antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults

7/21/2019 Antihypertensive Therapy and Progression of Nondiabetic Chronic Kidney Disease in Adults

http://slidepdf.com/reader/full/antihypertensive-therapy-and-progression-of-nondiabetic-chronic-kidney-disease 1/24

Official reprint from UpToDate

www.uptodate.com ©2015 UpToDate

Authors

Johannes FE Mann, MD

George L Bakris, MD

Section Editor

Gary C Curhan, MD, ScD

Deputy Editor

John P Forman, MD, MSc

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice,

diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional

regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use

©2015 UpToDate, Inc.

Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults

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

Literature review current through: May 2015. | This topic last updated: Oct 27, 2014.

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 m 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" and "Treatment of diabetic nephropathy" and "Overview of

hypertension in acute and chronic kidney disease".)

The approach to slowing the progression of CKD in children is discussed elsewhere. (See "Overview of the

management of chronic kidney disease in children", section on 'Slowing chronic kidney disease progression'.)

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 renal injury are interstitial fibrosis and focal segmental

glomerulosclerosis (called secondary FSGS), which are superimposed upon any primary renal injury that may bepresent. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on

'Nephron loss'.)

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".)

®

®

2

ypertensive therapy and progression of nondiabetic chronic kidney ... http://www.uptodate.com/contents/antihypertensive-therapy-and-

24 24/06/20



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 kidney disease. 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 glomerular filtration rate (GFR), regardless of the

primary cause of the renal disease and the initial GFR ( figure 1). In addition to the initial urinary protein excretion, anumber of studies have reported correlations between reduction in proteinuria with antihypertensive therapy and

slower progression of the renal 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 renal 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 moreeffective 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 nephropathy".)

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]. In contrast, nephrin expression is

increased by ACE inhibitor therapy [17].

•


24 24/06/20



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 m 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 about 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 renal 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 was best demonstrated in diabetic renal 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

nephropathy".)

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. Further studies of the efficacy and safety are required before such high-dose therapy can be

recommended.

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 renal

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

ACE inhibitors have an antifibrotic effect, which could contribute to the slowing of renal 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 renal disease progression. (See "Secondary factors and progression of chronic

kidney disease".)

●

2


24 24/06/20



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 minus 39 and plus 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 studied more

often than eplerenone) further reduce protein excretion when added to an ACE inhibitor and/or ARB [ 38-42]. 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 [38]:

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 (relative risk 3.1 in the

meta-analysis) [38]. Long-term trials are required to determine whether mineralocorticoid receptor antagonists slow

the rate of progression of the renal disease.

Direct renin inhibitors (DRI) — 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 (such as prazosin) 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 proteinuric CKD, the antiproteinuric effect of RAS inhibitors and

non-dihydropyridine calcium channel blockers is impaired with a high salt intake, even when blood pressure control

seems appropriate, and is enhanced with salt restriction [21,43-50]. In addition, the benefits of RAS inhibitors on

prevention of end-stage renal disease (ESRD) in patients with proteinuric CKD may be enhanced by a low-salt diet

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.

●


24 24/06/20



and/or mitigated by a high-salt diet [48-50]. Similar findings are seen in diabetic nephropathy. (See "Treatment of

diabetic nephropathy", section on 'Salt intake and proteinuria' .)

The following examples illustrate the range of findings:

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. (See "Assessment of kidney

function", section on 'Creatinine clearance'.)

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

[51,52]. 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 [53].

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", section on 'Effects of

dietary sodium restriction on blood pressure'.)

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

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 [43]. 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 end-stage renal disease (ESRD) in 500 proteinuric CKD patients

enrolled in the REIN and REIN-2 trials [48]. 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 adverseoutcomes 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 ESRD (32 versus 16 percent). This higher risk of ESRD with a

high-sodium diet was independent of age, sex, cause of renal 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.

•


24 24/06/20



nondiabetic CKD but supportive data are limited [27]. (See "Treatment of diabetic nephropathy", section on 'Renal

protection with ARBs'.)

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 [7,54-59]. 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 [ 55]. After statistical

adjustments, ACE inhibitor therapy compared with the alternative treatments was associated with significant

reductions in the rate of progression to end-stage renal disease (ESRD) (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 end-stage renal disease

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 [57].

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 five of the trials.

The benefits of ACE inhibitors and ARBs on CKD progression in proteinuric patients was confirmed in ameta-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") [60]. Compared with other antihypertensive drugs, therapy with ACE inhibitors

resulted in a significantly lower incidence of end-stage renal disease (2.6 versus 3.8 percent; relative risk 0.67, 95%

CI 0.54-0.84). ARB therapy also reduced the incidence of ESRD 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 [7,57]. 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 [57]. Patient outcomes may be worse at systolic pressures below 120 mmHg[61,62]. (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

[63]. 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"

●


24 24/06/20



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 [64]. 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 renal 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 [65]. The rate of

decline of renal 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) [65]. At 20

months (and at 44 months for the trial phase and observational follow-up combined), the following benefits were

noted:

Additional follow-up at 60 months found that some patients on continued ramipril therapy even had increased GFR

compared with baseline values [66].

