Antihypertensive Therapy and Progression of Nondiabetic Chronic Kidney Disease in Adults - UpToDate

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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
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2022. | This topic last updated: Sep 09, 2021.
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".)
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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: Epidemiology,
classification, 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. 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 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 [6]. 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) [7].
(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 [8,9]. 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 [10].
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 [11,12]. 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 [13].
• Acute administration of angiotensin II does not reverse the antiproteinuric effect,

despite inducing renal and systemic vasoconstriction, and increasing
intraglomerular pressure [14].
• In transgenic rats, overexpression of the angiotensin II receptor (type 1) in

glomerular podocytes results in significant proteinuria, foot process effacement,
and glomerulosclerosis [15].
• 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 [16]. By contrast, nephrin expression is increased by ACE inhibitor
therapy [17].
● 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-normal range, and
even lower if a diuretic is also given [18]. 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 [19-23]. 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 [21,24]. (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 [25]. 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 [26].
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 [27]. (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 [19,28-30]. 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) [19].
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
[31-34]. 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 [34]. 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 [19]. 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
[20,35,36]. 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 [19,35,37].
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 [35]. 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 [35].
Mineralocorticoid receptor antagonists — Mineralocorticoid receptor antagonists

(spironolactone has been studied more often than eplerenone) further reduce protein
excretion when added to an ACE inhibitor and/or ARB [38-43]. 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 [39]:
● 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) [39]. Long-term trials are required
to determine whether mineralocorticoid receptor antagonists slow the rate of progression of
the kidney disease.
Direct renin inhibitors — Direct renin inhibitors, like mineralocorticoid receptor

