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 a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Progression of chronic kidney disease (CKD), as defined by a reduction in the glomerular filtration rate (GFR), occurs at a variable rate, ranging from less than 1 to more than 12 mL/min per 1.73 m2 per year, depending upon the level of blood pressure control, the degree of proteinuria, the previous rate of GFR decline, and the underlying kidney disease, including diabetes [1-5].
There are two major components to slowing the rate of progression of CKD: treatment of the underlying disease, if possible; and treatment of secondary factors that are predictive of progression, such as elevated blood pressure and proteinuria. (See 'Importance of proteinuria and blood pressure control' below.)
The clinical trials evaluating antihypertensive therapy in nondiabetic CKD and our recommendations for choice of therapy as well as treatment goals will be reviewed here. The animal studies that provided the mechanisms and rationale for the clinical trials, the treatment of diabetic nephropathy, and general issues related to the treatment of hypertension in patients with CKD are discussed separately. (See "Antihypertensive therapy and progression of chronic kidney disease: Experimental studies" 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 be present. (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".)
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, a number 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 . 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) . (See 'Effect of goal blood pressure on progression of CKD' below.)
EFFECT OF ANTIHYPERTENSIVE DRUGS ON PROTEINURIA — The effect of antihypertensive drugs on proteinuria varies with drug class. When the blood pressure is controlled, renin-angiotensin system (RAS) inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are more effective than other antihypertensive drugs in reducing proteinuria and in slowing the rate progression of proteinuric chronic kidney disease (CKD), regardless of etiology . 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 .
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 .
•Acute administration of angiotensin II does not reverse the antiproteinuric effect, despite inducing renal and systemic vasoconstriction, and increasing intraglomerular pressure .
•In transgenic rats, overexpression of the angiotensin II receptor (type 1) in glomerular podocytes results in significant proteinuria, foot process effacement, and glomerulosclerosis .
•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 . In contrast, nephrin expression is increased by ACE inhibitor therapy .
●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".)
ACE inhibitors and ARBs have important side effects in patients with CKD, including the potential to induce hyperkalemia. The risk is low if the glomerular filtration rate is greater than 40 mL/min per 1.73 m2 and the initial serum potassium is in the low-normal range, and even lower if a diuretic is also given . 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 . 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 .
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 . (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) .
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 . 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 . 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 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 . 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 .
Aldosterone antagonists — Aldosterone 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 :
●There was a significantly greater reduction in proteinuria in the spironolactone group (weighted mean difference 800 mg/day, 95% CI 330-1270 mg/day).
●The patients treated with spironolactone also had a modestly but significantly lower systolic pressure (3.4 mmHg).
●Short-term changes in estimated GFR (less than one year of follow-up) were similar with spironolactone and placebo.
However, most of these studies did not first maximize the dose of the ACE inhibitor or ARB, and the aldosterone antagonist was associated with an increased risk of hyperkalemia (relative risk 3.1 in the meta-analysis) . Long-term trials are required to determine whether aldosterone antagonists slow the rate of progression of the renal disease.
Direct renin inhibitors (DRI) — Direct renin inhibitors, like aldosterone 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 . 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 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:
●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 . 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 . Patients on a high-sodium diet (defined as a 24-hour urinary sodium excretion greater than 250 mmol of sodium [14 grams of salt] per day) had the following adverse outcomes compared with patients on a low-sodium diet (defined as a 24-hour urinary sodium excretion less than 125 mmol of sodium [7 grams of salt] per day):
•A significantly smaller reduction in proteinuria in response to ramipril therapy at three months (20 versus 31 percent). In patients on a lower-sodium diet, this initial three-month reduction in proteinuria persisted over the entire four-year study period. However, the initial reduction in proteinuria waned in patients on a high-sodium diet, and returned to pre-ramipril levels by the end of the study.
•A significantly higher incidence of 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.
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 .
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 nondiabetic CKD but supportive data are limited . (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 . 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 . 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 a meta-analysis of 12 trials that included patients with severely increased albuminuria (formerly called "macroalbuminuria") or a combination of severely increased albuminuria and moderately increased albuminuria (formerly called "microalbuminuria") . 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 . 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 . The patients were already in reasonable blood pressure control on a variety of different medications and were then randomly assigned to benazepril or placebo in addition to their usual antihypertensive regimen. At baseline, the mean serum creatinine was 2.1 mg/dL (186 micromol/L) and mean protein excretion was 1.8 g/day.
The following results were noted:
●The mean attained blood pressure during the trial was significantly lower with benazepril than with placebo (135/84 versus 144/88 mmHg).
●Benazepril therapy reduced protein excretion by 25 percent compared with placebo.
●Progression to the primary endpoint (defined as doubling of the serum creatinine concentration or progression to dialysis) occurred in 31 of 300 patients treated with benazepril versus 57 of 283 in the placebo group. The relative risk reduction was 53 percent in the entire group, 71 percent in those with a baseline creatinine clearance above 45 mL/min, and 46 percent in those with a baseline creatinine clearance ≤45 mL/min.