Post-hoc analyses of the REIN trial evaluated the benefits of ramipril in patients with varying degrees of proteinuria

and reductions in GFR [67,68]:

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 [64-67,69,70]. Significant benefit was also seen in

hypertension) and in proteinuric blacks 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 "Course and treatment of autosomal dominant polycystic kidney disease", section on

'Treatment'.)

●

The mean rate of decline of the glomerular filtration rate (GFR) decreased from 0.44 to 0.10 mL/min per 1.73

m for patients originally randomized to ramipril, and from 0.81 to 0.14 mL/min per 1.73 m for those not

originally given ramipril.

●2 2

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 m ).

●2

During the entire 44 month period of follow-up (including the trial and observational phases), the incidence of

end-stage renal disease 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).

●

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 m per month for

other therapy) and a decreased incidence of end-stage renal disease (18 versus 52 percent) [ 67].

●2

Renal benefits of ramipril were observed whether the initial (baseline) GFR was within the lowest (11 to 33

mL/min/1.73 m ), middle (33 to 51 mL/min/1.73 m ), or highest tertile (51 to 101 mL/min/1.73 m ). Compared

with other drugs, ramipril therapy decreased the rate of GFR decline by 20, 22, and 35 percent, respectively,

and the incidence of end-stage renal disease by 33, 37, and 100 percent, respectively [ 68]. The incidence of

adverse events was similar across the tertiles and within each tertile for the ramipril and other treatment

groups.

●2 2 2


24 24/06/20



patients with non-nephrotic proteinuria (1.0 to 2.9 g/day) [67].

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 renal disease. Given that many patients had significant renal insufficiency (eg,

the lowest tertile had a GFR between 11 to 33 mL/min/1.73 m ), 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) [71]. 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 end-stage renal disease (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 renal disease, even with further blood pressure

reduction from that obtained with fixed doses of ACE inhibitors.

AASK trial of antihypertensive therapy — The blood pressure of hypertensive African Americans is generally

considered to respond better to monotherapy with a calcium channel blocker or a diuretic than an ACE inhibitor.

(See "Treatment of hypertension in blacks", section on 'Choice of antihypertensive drugs'.)

The African American Study of Kidney Disease and Hypertension (AASK) trial included 1094 African American

patients with hypertensive renal disease. The mean glomerular filtration rate was 46 (range 20 to 65) mL/min per

1.73 m and mean protein excretion was about 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 [ 72].

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 m ; end-stage renal disease; 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.

However, the relative efficacy of ramipril compared with amlodipine at three years varied with the degree of

proteinuria at baseline:

2

2

2

Approximately one-third of patients had a urine protein-to-creatinine ratio >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 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 the remaining patients who had a urine protein-to-creatinine ratio of 0.22 or less, there was no significant●


24 24/06/20



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) [73].

(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 [74,75]. 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 [75]. (See "Ambulatory blood pressure monitoring and white coat hypertension in adults",

section on 'Nocturnal blood pressure and nondippers' and "Ambulatory blood pressure monitoring and white coat

hypertension in adults", section on 'Masked hypertension'.)

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, isthere 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 [76]. Based upon the baseline serum

creatinine concentration, patients were divided into two groups:

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 renal 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 toadminister 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, end-stage renal disease (ESRD), or death,

while secondary endpoints were change in proteinuria and rate of progression of the renal disease.

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

difference in mean decline in GFR or the composite clinical endpoint among the treatment 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 m and 1.6 g/day, respectively.

●

2

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 m and 1.6

g/day.

●2

Significantly fewer group 2 patients (mean GFR of 26 mL/min per 1.73 m ) treated with benazepril reached the

primary endpoint (41 versus 60 percent with placebo), resulting in an overall risk reduction of 43 percent with

active therapy. The primary endpoint was reached less often in group 1 patients (22 percent), who had less

● 2


24 24/06/20



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 [77]. 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 renal insufficiency'.)

Further evidence in support of benefit from ACE inhibitors in patients with advanced renal 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 m )

had a 20 percent decrease in the rate of decline in GFR and a 33 percent reduction in the incidence of end-stage

renal disease [68] (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 [78]. ACE inhibitors also

appear to slow the rate of loss of residual renal function being treated with peritoneal dialysis [79].

Use in elderly 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 [70]. 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 m or an albumin-to-creatinine ratio >200 mg/g of creatinine (approximately 300 mg/day) [70]. 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 [57].

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 ESRD event was calculated, assuming that such medications result in a 30 percent lower relative risk

(similar to the effect in younger populations) [80]. The NNT ranged from 2500 among patients with an estimated

GFR 45 to 59 mL/min per 1.73 m and no dipstick proteinuria to 16 among those with an estimated GFR 15 to 29

mL/min per 1.73 m 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

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 ESRD 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 m per year).