antagonists, 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 [20,22,23]. As an example, beta blockers, diuretics, and the alpha-1-
blockers (prazosin, terazosin, doxazosin) typically have a lesser antiproteinuric effect than
RAS inhibitors [20,22,23]. 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 [20]. 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 [44]. 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
[21,45-52]. 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 [50-52]. 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 [45]. 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 [50]. 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 [53,54]. 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 [55].
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 [27]. (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 [7,56-61]. 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 [57]. 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
[59]. 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")
[62]. 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 [7,59]. There is no evidence of benefit from ACE
inhibitors or ARBs, or with systolic pressures below 120 mmHg in patients with proteinuria
less than 500 mg/day [59]. Patient outcomes may be worse at systolic pressures below 120
mmHg [63,64]. (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 [65]. 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'.)
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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
[66]. 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 [67]. 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) [67]. 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 [68].
Post-hoc analyses of the REIN trial evaluated the benefits of ramipril in patients with varying
degrees of proteinuria and reductions in GFR [69,70]:
● 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) [69].
● Renal 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 [70]. 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 [66-69,71,72]. Significant benefit was also seen in patients with non-nephrotic
proteinuria (1.0 to 2.9 g/day) [69].
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) [73]. 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 men and 400 mg/day in
women. 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 [74].
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 [37]. 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 men and 1.2 g/day in
women. 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) [75]. (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 [76,77]. 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 [77]. (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 [78]. 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 [79]. 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 [70] (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
[80]. ACE inhibitors also appear to slow the rate of loss of residual kidney function being
treated with peritoneal dialysis [81].
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 [72]. 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) [72].
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 [59].
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) [82]. 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 [83]. 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 [7,57,66,69,71,84-89]. 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 [87]. 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 [66].
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 [88]. 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 a
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 uncertain 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 [90,91]. The prognostic
implications of an acute and stable rise in serum creatinine of up to 30 percent are debated.
Several studies suggest that such reductions in GFR are associated with adverse
consequences [92,93]. 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 [90].
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 [19,94-99]. 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) [94]. 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 [100]. 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 men and 248 mg/g for women, thresholds that
roughly correlate with more than 300 mg of albumin on a 24-hour urine collection) [101].
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) [94]. (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
[7,59,65,69,102]. However, some experts would set the threshold at 500 to 1000 mg/day
[3,103].
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 [59]. (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 renal progression 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) [7]. 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 [104].
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 [105-109].
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) [107]. 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 [108]. 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 [102]. 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 [110]. (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 [111]. 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 [37]. 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
[112]. 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 [107]. 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 [104]. Achieved blood pressure,
which was measured using unattended automated oscillometric 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 [113].
Results were similar in a smaller trial [114]. 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 [115]. 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 [103]. However,
proteinuria estimated from the urine protein-to-creatinine ratio may be substantially
different from daily protein excretion. As an example, creatinine excretion in men under the
age of 50 years is 20 to 25 mg/kg of lean body weight per day. Thus, a nonobese man with 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, gender, and physical activity: in
patients under the age of 50 years, 20 to 25 mg/kg estimated lean body weight in men
and 15 to 20 mg/kg estimated lean body weight in women; 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 men). (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 [116]. 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).
Observational studies show that patients with CKD and a diastolic pressure below 90
mmHg have better preservation of glomerular filtration rate (GFR) than hypertensive
patients. 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 renal 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'.)
Use of UpToDate is subject to the Terms of Use.
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100. ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients
at high risk for vascular events. N Engl J Med 2008; 358:1547.
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102. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-
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103. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines
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104. Cheung AK, Rahman M, Reboussin DM, et al. Effects of Intensive BP Control in CKD. J Am
Soc Nephrol 2017; 28:2812.
105. Lv J, Ehteshami P, Sarnak MJ, et al. Effects of intensive blood pressure lowering on the
progression of chronic kidney disease: a systematic review and meta-analysis. CMAJ
2013; 185:949.
106. Upadhyay A, Earley A, Haynes SM, Uhlig K. Systematic review: blood pressure target in
chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med 2011;
154:541.
107. Ku E, Gassman J, Appel LJ, et al. BP Control and Long-Term Risk of ESRD and Mortality. J
108. Tsai WC, Wu HY, Peng YS, et al. Association of Intensive Blood Pressure Control and
Kidney Disease Progression in Nondiabetic Patients With Chronic Kidney Disease: A
Systematic Review and Meta-analysis. JAMA Intern Med 2017; 177:792.
109. Malhotra R, Nguyen HA, Benavente O, et al. Association Between More Intensive vs Less
Intensive Blood Pressure Lowering and Risk of Mortality in Chronic Kidney Disease
Stages 3 to 5: A Systematic Review and Meta-analysis. JAMA Intern Med 2017; 177:1498.
110. Hebert LA, Kusek JW, Greene T, et al. Effects of blood pressure control on progressive
renal disease in blacks and whites. Modification of Diet in Renal Disease Study Group.
Hypertension 1997; 30:428.
111. Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the
progression of kidney disease: long-term follow-up of the modification of diet in renal
disease study. Ann Intern Med 2005; 142:342.
112. Appel LJ, Wright JT Jr, Greene T, et al. Intensive blood-pressure control in hypertensive
chronic kidney disease. N Engl J Med 2010; 363:918.
113. Schrier RW, Abebe KZ, Perrone RD, et al. Blood pressure in early autosomal dominant
polycystic kidney disease. N Engl J Med 2014; 371:2255.
114. Schrier R, McFann K, Johnson A, et al. Cardiac and renal effects of standard versus
rigorous blood pressure control in autosomal-dominant polycystic kidney disease:
results of a seven-year prospective randomized study. J Am Soc Nephrol 2002; 13:1733.
115. Chapman AB, Johnson AM, Gabow PA, Schrier RW. Overt proteinuria and
microalbuminuria in autosomal dominant polycystic kidney disease. J Am Soc Nephrol
1994; 5:1349.
116. Troyanov S, Wall CA, Miller JA, et al. Idiopathic membranous nephropathy: definition and
relevance of a partial remission. Kidney Int 2004; 66:1199.
Topic 7169 Version 50.0
GRAPHICS
Relative risks of major complications of chronic kidney

disease based upon categorical meta-analysis
Summary of categorical meta-analysis (adjusted relative risk) for general

