but its selective efficacy was not
assessed.

The results in 585 patients with a mean baseline GFR of 39 mL/min and mean
urinary protein excretion of 1.1 g/day can be summarized as follows
( figure 2):

● The loss of GFR was lowest in patients excreting less than 1 g/day (2.8 to
3.0 mL/min year), but no benefit for GFR loss was seen with aggressive
blood pressure control.

● Patients excreting between 1 and 3 g/day had more rapid progression

and a modest benefit for GFR loss from aggressive blood pressure
control.
 ● Patients excreting 3 g/day or more had the fastest rate of progression
but a clinically and statistically significant slowing of the rate of
progression with aggressive blood pressure control (rate of GFR decline
of 10.2 with conventional versus 6.7 mL/min per year with aggressive
blood pressure control).

● A secondary analysis suggested that aggressive blood pressure control

may be particularly important in Black patients [112]. (See "Burden of
hypertension in Black individuals", section on 'Goal blood pressure'.)

A subsequent study reported the long-term outcomes of patients enrolled in

the initial MDRD study [113]. After the study was completed in 1993, all
participants were passively followed until 2000 for the incidence of kidney
failure (defined as dialysis or kidney transplantation) and all-cause mortality.
The mean difference in blood pressure between the two groups during the
trial phase was 7.6/3.8 mmHg; blood pressure was not recorded during
passive follow-up. On intention-to-treat analysis, patients in the aggressive
control group were significantly less likely to experience kidney failure
(adjusted hazard ratio 0.68, 95% CI 0.57-0.91), or either kidney failure or death
(0.77, 95% CI 0.65-91). Kidney failure accounted for approximately 90 percent
of events and a hazard ratio was not provided for mortality alone.

However, a subgroup analysis of this extended follow-up revealed that the

benefit from aggressive blood pressure control was only significant in
patients with protein excretion exceeding 1 g/day (hazard ratio approximately
0.6 to 0.7). The hazard ratio was higher and not significant in patients
excreting 300 to 1000 mg/day or less than 300 mg/day (hazard ratios of 0.8
and >0.9, respectively). When all patients with protein excretion of 1000
mg/day or less were combined, there was a significant reduction in the
hazard ratio for kidney failure (0.79, 95% CI 0.63-0.99) but not for the
composite outcome of kidney failure and death.
A substantial limitation of this report was that blood pressure measurements
were not available for either group after 1993. As a result, it is unclear
whether the correlation between improved outcomes and being originally
assigned to a lower target blood pressure is related to the maintenance of
lower blood pressures during this period.

AASK trial of goal blood pressure — In the African American Study of Kidney
Disease and Hypertension (AASK) trial, 1094 African-Americans with long-
standing hypertension, otherwise unexplained slowly progressive CKD, and
usually mild proteinuria (median approximately 100 mg/day) were randomly
assigned to one of two blood pressure goals: 125/75 or 140/90 mmHg [38].
The attained blood pressures were 128/78 and 141/85 mmHg. At a mean
follow-up of approximately four years, the mean rate of change in glomerular
filtration rate and other kidney parameters were not different between the
two groups.

Following completion of the trial phase, participants were invited to continue

in a cohort phase of the study, in which the blood pressure target for
everyone was <130/80 mmHg [114]. During the cohort phase, which lasted
approximately five years, the mean blood pressure was 131/78 and 134/78
mmHg in the intensive control and standard control groups, respectively. The
use of ACE inhibitors and ARBs was similar in the two groups. As was
observed during the trial phase, there was no difference between groups in
the progression of kidney disease (defined as doubling of the serum
creatinine, a diagnosis of ESKD, or death). However, among patients with a
baseline urine protein-to-creatinine ratio of greater than 0.22 (corresponding
to absolute protein excretion of 300 mg/day; the median 24-hour protein
excretion in these patients was approximately 1000 mg/day), there was a
significant reduction in risk of progression with intensive blood pressure
control (hazard ratio 0.73, 95% CI 0.58 to 0.93). By contrast, patients with
urine protein-to-creatinine ratios less than 0.22 (median 24-hour protein
excretion was 60 mg, ie, nonproteinuric) showed no benefit from intensive
therapy.

After the cohort phase was complete, AASK participants were followed for a
median of 14 years for the occurrence of ESKD and death using the United
States Renal Data System (USRDS), the national ESKD registry, and the Social
Security Death Index [109]. The effect of more intensive blood pressure
control on the incidence of ESKD depended upon whether or not patients had
proteinuria (hazard ratio 0.59, 95% CI 0.41-0.85 in patients with proteinuria >1
g/day and hazard ratio 1.05, 95% CI 0.83-1.32 in patients with lower amounts
of proteinuria). By contrast, the benefit of aggressive blood pressure lowering
on mortality did not vary according to proteinuria (hazard ratio 0.81, 95% CI
0.68-0.98).