●

2

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.●

2

2

2

2


24 24/06/20



RAS inhibition for renoprotection and may have harm from a higher rate of side effects [ 81]. 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 renal disease

[7,55,64,67,69,82-87]. As examples:

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 renal dysfunction. This was

illustrated in a report of 33 patients with nondiabetic renal disease and an initial antiproteinuric response to ACE

inhibition, 14 of whom escaped from this benefit after approximately 19 months [86]. 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 renal 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 renal disease, ACE inhibitors and ARBs can cause a decline in renal 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 [ 88,89].

Rather than being an adverse effect, 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 renal function [ 88].

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 [19,90-95]. 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

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 [ 85]. 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 [64].

●


24 24/06/20



a normal level of albumin excretion (by 9.4 percent) [90]. 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

renal endpoints during approximately 4.5 years of follow-up [96]. A later report from ONTARGET evaluated the

effects of combination therapy versus monotherapy in the subset of 5623 patients who, at baseline, had reduced

renal function (defined as an estimated glomerular filtration rate less than 60 mL/min per 1.73 m ) 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) [ 97].

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

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) [90]. (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 "Treatment and prognosis of IgA nephropathy", section on 'Proteinuria and blood pressure goals'.)

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 [7,57,63,67,98].

However, some experts would set the threshold at 500 to 1000 mg/day [ 3,99].

In 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 [57]. (See "Clinical features,

diagnosis, and treatment of hypertensive nephrosclerosis", section on 'Choice of antihypertensive agent' and

"Hypertension in autosomal dominant polycystic kidney disease", section on 'Choice of agent' .)

EFFECT OF GOAL BLOOD PRESSURE ON PROGRESSION OF CKD — In 2003, the ACE Inhibition in

Progressive Renal Disease study group concluded that 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 ≥1000 mg/g

(which approximately represents protein excretion of greater than 1000 mg/day) [ 7]. In 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. 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

2

Combination therapy resulted in a small but significant increase in the incidence of end-stage renal disease

(ESRD, 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 ESRD alone (0.34 versus 0.27 percent per year).

●

In the group of patients who had both reduced renal function and proteinuria, combination therapy significantly

increased the risk of ESRD or doubling of the serum creatinine (4.8 versus 2.8 percent per year), as well as

ESRD alone (2.7 versus 1.6 percent per year).

●

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


24 24/06/20



(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 aggressive blood pressure lowering

on the progression of CKD [100,101]. Overall, more aggressive blood pressure lowering reduces the risk of CKD

progression among patients with proteinuric renal 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:

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 [98]. 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 selectiveefficacy 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):

A subsequent study reported the long-term outcomes of patients enrolled in the initial MDRD study [103]. After the

study was completed in 1993, all participants were passively followed until 2000 for the incidence of renal failure

(defined as dialysis or renal 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 measured during passive

follow-up. On intention-to-treat analysis, patients in the aggressive control group were significantly less likely to

One meta-analysis, for example, combined seven goal blood pressure trials including 5,308 patients with CKD

that were followed for at least 1.6 years [100]. Compared with a standard blood pressure lowering, more

aggressive blood pressure control significantly reduced the risk of renal events (defined as end-stage renal

disease [ESRD], a doubling of serum creatinine, or 50 percent reduction in glomerular filtration rate [GFR])

among those with proteinuric CKD (38.5 versus 40.5 percent). In contrast, event rates were nonsignificantly

higher with aggressive blood pressure lowering among patients with nonproteinuric CKD (37.7 versus 35.0

percent), although this result was based upon a smaller subgroup.

●

A separate systematic review of the three largest of these seven trials (MDRD, AASK, and REIN-2) reached a

similar conclusion [101]. Aggressive blood pressure control was associated with a lower risk of ESRD or death

and a slower rate of decline in glomerular filtration rate in proteinuric patients, but not in patients withoutproteinuria. In addition, aggressive blood pressure control did not reduce the risk of cardiovascular outcomes or

death in nonproteinuric patients; this issue is discussed elsewhere. (See "Chronic kidney disease and coronary

heart disease", section on 'Blood pressure control'.)

●

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 was

seen with aggressive blood pressure control.

●

Patients excreting between 1 and 3 g/day had more rapid progression and a modest benefit 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 withconventional 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 blacks

[102]. (See "Hypertensive complications in blacks", section on 'Goal blood pressure'.)

●


24 24/06/20



experience renal failure (adjusted hazard ratio 0.68, 95% CI 0.57-0.91), or either renal failure or death (0.77, 95% CI

0.65-91). Renal 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 renal failure (0.79, 95% CI 0.63-0.99) but notfor the composite outcome of renal 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 about 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 renal 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 [ 104]. 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 ESRD, 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). In contrast, patients with urine protein-to-creatinine ratios less than 0.22 (median 24-hour protein excretionwas 60 mg, ie, nonproteinuric) showed no benefit from intensive therapy.

Polycystic kidney disease — 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 [105]. Patients with more advanced renal dysfunction have more proteinuria (mean

about 900 mg/day). (See "Renal manifestations of autosomal dominant polycystic kidney disease", section on

'Proteinuria'.)

In a randomized trial, 75 patients with ADPKD, hypertension, and left ventricular hypertrophy were randomly

assigned to rigorous (less than 120/80 mmHg) or standard blood pressure control (135 to 140/85 to 90 mmHg) [ 106].