●There was benefit in patients with chronic glomerular diseases and in the few patients with diabetic nephropathy who were enrolled; the findings were inconclusive in hypertensive nephrosclerosis because too few events occurred. Subsequent trials have shown that ACE inhibitors are associated with a slower rate of decline in glomerular filtration rate in proteinuric patients with primary hypertension (formerly called "essential" hypertension) and in proteinuric 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'.)
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 . 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 . 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) . At 20 months (and at 44 months for the trial phase and observational follow-up combined), the following benefits were noted:
●The mean rate of decline of the glomerular filtration rate (GFR) decreased from 0.44 to 0.10 mL/min per 1.73 m2 for patients originally randomized to ramipril, and from 0.81 to 0.14 mL/min per 1.73 m2 for those not originally given ramipril.
●At the end of the observational follow-up, the group originally randomized to ramipril had a significantly higher GFR (35.5 versus 23.8 mL/min per 1.73 m2).
●During the entire 44 month period of follow-up (including the trial and observational phases), the incidence of 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 m2 per month for other therapy) and a decreased incidence of end-stage renal disease (18 versus 52 percent) .
●Renal benefits of ramipril were observed whether the initial (baseline) GFR was within the lowest (11 to 33 mL/min/1.73 m2), middle (33 to 51 mL/min/1.73 m2), or highest tertile (51 to 101 mL/min/1.73 m2). Compared with other drugs, ramipril therapy decreased the rate of GFR decline by 20, 22, and 35 percent, respectively, and the incidence of end-stage renal disease by 33, 37, and 100 percent, respectively . The incidence of adverse events was similar across the tertiles and within each tertile for the ramipril and other treatment groups.
Thus, the original and follow-up ramipril studies strongly suggest that patients who particularly benefit are those with prominent proteinuria, a finding similar to that noted in other trials [64-67,69,70]. Significant benefit was also seen in patients with non-nephrotic proteinuria (1.0 to 2.9 g/day) .
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 m2), the low incidence of adverse effects with ramipril reflects the exclusion of patients with evidence of hypovolemia and renal artery stenosis, as well as the discontinuation of diuretics prior to initiating ACE inhibitor therapy.
REIN-2 trial — A lack of renoprotection with a dihydropyridine calcium channel blocker, even when used as add-on therapy to an ACE inhibitor to attain aggressive blood pressure control, was found in the REIN-2 trial of patients with nondiabetic proteinuric CKD (mean baseline GFR 35 mL/min and mean proteinuria 2.9 g/day) . 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 m2 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 .
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 . The primary outcome was the rate of change in glomerular filtration rate (GFR); the main secondary outcome was a composite endpoint of: reduction in GFR of more than 50 percent or more than 25 mL/min per 1.73 m2; 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.
●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 difference in mean decline in GFR or the composite clinical endpoint among the treatment groups.
The final results at four years of follow-up showed no difference among the drug groups in reducing the rate of decline of GFR. However, the incidence of the composite endpoint was significantly lower in those treated with ramipril than with amlodipine (6.9 versus 8.2 percent per year) or metoprolol (6.9 versus 8.7 percent per year) . (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 . (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, is there a serum creatinine concentration above which one would not use such therapy? The answer to this question appears to be no, except for truly end-stage disease.
The potential value of RAS inhibition in advanced disease was best shown in a Chinese study in which 422 patients with nondiabetic CKD were randomly assigned to benazepril or placebo plus other antihypertensive therapy to attain a systolic and diastolic pressure below 130 and 80 mmHg, respectively . Based upon the baseline serum creatinine concentration, patients were divided into two groups:
●Group 1 consisted of 141 patients with a serum creatinine concentration between 1.5 to 3.0 mg/dL (133 to 265 micromol/L). The mean estimated glomerular filtration rate (GFR) and level of proteinuria were 37 mL/min per 1.73 m2 and 1.6 g/day, respectively.
●Group 2 consisted of 281 patients with a serum creatinine concentration between 3.1 to 5.0 mg/dL (274 to 442 micromol/L). The mean estimated GFR and proteinuria were approximately 26 mL/min per 1.73 m2 and 1.6 g/day.
All patients had an eight-week run-in period in which they received benazepril at 10 mg/day for four weeks; they were closely monitored with weekly measurements of serum creatinine and potassium levels and blood pressure; the dose was increased to 10 mg twice daily if the serum creatinine concentration increased less than 30 percent, the serum potassium remained below 5.6 meq/L, and no adverse effects occurred. During this period, 94 patients were excluded from further study because of dry cough, marked changes in 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 to administer placebo), while the 224 patients remaining in group 2 were randomly assigned to benazepril (10 mg twice daily) or placebo. Additional antihypertensive therapy was administered to attain blood pressure goals. The primary endpoint was the composite of doubling of the serum creatinine level, 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:
●Significantly fewer group 2 patients (mean GFR of 26 mL/min per 1.73 m2) treated with benazepril reached the primary endpoint (41 versus 60 percent with placebo), resulting in an overall risk reduction of 43 percent with active therapy. The primary endpoint was reached less often in group 1 patients (22 percent), who had less severe disease and were all treated with benazepril.