SPRINT CKD — The Systolic Pressure Intervention Trial (SPRINT) enrolled

patients aged 50 years or older who had a systolic blood pressure of 130 to
180 mmHg plus one or more additional risk factors for cardiovascular disease
(including CKD, defined as estimated GFR of 20 to 59 mL/min/1.73 m2) and
assigned them to one of two systolic pressure goals (<120 versus <140
mmHg). Patients with proteinuria >1 g/day were excluded. The overall
findings from SPRINT and the implications of these findings on
recommended goal blood pressure are presented elsewhere. (See "Goal
blood pressure in adults with hypertension".)

The CKD subgroup in SPRINT included 2646 patients; the mean age of this
subgroup was 72 years, the mean estimated GFR was 48 mL/min/1.73 m2,
and 78 percent had a 10-year Framingham Risk Score greater than or equal to
15 percent [106]. Achieved blood pressure, which was measured using
automated office blood pressure (AOBP), was 123/67 mmHg in the intensive
goal group and 137/74 mmHg in the standard goal group. The following
findings were noted among SPRINT participants who had CKD at baseline:
 ● Intensive blood pressure lowering significantly reduced all-cause
mortality (annual mortality of 1.6 versus 2.2 percent).

● The primary outcome, a composite of myocardial infarction, acute

coronary syndrome, stroke, heart failure, or cardiovascular death, was
also less frequent in the intensive goal group (2.7 versus 3.2), and this
was consistent with data from the entire SPRINT population. However,
the result in the CKD subgroup was nonsignificant, possibly because of
reduced statistical power.

● There was no difference in the incidence of ESKD or a 50 percent decline

in estimated GFR. By contrast, intensive blood pressure lowering
increased the risk of a 30 percent decline in estimated GFR. However, this
decline principally occurred in the first six months of the trial, suggesting
an acute hemodynamic effect of a lower blood pressure; after six
months, the rate of change in estimated GFR did not differ between the
groups ( figure 3).

Polycystic kidney disease — The HALT-PKD trial assigned 558 young,

hypertensive patients with autosomal dominant polycystic kidney disease
(ADPKD) and normal estimated GFR to more intensive (95/60 to 110/75
mmHg) or less intensive (120/70 to 130/80 mmHg) blood pressure lowering;
no significant difference in estimated GFR decline was observed [115]. Results
were similar in a smaller trial [116]. Treatment of hypertension in ADPKD is
presented in detail elsewhere. (See "Autosomal dominant polycystic kidney
disease (ADPKD): Evaluation and management of hypertension".)

Polycystic kidney disease is typically associated with little or no proteinuria. In

a study of 270 patients, for example, mean urinary protein excretion was 260
mg/day, with only 48 (18 percent) excreting more than 300 mg/day [117].
Patients with more advanced kidney dysfunction have more proteinuria
(mean approximately 900 mg/day). (See "Autosomal dominant polycystic
kidney disease (ADPKD): Kidney manifestations", section on 'Proteinuria'.)

PROTEINURIA GOAL

The proteinuria goal discussed here applies only to patients with proteinuric
chronic kidney disease (CKD). The 2004 K/DOQI Clinical Practice Guidelines on
hypertension and antihypertensive agents in CKD recommends a goal less
than 500 to 1000 mg/g creatinine from the urine protein-to-creatinine ratio
on a random urine specimen [105]. However, proteinuria estimated from the
urine protein-to-creatinine ratio may be substantially different from daily
protein excretion. As an example, creatinine excretion in males under the age
of 50 years is 20 to 25 mg/kg of lean body weight per day. Thus, a male with
obesity who has a lean body weight of 80 kg may excrete 2000 mg of
creatinine. In such a patient, a urine protein-to-creatinine ratio of 1000 mg/g
represents protein excretion of approximately 2 g/day. This would be a
suboptimal outcome in patients with IgA nephropathy in whom protein
excretion above 1000 mg/day is associated with an adverse kidney prognosis.
(See "Assessment of urinary protein excretion and evaluation of isolated non-
nephrotic proteinuria in adults" and "IgA nephropathy: Treatment and
prognosis", section on 'Risk factors for disease progression'.)