The mean attained blood pressures were 90 and 101 mmHg in the rigorous and standard blood pressure groups,

respectively (approximately 116/77 versus 133/87 mmHg in the two groups). At seven years, there was no differencein renal function in the groups. (See "Hypertension in autosomal dominant polycystic kidney disease".)

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 [99]. 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 per day. Thus, a nonobese man who weighs 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


24 24/06/20



is associated with an adverse renal prognosis. (See "Treatment and prognosis of IgA nephropathy", section on

'Protein excretion above 1 g/day' and "Assessment of urinary protein excretion and evaluation of isolated

non-nephrotic proteinuria in adults".)

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:

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 [ 107]. 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 renal disease (ESRD) (9 versus 29 percent, adjusted hazard ratio 0.17). Subnephrotic proteinuria is alsoassociated with a good renal prognosis in primary focal segmental glomerulosclerosis. (See "Treatment of idiopathic

membranous nephropathy", section on 'Importance of attaining remission' and "Treatment of primary focal

segmental glomerulosclerosis", section on 'Degree of proteinuria'.)

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 "Treatment and prognosis of IgA nephropathy", section on 'Protein excretion above 1 g/day' and

"Treatment and prognosis of IgA nephropathy", section on 'Proteinuria and blood pressure goals' .)

BLOOD PRESSURE GOAL

Blood pressure goals depend upon protein excretion — Our approach to goal blood pressure in patients with

nondiabetic CKD is as follows:

These recommendations are similar to those made by the 2012 international KDIGO guidelines for blood pressure

management in patients with CKD. They are also consistent with the Eighth Joint National Committee (JNC 8) and

Canadian Society of Nephrology guidelines, although these groups did not comment on whether a lower goal should

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 about 10 mg/kg estimated lean body weight in men).

(See "Assessment of kidney function", section on 'Creatinine clearance'.)

●

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 aratio below 0.7 would represent goal proteinuria below 1 g/day.

●

We recommend that blood pressure be lowered to at least less than 140/90 mmHg in all hypertensive patients.●

We recommend that blood pressure be lowered to below 130/80 mmHg, rather than below 140/90 mmHg, in

patients with proteinuric CKD (defined as protein excretion 500 to 1000 mg/day or more).

●


24 24/06/20



apply to proteinuric patients [108,109]. Lowering the blood pressure to below 120 mmHg systolic is not

recommended since patient outcomes may be worse [61,62]. Our recommendations for goal blood pressure in

patients with diabetes mellitus, with or without nephropathy, are discussed separately. (See "Treatment of

hypertension in patients with diabetes mellitus", section on 'Goal blood pressure' and "Treatment of diabetic

nephropathy".)

In patients with established atherosclerotic cardiovascular disease, outcomes are better when the systolic pressure

is lowered to below 130 to 135 mmHg. The data are presented elsewhere. (See "Blood pressure management in

patients with atherosclerotic cardiovascular disease", section on 'Placebo-controlled trials with a mean baseline BPless than 140/90 mmHg' and "Blood pressure management in patients with atherosclerotic cardiovascular disease",

section on 'Goal blood pressure'.)

Proteinuric patients — The best data supporting our recommendations for goal blood pressure in proteinuric

patients with nondiabetic CKD come from the MDRD trial described above, which assessed the efficacy of both

dietary protein restriction and more aggressive blood pressure lowering in patients with CKD. With respect to blood

pressure lowering, the achieved mean arterial pressures in the usual and more aggressive blood pressure control

arms were 96 and 91 mmHg (equivalent to 130/80 and 125/75 mmHg, respectively). This study suggested that, with

increasing degrees of proteinuria at baseline, more aggressive blood pressure lowering provides benefit as

compared with less aggressive blood pressure lowering. As an example, more aggressive lowering was associated

with slowing of the rate of loss of glomerular filtration rate that was statistically significant only in patients with protein

excretion of 3 g/day or more at study end (figure 2) [98]. (See 'MDRD study' above.)

In addition, both patients excreting ≥3 g/day and those excreting 1 to 3 g/day had, at a mean of 6.2 years, a

significantly lower rate of both renal failure, defined as dialysis or renal transplantation, and the combined endpoint

of renal failure or all-cause mortality [103]. However, it was not clear that this difference was due to the lower target

pressure since blood pressure measurements over this period were not available for either group. Nevertheless,

these findings are consistent with the meta-analysis cited above, showing benefit from systolic blood pressure

lowering to levels below 130 mmHg among CKD patients with protein excretion of 500 to 1000 mg/day or higher.

Nonproteinuric patients — In patients with nonproteinuric (less than 500 to 1000 mg/day) nondiabetic CKD,

there is no evidence of renal benefit from lowering the blood pressure below the usual goal of less than 140/90

mmHg. (See 'Effect of goal blood pressure on progression of CKD' above.)