population cohorts with ACR. Mortality is reported for general population
cohorts assessing albuminuria as urine ACR. Kidney outcomes are reported
for general population cohorts assessing albuminuria as either urine ACR or
dipstick. eGFR and albuminuria are expressed as categorical variables. All
results are adjusted for covariates and compared with the Ref. Each cell
represents a pooled RR from a meta-analysis; bold numbers indicate
statistical significance at p<0.05. Incidence rates per 1000 person-years for
the reference cells are 7.0 for all-cause mortality, 4.5 for CVD mortality, 0.04
for kidney failure, 0.98 for AKI, and 2.02 for kidney disease progression.
Absolute risk can be computed by multiplying the RRs in each cell by the
incidence rate in the reference cell. Colors reflect the ranking of adjusted RR.
The point estimates for each cell were ranked from 1 to 28 (the lowest RR
having rank number 1, and the highest number 28). The categories with rank
numbers 1 through 8 are green; rank numbers 9 through 14 are yellow; rank
numbers 15 through 21 are orange; and trank numbers 22 through 28 are
colored red. (For the outcome of kidney disease progression, two cells with
RR of 1.0 are also green, leaving fewer cells as orange.)
RR: relative risk; ACR: albumin creatinine ratio; eGFR: estimated glomerular
filtration rate; Ref: reference cell; ESRD: end-stage renal disease; AKI: acute
kidney injury; CKD: chronic kidney disease; CVD: cardiovascular disease.
* Dipstick included (-, ±, +, ≥++).
Reprinted by permission from Macmillan Publishers Ltd: Levey AS, de Jong PE, Coresh J, et al.
The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies
Conference report. Kidney Int 2010; 80:17. Copyright © 2010.
Graphic 68921 Version 9.0
Aggressive BP control preserves kidney function in

proteinuric patients
Mean fall in glomerular filtration rate (GFR) according to the degree

of proteinuria in patients treated with usual BP control (mean BP
about 130/80 mmHg) or with more aggressive antihypertensive
therapy in which the mean BP was 4.7 mmHg lower over a 3-year
period. The rate of fall in GFR varied directly with protein excretion,
and the benefit of aggressive BP control was absent in the 420
patients excreting less than 1 g/day, modest in the 104 patients
excreting between 1 and 3 g/day, and substantial (3.5 mL/min/year
slower) and statistically significant in the 54 patients excreting at
least 3 g/day.
BP: blood pressure.
Data from: Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction
and blood-pressure control on the progression of chronic renal disease. Modification
of Diet in Renal Disease Study Group. N Engl J Med 1994; 330:877.
Estimated glomerular filtration rate (eGFR) over time during follow-up in SPR
participants with chronic kidney disease (CKD)
Two phases of eGFR changes during follow-up in the SPRINT participants with CKD. The rate of change in
using the values at 6 months after randomization as the baseline was -0.47 mL/minute/1.73 m2 per year
intensive group (dashed line and triangles) and -0.32 mL/minute/1.73 m2 per year in the standard group
and circles). Open symbols denote fasting visits; closed symbols denote nonfasting visits.
SPRINT: Systolic Blood Pressure Intervention Trial.
Republished with permission of the American Society of Nephrology, from: Cheung AK, Rahman M, Reboussin DM, et al. Effects of
Control in CKD. J Am Soc Nephrol 2017. Copyright © 2017; permission conveyed through Copyright Clearance Center, Inc.
Goal blood pressure according to baseline risk for cardiovascular disease

and method of measuring blood pressure
Routine/conventional
office blood pressure Unattended AOBPM,
(manual measurement daytime ABPM, or home
with stethoscope or blood pressure¶
oscillometric device)*
Higher-risk populationΔ
Known ASCVD◊ 125 to 130/<80 120 to 125/<80

Heart failure
Diabetes mellitus
Chronic kidney disease
Age ≥65 years§
Calculated 10-year risk
of ASCVD event ≥10%¥
Lower-risk‡
None of the above risk 130 to 139/<90 125 to 135/<90

factors
All target ranges presented above are in mmHg.