Because of this potential limitation in using only the urine protein-to-

creatinine ratio, we suggest the following approach to measuring and
monitoring protein excretion, which takes into account both the greater
accuracy of a complete 24-hour urine collection and the greater ease of
monitoring with a spot urine specimen:

● A 24-hour urine collection should be obtained during the initial

evaluation, measuring the excretion of both protein and creatinine. The
completeness of the 24-hour urine collection can be estimated from
 creatinine excretion. Normal values of creatinine excretion vary with
muscle mass and, hence, age, sex, and physical activity: in patients under
the age of 50 years, 20 to 25 mg/kg estimated lean body weight in males
and 15 to 20 mg/kg estimated lean body weight in females; and, in
patients between the ages of 50 and 90 years, there is a progressive 50
percent decline in creatinine excretion (to approximately 10 mg/kg
estimated lean body weight in males). (See "Assessment of kidney
function".)

● If the initial 24-hour urine collection seems complete, then the rate of
protein excretion is probably an accurate estimate. The urine protein-to-
creatinine ratio on this specimen can be related to the total amount of
proteinuria, and the urine protein-to-creatinine ratio on a random
specimen can subsequently be used to monitor the degree of
proteinuria, as long as muscle mass appears stable. If, for example, 24-
hour protein excretion is 3 g/day in an apparently complete collection
and the urine protein-to-creatinine ratio is 2.0, then a ratio below 0.7
would represent goal proteinuria below 1 g/day.

We suggest a proteinuria goal of less than 1000 mg/day, which is similar to

the K/DOQI recommendation of 500 to 1000 mg/g creatinine. It may be
difficult to attain this goal, particularly in patients with the nephrotic
syndrome. In such patients, we suggest a minimum reduction in proteinuria
of at least 50 to 60 percent from baseline values plus protein excretion less
than 3.5 g/day. This approach is based upon an observational study in 348
patients with membranous nephropathy and nephrotic syndrome who were
treated with renin-angiotensin system (RAS) inhibition and, in some cases,
immunosuppressive therapy and were followed for a minimum of one year
[118]. The patients who attained these goals, when compared with patients
who reached only one or neither of these goals, had marked reductions in the
rate of loss of glomerular filtration rate (0.17 versus 0.86 mL/min per month)
and in the incidence of end-stage kidney disease (ESKD) (9 versus 29 percent,
adjusted hazard ratio 0.17). Subnephrotic proteinuria is also associated with a
good kidney prognosis in primary focal segmental glomerulosclerosis. (See
"Membranous nephropathy: Treatment and prognosis", section on 'General
measures in all patients' and "Focal segmental glomerulosclerosis: Treatment
and prognosis", section on 'Prognosis'.)

IgA nephropathy represents an exception to the above approach since

protein excretion above 1000 mg/day and perhaps above 500 mg/day is
associated with a higher risk of disease progression. Thus, the proteinuria
goal is less than 1000 mg/day and perhaps less than 500 mg/day, if possible,
in all patients. The supportive data are presented elsewhere. (See "IgA
nephropathy: Treatment and prognosis", section on 'Risk factors for disease
progression'.)

BLOOD PRESSURE GOAL

Our approach to goal blood pressure in patients with chronic kidney disease
(CKD) is discussed elsewhere ( table 1). (See "Goal blood pressure in adults
with hypertension", section on 'Patients with chronic kidney disease'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected

countries and regions around the world are provided separately. (See "Society
guideline links: Chronic kidney disease in adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at
the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Medicines for chronic kidney disease
(The Basics)")

SUMMARY AND RECOMMENDATIONS

Background

● In patients with chronic kidney disease (CKD), higher degrees of urinary

protein excretion are associated with a more rapid decline in glomerular
filtration rate (GFR), regardless of the primary cause of the kidney disease
and the initial GFR ( figure 1). Lower blood pressure targets (below
130/80 mmHg) are associated with better kidney outcomes in patients
with proteinuric CKD (defined as urine protein excretion greater than 500
to 1000 mg/day). (See 'Importance of proteinuria and the proteinuric
response' above and 'Importance of blood pressure control' above.)

● The effect of antihypertensive drugs on proteinuria varies with drug class

and salt intake:
• When the blood pressure is controlled, renin-angiotensin system (RAS)
inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs) are more effective than other
antihypertensive drugs in reducing proteinuria, regardless of the
etiology of CKD. This preferential effect is thought to be due to a
reduction in intraglomerular pressure and perhaps other factors. The
antiproteinuric effects of ACE inhibitors and ARBs appear to be similar.
(See 'Renin-angiotensin system inhibitors' above.)

• The non-dihydropyridine calcium channel blockers diltiazem and

verapamil have significant antiproteinuric effects in patients with
proteinuria. By comparison, the dihydropyridines, such as amlodipine
and nifedipine, have a variable effect on proteinuria, ranging from an
increase to no effect to a fall in protein excretion. (See 'Calcium
channel blockers' above.)