However, in patients with established atherosclerotic cardiovascular disease, outcomes are better when the systolic

pressure is lowered to below 130 to 135 mmHg. (See "Blood pressure management in patients with atherosclerotic

cardiovascular disease", section on 'Placebo-controlled trials with a mean baseline BP less than 140/90 mmHg' and

"Blood pressure management in patients with atherosclerotic cardiovascular disease", section on 'Goal blood

pressure'.)

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 5 to 6 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 the10 to 12 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.)

SUMMARY AND RECOMMENDATIONS

th th

th th

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


24 24/06/20



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 renal 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 renal 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 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 renal 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. In 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

●


24 24/06/20



Management

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

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 2011; 80:17.

1.

Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: renoprotective benefits of renin-angiotensin

system inhibition. Ann Intern Med 2002; 136:604.

2.

protein excretion (figure 2). Meta-analyses of randomized trials support this conclusion. (See 'Effect of goal

blood pressure on progression of CKD' above.)

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 1A). (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 theprotein-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 proteinuric nondiabetic CKD, we recommend a blood pressure goal of less than 130/80 mmHg

rather than 140/90 mmHg (Grade 1B). (See 'Effect of goal blood pressure on progression of CKD' above.)

In patients with nonproteinuric nondiabetic CKD, we recommend a blood pressure goal of at least less than

140/90 mmHg (Grade 1B).

In patients with established atherosclerotic cardiovascular disease, outcomes are better when the systolicpressure is lowered to below 130 to 135 mmHg. The data are presented elsewhere. (See "Blood pressure

management in patients with atherosclerotic cardiovascular disease", section on 'Placebo-controlled trials with

a mean baseline BP less than 140/90 mmHg' and "Blood pressure management in patients with atherosclerotic

cardiovascular disease", section on 'Goal blood pressure'.)

●

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 "Treatment and prognosis of IgA nephropathy", section on 'Combination of ACE inhibitor and

ARB'.)

●


24 24/06/20



Sarafidis PA, Khosla N, Bakris GL. Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis

2007; 49:12.

3.

Weir MR. Progressive renal and cardiovascular disease: optimal treatment strategies. Kidney Int 2002;

62:1482.

4.

Yu HT. Progression of chronic renal failure. Arch Intern Med 2003; 163:1417.5.

Anderson AH, Yang W, Townsend RR, et al. Time-updated systolic blood pressure and the progression of

chronic kidney disease: a cohort study. Ann Intern Med 2015; 162:258.

6.

Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic kidney disease: the role of blood pressurecontrol, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann Intern

Med 2003; 139:244.

7.

Anderson S, Rennke HG, Garcia DL, Brenner BM. Short and long term effects of antihypertensive therapy in

the diabetic rat. Kidney Int 1989; 36:526.

8.

Rosenberg ME, Smith LJ, Correa-Rotter R, Hostetter TH. The paradox of the renin-angiotensin system in

chronic renal disease. Kidney Int 1994; 45:403.

9.

Yoshioka T, Rennke HG, Salant DJ, et al. Role of abnormally high transmural pressure in the permselectivity

defect of glomerular capillary wall: a study in early passive Heymann nephritis. Circ Res 1987; 61:531.

10.

Remuzzi A, Puntorieri S, Battaglia C, et al. Angiotensin converting enzyme inhibition ameliorates glomerular

filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest 1990; 85:541.

11.

Remuzzi A, Perticucci E, Ruggenenti P, et al. Angiotensin converting enzyme inhibition improves glomerular

size-selectivity in IgA nephropathy. Kidney Int 1991; 39:1267.

12.

Gansevoort RT, de Zeeuw D, de Jong PE. Dissociation between the course of the hemodynamic and

antiproteinuric effects of angiotensin I converting enzyme inhibition. Kidney Int 1993; 44:579.

13.

Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Angiotensin II does not acutely reverse the reduction of

proteinuria by long-term ACE inhibition. Kidney Int 1991; 40:734.

14.

Hoffmann S, Podlich D, Hähnel B, et al. Angiotensin II type 1 receptor overexpression in podocytes induces

glomerulosclerosis in transgenic rats. J Am Soc Nephrol 2004; 15:1475.

15.

Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr

Diabetes Rev 2008; 4:39.

16.

Langham RG, Kelly DJ, Cox AJ, et al. Proteinuria and the expression of the podocyte slit diaphragm protein,nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition. Diabetologia 2002;

45:1572.

17.

Weinberg JM, Appel LJ, Bakris G, et al. Risk of hyperkalemia in nondiabetic patients with chronic kidney

disease receiving antihypertensive therapy. Arch Intern Med 2009; 169:1587.

18.

Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with

inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008; 148:30.

19.

Gansevoort RT, Sluiter WJ, Hemmelder MH, et al. Antiproteinuric effect of blood-pressure-lowering agents: a

meta-analysis of comparative trials. Nephrol Dial Transplant 1995; 10:1963.

20.

Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of

ACE inhibition by lisinopril. Kidney Int 1989; 36:272.

21.

Apperloo AJ, de Zeeuw D, Sluiter HE, de Jong PE. Differential effects of enalapril and atenolol on proteinuria

and renal haemodynamics in non-diabetic renal disease. BMJ 1991; 303:821.

22.