On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or
out-of-office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure)
than with routine/standard methods of office measurement (ie, manual auscultatory or
oscillometric measurement), presumably due to the "white coat effect." However, it is critical
to realize that this average difference in blood pressures according to the methodology of
measurement applies to the population and not the individual. Some patients do not
experience a white coat effect, and, therefore, there is some uncertainty in setting goals that
are specific to the method of measurement.
When treating to these goals, a patient may (inadvertently) attain a blood pressure below the
given target. Provided the patient does not develop symptoms, side effects, or adverse events
as a result of the treatment regimen, then reducing or withdrawing antihypertensive
medications is unnecessary.
Less aggressive goals than those presented in the table may be appropriate for specific
groups of patients, including those with postural hypotension, the frail older adult patient,
and those with side effects to multiple antihypertensive medications.
AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure
monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of
Cardiology/American Heart Association.
* Office blood pressure must be performed adequately in order to use such measurements to
manage patients. Critical to an adequate office assessment of blood pressure are proper patient
positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering
the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff).
The average of multiple measurements should be used for management. Refer to UpToDate
topics on measurement of blood pressure. Office readings should not be used to manage blood
pressure unless it is performed adequately.
¶ Home blood pressure, like office blood pressure, must be performed adequately in order for
the measurements to be used to manage patients. First, the accuracy of the home blood
pressure device must be verified in the clinician's office. Second, the clinician should verify that
the cuff and bladder that the patient will use are the appropriate size. Third, patients should
measure their pressure after several minutes of rest and while seated in a chair (back supported
and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood
pressure should be measured at different times per day and over multiple days. The average
value of these multiple measurements is used for management. Home blood pressure readings
should not be used to manage blood pressure unless it is performed adequately and in
conjunction with office blood pressure or ambulatory blood pressure.
Δ The level of evidence supporting the lower goal in higher-risk individuals is stronger for some
risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year
risk ≥15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients
with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the
evidence.
◊ Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior
stroke or transient ischemic attack, prior history of peripheral artery disease.
§ In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who
are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize
goals and share decision-making with the patient, relatives, and caretakers, rather than targeting
one of the blood pressure goals in the table.
¥ The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-
year cardiovascular disease risk.
‡ In the large subgroup of patients who have an initial (pretreatment) blood pressure ≥140/≥90
mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts
would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those
presented in the table. This more aggressive goal would likely reduce the chance of developing
severe hypertension and ultimately lower the relative risk of cardiovascular events in these
lower-risk patients over the long term. However, the absolute benefit of more aggressive blood
pressure lowering in these patients is comparatively small, and a lower goal would require more
intensive pharmacologic therapy and corresponding side effects.
Contributor Disclosures
Johannes FE Mann, MD Grant/Research/Clinical Trial Support: NovoNordisk [Diabetes]; European
Union [Diabetes]; Boehringer Ingelheim [SGLT2-I, ketoacidosis]; Sanofi [SGLT2-I, autosomal dominant
polycystic kidney disease]; Idorsia [Endothelial antagonists]; AstraZeneca [SGLT2-I]; Bayer
[Anticoagulant]. Consultant/Advisory Boards: NovoNordisk [Diabetes]; Vifor [Hyperkalemia];
Boehringer Ingelheim [Diabetes]; Bayer [Chronic kidney disease]; AstraZeneca [Nephrology]. Speaker's
Bureau: NovoNordisk [Diabetes]; Novartis [Hypertension]; AstraZeneca [SGLT2-I]; Boehringer
Ingelheim [Diabetes]; Bayer [Chronic kidney disease]. All of the relevant financial relationships listed
have been mitigated. George L Bakris, MD Grant/Research/Clinical Trial Support: Bayer [Diabetic
nephropathy]; KBP Biosciences [Resistant hypertension]. Consultant/Advisory Boards: Alnylam
[Resistant hypertension]; AstraZeneca [Diabetic nephropathy]; Bayer [Nephropathy]; Ionis [Resistant
hypertension]; KBP BioSciences [Resistant hypertension]; Vifor [Hyperkalemia]. All of the relevant
financial relationships listed have been mitigated. Gary C Curhan, MD, ScD Equity Ownership/Stock
Options: Allena Pharmaceuticals [Oxalate]. Grant/Research/Clinical Trial Support: Decibel Therapeutics
[Hearing loss, tinnitus];GlaxoSmithKline [Shingles]. All of the relevant financial relationships listed have
been mitigated. William B White, MD Consultant/Advisory Boards: AB Science [Alzheimer's disease,
mastocytosis]; Alynam [Heart failure]; AstraZeneca [Lupus, lung disease]; Bristol-Myers Squibb
[Psoriasis]; Cadence [Oral contraception]; Cerevel Therapeutics [Cancer, schizophrenia]; JAZZ
[Narcolepsy]; Marius [Hypogonadism]; Takeda [Gout, narcolepsy, cancer]; Travere [IgA nephropathy];
UCB [Psoriasis, arthritis]. All of the relevant financial relationships listed have been mitigated. John P
Forman, MD, MSc No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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13/9/22, 18:30 Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults - UpToDate