• Mineralocorticoid receptor antagonists (spironolactone studied more

often than eplerenone) further reduce protein excretion when added
to an ACE inhibitor and/or ARB. (See 'Mineralocorticoid receptor
antagonists' above.)

• Other antihypertensive drugs have little or no effect on protein

excretion. (See 'Drugs with little or no effect' above.)

• In patients with proteinuric CKD, the antiproteinuric effect of RAS

inhibitors and non-dihydropyridine calcium channel blockers is greatly
impaired with a high salt intake, even when blood pressure control
seems appropriate, and is enhanced with salt restriction. Similar
findings are seen in diabetic nephropathy. If a low-salt diet is not
achieved, administration of a diuretic can also enhance the
antiproteinuric effect of RAS inhibitors. (See 'Importance of salt intake'
above.)
 ● Multiple randomized clinical trials in patients with nondiabetic CKD, some
with placebo control and some with an active control, have demonstrated
a benefit of antihypertensive therapy with RAS inhibitors, mostly
angiotensin-converting enzyme (ACE) inhibitors, in patients with
proteinuric nondiabetic CKD. It seems likely that angiotensin receptor
blockers have a similar renoprotective effect as ACE inhibitors in
nondiabetic CKD but supportive data are limited. Additional evidence in
support of a preferential benefit with ACE inhibitors in proteinuric
patients has come from meta-analyses. (See 'Effect of renin-angiotensin
system inhibitors on progression of CKD' above.)

● Post-hoc analyses of these and other studies have shown correlations

between the reduction in proteinuria with therapy and slower
progression of kidney disease. (See 'The proteinuric response as a
predictor of outcome' above.)

● When trying to slow the progression of nondiabetic CKD, protein

excretion above 500 to 1000 mg/day identifies patients who are most
likely to benefit from antihypertensive therapy with RAS inhibitors. By
contrast, there appears to be no preferential benefit of RAS inhibitors in
patients excreting less than 500 mg/day. (See 'Lack of benefit in
nonproteinuric CKD' above.)

● The three major trials in adults that evaluated the effect of goal blood
pressure on CKD progression suggest that the kidney benefit of more
aggressive blood control is primarily restricted to patients with higher
rates of protein excretion ( figure 2). Meta-analyses of randomized trials
support this conclusion. (See 'Effect of goal blood pressure on
progression of CKD' above.)

Management
● In patients with proteinuric (defined as protein excretion above 500 to
1000 mg/day) nondiabetic CKD, we recommend a renin-angiotensin
system (RAS) inhibitor as first-line therapy for the treatment of
hypertension (Grade 1B). (See 'Effect of renin-angiotensin system
inhibitors on progression of CKD' above.)

In hypertensive patients with nonproteinuric nondiabetic CKD who have

edema, we suggest initiation of a diuretic as first-line therapy (Grade 2C).
If there is no edema, we suggest RAS inhibitors as first line therapy
(Grade 2C). (See "Overview of hypertension in acute and chronic kidney
disease", section on 'Sequence of antihypertensive therapy in
nonproteinuric CKD'.)

● In patients with proteinuric nondiabetic CKD, we suggest a proteinuria

goal of less than 1000 mg/day (Grade 2C). In patients who are initially
nephrotic and in whom this goal is unobtainable, we attempt to achieve a
minimum reduction in proteinuria of at least 50 to 60 percent from
baseline values plus protein excretion less than 3.5 g/day. (See
'Proteinuria goal' above.)

Because of potential limitations in using only the urine protein-to-

creatinine ratio to follow protein excretion, we obtain a 24-hour urine for
protein and creatinine excretion during the initial evaluation, and then
compare the protein-to-creatinine ratio to the 24-hour protein excretion.
This allows the subsequent use of spot urine protein-to-creatinine ratios
to more accurately estimate the degree of proteinuria. (See 'Proteinuria
goal' above.)

● In patients with nondiabetic CKD, the blood pressure goal depends

largely upon the method of measurement ( table 1). Goal blood
pressure in patients with CKD is presented elsewhere. (See "Goal blood
 pressure in adults with hypertension", section on 'Patients with chronic
kidney disease'.)

● In most patients with nondiabetic CKD, we recommend not using

combination therapy with ACE inhibitors and ARBs (Grade 1B). The
potential use of this combination in patients with IgA nephropathy is
discussed separately. (See 'Combination of ACE inhibitors and ARBs'
above and "Major side effects of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers", section on 'Combination
of ACE inhibitors and ARBs' and "IgA nephropathy: Treatment and
prognosis", section on 'Angiotensin inhibition'.)
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