Rosenberg ME, Hostetter TH. Comparative effects of antihypertensives on proteinuria: angiotensin-converting

enzyme inhibitor versus alpha 1-antagonist. Am J Kidney Dis 1991; 18:472.

23.

Bedogna V, Valvo E, Casagrande P, et al. Effects of ACE inhibition in normotensive patients with chronic

glomerular disease and normal renal function. Kidney Int 1990; 38:101.

24.

Haas M, Leko-Mohr Z, Erler C, Mayer G. Antiproteinuric versus antihypertensive effects of high-dose ACE

inhibitor therapy. Am J Kidney Dis 2002; 40:458.

25.

Navis G, Kramer AB, de Jong PE. High-dose ACE inhibition: can it improve renoprotection? Am J Kidney Dis26.


24 24/06/20



2002; 40:664.

Li PK, Leung CB, Chow KM, et al. Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-

blind, randomized, placebo-controlled study. Am J Kidney Dis 2006; 47:751.

27.

Hilgers KF, Mann JF. ACE inhibitors versus AT(1) receptor antagonists in patients with chronic renal disease. J

Am Soc Nephrol 2002; 13:1100.

28.

Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by

interference in the renin-angiotensin system? Kidney Int 1994; 45:861.

29.

Remuzzi A, Perico N, Sangalli F, et al. ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy. Am J Physiol 1999; 276:F457.30.

Schmieder RE, Klingbeil AU, Fleischmann EH, et al. Additional antiproteinuric effect of ultrahigh dose

candesartan: a double-blind, randomized, prospective study. J Am Soc Nephrol 2005; 16:3038.

31.

Rossing K, Schjoedt KJ, Jensen BR, et al. Enhanced renoprotective effects of ultrahigh doses of irbesartan in

patients with type 2 diabetes and microalbuminuria. Kidney Int 2005; 68:1190.

32.

Aranda P, Segura J, Ruilope LM, et al. Long-term renoprotective effects of standard versus high doses of

telmisartan in hypertensive nondiabetic nephropathies. Am J Kidney Dis 2005; 46:1074.

33.

Burgess E, Muirhead N, Rene de Cotret P, et al. Supramaximal dose of candesartan in proteinuric renal

disease. J Am Soc Nephrol 2009; 20:893.

34.

Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of

nephropathy progression. Kidney Int 2004; 65:1991.

35.

Ruggenenti P, Perna A, Benini R, Remuzzi G. Effects of dihydropyridine calcium channel blockers,

angiotensin-converting enzyme inhibition, and blood pressure control on chronic, nondiabetic nephropathies.

Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). J Am Soc Nephrol 1998; 9:2096.

36.

Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive

nephrosclerosis: a randomized controlled trial. JAMA 2001; 285:2719.

37.

Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the

progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;

4:542.

38.

Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with

chronic renal disease. N Engl J Med 2001; 345:925.

39.

Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces

albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006; 1:940.

40.

Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect

of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on

long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker.

Clin J Am Soc Nephrol 2006; 1:256.

41.

Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in

patients with chronic kidney disease. Kidney Int 2006; 70:2116.

42.

Slagman MC, Waanders F, Hemmelder MH, et al. Moderate dietary sodium restriction added to angiotensin

converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure:

randomised controlled trial. BMJ 2011; 343:d4366.

43.

Gansevoort RT, Wapstra FH, Weening JJ, et al. Sodium depletion enhances the antiproteinuric effect of ACE

inhibition in established experimental nephrosis. Nephron 1992; 60:246.

44.

Mishra SI, Jones-Burton C, Fink JC, et al. Does dietary salt increase the risk for progression of kidney

disease? Curr Hypertens Rep 2005; 7:385.

45.

Bakris GL, Weir MR. Salt intake and reductions in arterial pressure and proteinuria. Is there a direct link? Am J

Hypertens 1996; 9:200S.

46.

Barnes CE, Wilmer WA, Hernandez RA Jr, et al. Relapse or worsening of nephrotic syndrome in idiopathic

membranous nephropathy can occur even though the glomerular immune deposits have been eradicated.

Nephron Clin Pract 2011; 119:c145.

47.


24 24/06/20



Vegter S, Perna A, Postma MJ, et al. Sodium intake, ACE inhibition, and progression to ESRD. J Am Soc

Nephrol 2012; 23:165.

48.

Lambers Heerspink HJ, Holtkamp FA, Parving HH, et al. Moderation of dietary sodium potentiates the renal

and cardiovascular protective effects of angiotensin receptor blockers. Kidney Int 2012; 82:330.

49.

Fan L, Tighiouart H, Levey AS, et al. Urinary sodium excretion and kidney failure in nondiabetic chronic kidney

disease. Kidney Int 2014; 86:582.

50.

Buter H, Hemmelder MH, Navis G, et al. The blunting of the antiproteinuric efficacy of ACE inhibition by high

sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 1998; 13:1682.

51.

Esnault VL, Ekhlas A, Delcroix C, et al. Diuretic and enhanced sodium restriction results in improved

antiproteinuric response to RAS blocking agents. J Am Soc Nephrol 2005; 16:474.