Official reprint from UpToDate®

Antihypertensive therapy and progression of

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

● (See "Antihypertensive therapy and progression of chronic kidney disease:

● (See "Treatment of diabetic kidney disease".)

● (See "Overview of hypertension in acute and chronic kidney disease".)

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

IMPORTANCE OF PROTEINURIA AND BLOOD PRESSURE CONTROL

Identification of the factors responsible for secondary injury, such as intraglomerular

Studies of antihypertensive therapy in proteinuric nondiabetic CKD have focused on two

EFFECT OF ANTIHYPERTENSIVE DRUGS ON PROTEINURIA

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

In addition to the reduction in intraglomerular pressure, a variety of other mechanisms may

● Direct improvement in the permselective properties of the glomerulus by ACE

• Acute administration of angiotensin II does not reverse the antiproteinuric effect,

• In transgenic rats, overexpression of the angiotensin II receptor (type 1) in

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

ACE inhibitors — ACE inhibitors generally reduce protein excretion by approximately 30 to

Angiotensin II receptor blockers — The antiproteinuric effect of angiotensin II receptor

Other antihypertensive drugs — Other antihypertensive drugs have a variable effect on

Calcium channel blockers — The non-dihydropyridine calcium channel blockers, such as

Differences between non-dihydropyridine and dihydropyridine calcium channel blockers

Mineralocorticoid receptor antagonists — Mineralocorticoid receptor antagonists

● There was a significantly greater reduction in proteinuria in the spironolactone group

Direct renin inhibitors — Direct renin inhibitors, like mineralocorticoid receptor

The following examples illustrate the range of findings:

valsartan to either a regular or low-sodium diet reduced blood pressure by only 2 to 3

• A significantly smaller reduction in proteinuria in response to ramipril therapy at

EFFECT OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS ON PROGRESSION

Clinical trials have demonstrated a benefit of antihypertensive therapy with renin-

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

The following results were noted:

● Benazepril therapy reduced protein excretion by 25 percent compared with placebo.

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

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

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

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

● Approximately one-third of patients had a urine protein-to-creatinine ratio of >0.22 (this

randomly assigned to benazepril (10 mg twice daily) or placebo. Additional antihypertensive

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

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

with therapy, and decreased progression of kidney disease [7,57,66,69,71,84-89]. As

With respect to monitoring proteinuria, we generally monitor protein excretion by repeated

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

disease progression. An initial elevation in serum creatinine of as much as 30 to 35 percent

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

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

EFFECT OF GOAL BLOOD PRESSURE ON PROGRESSION OF CKD

Overall, the best evidence supports the following points:

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

The following examples are illustrative:

● A secondary analysis suggested that aggressive blood pressure control may be

● Intensive blood pressure lowering significantly reduced all-cause mortality (annual

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

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

the ages of 50 and 90 years, there is a progressive 50 percent decline in creatinine

BLOOD PRESSURE GOAL

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