●In group 2 patients, benazepril was associated with the following significant benefits: a lower rate of doubling of the serum creatinine concentration and of reaching 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 m2 per year).
●The extent of proteinuria reduction in patients with protein excretion above 1 g/day correlated significantly with the rate of decline in estimated GFR.
●The benefits with benazepril were independent of blood pressure lowering since the attained blood pressures were comparable in all groups.
●The incidence of major adverse effects was similar with benazepril and placebo.
The absence of serious hyperkalemia may have resulted from one or more of the following factors: approximately 5 percent of patients in group 2 were excluded from the study because of hyperkalemia during the eight-week run-in period; dietary intake of potassium was likely to be lower than in Western patients; and diuretics were used in more than 80 percent of patients, possibly resulting in increased renal potassium excretion . 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 m2) 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  (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 . ACE inhibitors also appear to slow the rate of loss of residual renal function being treated with peritoneal dialysis .
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 . This is an important issue since older patients are more likely to have adverse effects from therapy, including acute kidney injury and hyperkalemia. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Reduction in GFR' and "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Hyperkalemia'.)
Older patients with CKD are also less likely to have proteinuria, which was required in most of the RAS inhibition trials cited above. This was demonstrated in an analysis of 1190 National Health and Nutrition Examination Survey (NHANES) participants who were over age 70 years and had CKD, which was defined as an estimated GFR <60 mL/min per 1.73 m2 or an albumin-to-creatinine ratio >200 mg/g of creatinine (approximately 300 mg/day) . 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 .
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) . The NNT ranged from 2500 among patients with an estimated GFR 45 to 59 mL/min per 1.73 m2 and no dipstick proteinuria to 16 among those with an estimated GFR 15 to 29 mL/min per 1.73 m2 and 2+ or greater dipstick proteinuria. More than 90 percent of the cohort had a NNT greater than 100, comparing unfavorably to the NNT calculated from trials of younger patients (which were usually less than 25).
The findings above suggest that the great majority of patients over age 70 years with CKD would not benefit from RAS inhibition for renoprotection and may have harm from a higher rate of side effects . 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 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 . 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 .
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 . 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 .
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 a normal level of albumin excretion (by 9.4 percent) . 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 . 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 m2) and/or proteinuria (defined as a urine albumin–to-creatinine ratio greater than 177 mg/g for men and 248 mg/g for women, thresholds that roughly correlate with more than 300 mg of albumin on a 24-hour urine collection) .
The following observations were made among the patients with reduced renal function:
●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.
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) . (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 . (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) . 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 (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:
●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 . 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 . 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 without proteinuria. 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'.)
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 . Two groups were compared: one with usual blood pressure control (target mean arterial pressure less than 107 mmHg, which is equivalent to 140/90 mmHg) and one with more aggressive control (target mean arterial pressure less than 92 mmHg, which is equivalent to 125/75 mmHg) over a three-year period. The achieved mean arterial pressures were 96 and 91 mmHg (equivalent to 130/80 and 125/75 mmHg, respectively). Almost one-half of the patients were treated with an ACE inhibitor, but its selective efficacy was not assessed.
The results in 585 patients with a mean baseline GFR of 39 mL/min and mean urinary protein excretion of 1.1 g/day can be summarized as follows (figure 2):
●The loss of GFR was lowest in patients excreting less than 1 g/day (2.8 to 3.0 mL/min year), but no benefit 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 with conventional versus 6.7 mL/min per year with aggressive blood pressure control).
●A secondary analysis suggested that aggressive blood pressure control may be particularly important in blacks . (See "Hypertensive complications in blacks", section on 'Goal blood pressure'.)
A subsequent study reported the long-term outcomes of patients enrolled in the initial MDRD study . 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 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 not for 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 . 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 . 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 excretion was 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 . 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) . 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 difference in 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 . 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 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:
●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 a ratio below 0.7 would represent goal proteinuria below 1 g/day.
We suggest a proteinuria goal of less than 1000 mg/day, which is similar to the K/DOQI recommendation of 500 to 1000 mg/g creatinine. It may be difficult to attain this goal, particularly in patients with the nephrotic syndrome. In such patients, we suggest a minimum reduction in proteinuria of at least 50 to 60 percent from baseline values plus protein excretion less than 3.5 g/day. This approach is based upon an observational study in 348 patients with membranous nephropathy and nephrotic syndrome who were treated with renin-angiotensin system (RAS) inhibition and, in some cases, immunosuppressive therapy and were followed for a minimum of one year . 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 also associated 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:
●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).
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 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 BP less 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) . (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 . 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 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient information: Medicines for chronic kidney disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●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.)
•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 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 the protein-to-creatinine ratio to the 24-hour protein excretion. This allows the subsequent use of spot urine protein-to-creatinine ratios to more accurately estimate the degree of proteinuria. (See 'Proteinuria goal' above.)
●In patients with 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 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 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'.)
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