52.

Vogt L, Waanders F, Boomsma F, et al. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric

efficacy of losartan. J Am Soc Nephrol 2008; 19:999.

53.

Fink HA, Ishani A, Taylor BC, et al. Screening for, monitoring, and treatment of chronic kidney disease stages

1 to 3: a systematic review for the U.S. Preventive Services Task Force and for an American College of

Physicians Clinical Practice Guideline. Ann Intern Med 2012; 156:570.

54.

Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of

nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 2001; 135:73.

55.

Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of

nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibitionand Progressive Renal Disease Study Group. Ann Intern Med 1997; 127:337.

56.

Kent DM, Jafar TH, Hayward RA, et al. Progression risk, urinary protein excretion, and treatment effects of

angiotensin-converting enzyme inhibitors in nondiabetic kidney disease. J Am Soc Nephrol 2007; 18:1959.

57.

Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other

antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005; 366:2026.

58.

Sharma P, Blackburn RC, Parke CL, et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor

blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev

2011; :CD007751.

59.

Maione A, Navaneethan SD, Graziano G, et al. Angiotensin-converting enzyme inhibitors, angiotensin receptor

blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk

factors: a systematic review of randomized controlled trials. Nephrol Dial Transplant 2011; 26:2827.

60.

Weiner DE, Tighiouart H, Levey AS, et al. Lowest systolic blood pressure is associated with stroke in stages 3

to 4 chronic kidney disease. J Am Soc Nephrol 2007; 18:960.

61.

Mulrow CD, Townsend RR. Guiding lights for antihypertensive treatment in patients with nondiabetic chronic

renal disease: proteinuria and blood pressure levels? Ann Intern Med 2003; 139:296.

62.

Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the

progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal

Insufficiency Study Group. N Engl J Med 1996; 334:939.

63.

Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of

terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi

Epidemiologici in Nefrologia). Lancet 1997; 349:1857.

64.

Ruggenenti P, Perna A, Gherardi G, et al. Renal function and requirement for dialysis in chronic nephropathy

patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia

(GISEN). Ramipril Efficacy in Nephropathy. Lancet 1998; 352:1252.

65.

Ruggenenti P, Perna A, Benini R, et al. In chronic nephropathies prolonged ACE inhibition can induce

remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN Group. Gruppo Italiano

Studi Epidemiologici in Nefrologia. J Am Soc Nephrol 1999; 10:997.

66.

Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic

nephropathies with non-nephrotic proteinuria. Lancet 1999; 354:359.

67.

Ruggenenti P, Perna A, Remuzzi G, Gruppo Italiano di Studi Epidemiologici in Nefrologia. ACE inhibitors to

prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the

68.


24 24/06/20



REIN trial results. Ramipril Efficacy in Nephropathy. J Am Soc Nephrol 2001; 12:2832.

Ruggenenti P, Perna A, Gherardi G, et al. Chronic proteinuric nephropathies: outcomes and response to

treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis 2000;

35:1155.

69.

O'Hare AM, Kaufman JS, Covinsky KE, et al. Current guidelines for using angiotensin-converting enzyme

inhibitors and angiotensin II-receptor antagonists in chronic kidney disease: is the evidence base relevant to

older adults? Ann Intern Med 2009; 150:717.

70.

Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with non-diabetic

chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005; 365:939.

71.

Fogo A, Breyer JA, Smith MC, et al. Accuracy of the diagnosis of hypertensive nephrosclerosis in African

Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK Pilot Study

Investigators. Kidney Int 1997; 51:244.

72.

Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on

progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002; 288:2421.

73.

Appel LJ, Wright JT Jr, Greene T, et al. Long-term effects of renin-angiotensin system-blocking therapy and a

low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans. Arch

Intern Med 2008; 168:832.

74.

Pogue V, Rahman M, Lipkowitz M, et al. Disparate estimates of hypertension control from ambulatory and

clinic blood pressure measurements in hypertensive kidney disease. Hypertension 2009; 53:20.

75.

Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency.

N Engl J Med 2006; 354:131.

76.

Hebert LA. Optimizing ACE-inhibitor therapy for chronic kidney disease. N Engl J Med 2006; 354:189.77.

Hsu TW, Liu JS, Hung SC, et al. Renoprotective effect of renin-angiotensin-aldosterone system blockade in

patients with predialysis advanced chronic kidney disease, hypertension, and anemia. JAMA Intern Med 2014;

174:347.

78.

Li PK, Chow KM, Wong TY, et al. Effects of an angiotensin-converting enzyme inhibitor on residual renal

function in patients receiving peritoneal dialysis. A randomized, controlled study. Ann Intern Med 2003;

139:105.

79.

O'Hare AM, Hotchkiss JR, Kurella Tamura M, et al. Interpreting treatment effects from clinical trials in the

context of real-world risk information: end-stage renal disease prevention in older adults. JAMA Intern Med2014; 174:391.

80.

Sarafidis PA, Bakris GL. Does evidence support renin-angiotensin system blockade for slowing nephropathy

progression in elderly persons? Ann Intern Med 2009; 150:731.

81.

de Jong PE, Anderson S, de Zeeuw D. Glomerular preload and afterload reduction as a tool to lower urinary

protein leakage: will such treatments also help to improve renal function outcome? J Am Soc Nephrol 1993;

3:1333.

82.

Praga M, Hernández E, Montoyo C, et al. Long-term beneficial effects of angiotensin-converting enzyme

inhibition in patients with nephrotic proteinuria. Am J Kidney Dis 1992; 20:240.

83.

Bakris GL, Mangrum A, Copley JB, et al. Effect of calcium channel or beta-blockade on the progression of

diabetic nephropathy in African Americans. Hypertension 1997; 29:744.

84.

Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal

disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 1995; 123:754.

85.

Shiigai T, Shichiri M. Late escape from the antiproteinuric effect of ace inhibitors in nondiabetic renal disease.

Am J Kidney Dis 2001; 37:477.

86.

Lea J, Greene T, Hebert L, et al. The relationship between magnitude of proteinuria reduction and risk of

end-stage renal disease: results of the African American study of kidney disease and hypertension. Arch Intern

Med 2005; 165:947.

87.

Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this

a cause for concern? Arch Intern Med 2000; 160:685.

88.

Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention,89.


24 24/06/20



Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560.

Susantitaphong P, Sewaralthahab K, Balk EM, et al. Efficacy and safety of combined vs. single renin-

angiotensin-aldosterone system blockade in chronic kidney disease: a meta-analysis. Am J Hypertens 2013;

26:424.

90.

Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt

progression of chronic renal disease: pathophysiology and indications. Kidney Int 2005; 67:799.

91.

Kincaid-Smith P, Fairley KF, Packham D. Dual blockade of the renin-angiotensin system compared with a 50%

increase in the dose of angiotensin-converting enzyme inhibitor: effects on proteinuria and blood pressure.

Nephrol Dial Transplant 2004; 19:2272.

92.

Laverman GD, Navis G, Henning RH, et al. Dual renin-angiotensin system blockade at optimal doses for

proteinuria. Kidney Int 2002; 62:1020.

93.

Russo D, Pisani A, Balletta MM, et al. Additive antiproteinuric effect of converting enzyme inhibitor and

losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 1999; 33:851.

94.

Catapano F, Chiodini P, De Nicola L, et al. Antiproteinuric response to dual blockade of the renin-angiotensin

system in primary glomerulonephritis: meta-analysis and metaregression. Am J Kidney Dis 2008; 52:475.

95.

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.

96.

Tobe SW, Clase CM, Gao P, et al. Cardiovascular and renal outcomes with telmisartan, ramipril, or both in

people at high renal risk: results from the ONTARGET and TRANSCEND studies. Circulation 2011; 123:1098.

97.

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.

98.

Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and

antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43:S1.

99.

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.

100.

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.

101.

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.

102.

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.

103.

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.

104.

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.

105.

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.

106.

Troyanov S, Wall CA, Miller JA, et al. Idiopathic membranous nephropathy: definition and relevance of a partialremission. Kidney Int 2004; 66:1199.

107.

James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood

pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).

JAMA 2014; 311:507.

108.

Ruzicka M, Quinn RR, McFarlane P, et al. Canadian Society of Nephrology commentary on the 2012 KDIGO

clinical practice guideline for the management of blood pressure in CKD. Am J Kidney Dis 2014; 63:869.

109.

Topic 7169 Version 32.0


24 24/06/20



Disclosures: Johannes FE Mann, MD Grant/Research/Clinical Trial Support: NovoNordisk [Diabetes (Liraglutide)]; Vifor [Dialysis (Iron-

hydroxide)]; Clegene [Dialysis (Sotatercept)]. Speaker's Bureau: Amgen [Anemia (Darbepoetin); Roche [Anemia (Methoxy polyethylene glycol-

epoetin beta); Novartis [Hypertension (Valsartan)]; Bruan [Dialysis (dialysis devices)]; Fresenius [Dialysis (dialysis devices)].

Consultant/Advisory Boards: NovoNordisk [Diabetes (Liraglutide)]; Relypsa [K-binder (Patiromer)]; Abbvie [CKD (Paricalcitol)]; Bayer

[Hypertension (Diuretics)]. George L Bakris, MD Grant/Research/Clinical Trial Support: Medtronic; Relypsa [Hypertension, hyperkalemia].

Consultant/Advisory Boards: Medtronic; Relypsa; Bayer; Novartis; DSI; Boehringer-Ingelheim; Lexicon; Janssen; Astra-Zeneca; Kona

[Diabetes, hyperkalemia, resistant hypertension (Canagliflozin, dapagliflozin, empagliflozin)]. Gary C Curhan, MD, ScD Consultant/Advisory

Boards: AstraZeneca [Gout (Lesinurad)]; Allena Pharmaceuticals [Kidney stones (Oral oxalate degrading product)]. Other Financial Interest:

American Society of Nephrology [CJASN Editor-in-Chief]. John P Forman, MD, MSc Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-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

Disclosures


antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults

Documents