Does Blockade of the Renin-Angiotensin-Aldosterone System Slow Progression of All Forms of Kidney Disease?
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- Lattanzio, M.R. & Weir, M.R. Curr Hypertens Rep (2010) 12: 369. doi:10.1007/s11906-010-0142-2
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The velocity of chronic kidney disease (CKD) progression is only partly dependent on the nature and activity of the underlying disease process. Activation of the renin-angiotensin-aldosterone system (RAAS) is a crucial, and often universal, event responsible for the pathophysiologic mechanisms that accelerate CKD progression. Thus, it would appear that interruption of the RAAS through the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or direct renin inhibitors can play a principal role in slowing CKD progression, regardless of the cause. Unfortunately, applying this generalized approach to all forms of CKD has been delayed by the lack of strong, evidence-based data. The aim of this review is to provide the most current evidence available for the use of RAAS blockade as a method of slowing the progression of the various forms of CKD.
KeywordsChronic kidney diseaseCKDRenal diseaseProgressionProteinuriaRenin-angiotensin-aldosterone systemRAASRASDiabetes
Clinical Trial Acronyms
African American Study of Kidney Disease
Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension
Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints
Aliskiren in the Evaluation of Proteinuria in Diabetes
- HALT PKD
Halt Progression of Polycystic Kidney Disease
Hong Kong Study using Valsartan n IgA Nephropathy
Irbesartan in Diabetic Nephropathy Trial
Modification of Diet in Renal Disease
Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial
Ramipril Efficacy in Nephropathy
Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan
- VA NEPHRON-D
Veterans Affairs Nephropathy in Diabetes
The progression of chronic kidney disease (CKD) occurs at a variable and unpredictable rate and is accelerated by poor blood pressure control, proteinuria, and the existence of diabetes. Numerous studies in animals and humans have demonstrated that progression of various forms of CKD is largely influenced by secondary hemodynamic and metabolic factors, rather than by the nature and activity of the underlying disease. Intraglomerular hypertension, glomerular hypertrophy, and albuminuria are among some of the factors responsible for secondary renal injury. Fortunately, these secondary factors can be ameliorated by the implementation of renin-angiotensin-aldosterone system (RAAS) blockade, so this strategy may play a pivotal role in slowing the decline in renal function. The paucity of large-scale, randomized controlled trials applying RAAS blockade to all forms of renal disease has hindered the generalized use of this strategy. Additionally, the response to RAAS blockade involving therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), or direct renin inhibitors (DRIs) may not be uniform among all patient populations. This article provides a current overview of the available literature focusing on the role of RAAS blockade as a method of slowing the progression of all forms of renal disease.
The Value of Proteinuria Reduction to Slow Renal Disease Progression
Numerous studies have shown that treating patients with diabetic or nondiabetic CKD and proteinuria with an ACE inhibitor or ARB reduces proteinuria and slows progression of CKD, and that the greater the diminution in proteinuria, the greater the benefit. Post hoc analyses of data from the RENAAL, IDNT, and AASK studies have demonstrated clearly that a reduction in clinical albuminuria or proteinuria correlated with a decrease in the risk of renal end points, including renal disease progression [1–3]. For example, in a post hoc analysis of IDNT, for each halving of proteinuria level between baseline and 12 months with irbesartan, the risk for kidney failure was reduced by more than half (HR, 0.44; 95% CI, 0.40–0.49; P < 0.001) . More convincingly, these reductions in composite end points occur either in conjunction with or independent of the reduction of blood pressure. It is certain that proteinuria reduction through RAAS blockade represents an effective strategy to slow renal disease progression and can serve as a surrogate measure for treatment efficacy with regard to both medication and level of achieved blood pressure. With this background, we will discuss the value of RAAS blockade in proteinuric forms of CKD.
Proteinuric Chronic Kidney Disease
Large-scale renal outcome trials have demonstrated the efficacy of blocking the RAAS with ACE inhibitors and ARBs to reduce proteinuria and retard the progression of diabetic nephropathy. For example, the RENAAL study examined the effect of losartan versus placebo on renal outcomes in diabetic nephropathy patients (mean serum creatinine, 1.9 mg/dL; median albumin-creatinine ratio, 1.237 mg/g) . After a mean follow-up of 3.4 years, losartan was associated with a 16% reduction in the primary end point (doubling serum creatinine level, progression to end-stage renal disease [ESRD], or death), a 35% reduction in albumin-creatinine ratio, a 15% decrease in the rate of decline in estimated creatinine clearance, and a 28% reduction in ESRD . Based on these and other compelling data, the National Kidney Foundation K/DOQI guidelines recommend an ACE inhibitor or ARB as standard therapy for all patients with diabetic and nondiabetic kidney disease and a spot urine protein-to-creatinine ratio of 200 mg/g or more, regardless of their blood pressure control . Because the effectiveness of ACE inhibitors and ARBs for the management of diabetic nephropathy is conclusive, the focus in this section is on newer agents and strategies to block the RAAS system and their impact on diabetic nephropathy progression.
Data have emerged that blocking multiple constituents of the RAAS simultaneously may have additive benefit in managing proteinuric diabetic kidney disease. In a recent meta-analysis comprising mostly diabetic patients, 10 of the 14 trials (71.4%) comparing combination therapy versus single-agent therapy with an ACE inhibitor or ARB favored treatment with combination therapy, given the primary end point of reduction in proteinuria at 5–12 months (ratio of means, 0.48–0.76) . In total, combination therapy reduced proteinuria by 20–25% more than either drug alone . From a safety perspective, Jennings et al.  recently reviewed 10 clinical trials in 315 patients with diabetic nephropathy and observed only a 0.2 mmol/L increase in serum potassium concentration with combination therapy compared with ACE inhibitor monotherapy (P < 0.001). Targeting different components of the RAAS appears to be a safe and powerful strategy for reducing proteinuria in patients with diabetic nephropathy.
The addition of MRA to conventional ACE inhibitor or ARB therapy may have other renoprotective properties. A recent study examined the renoprotective effects of adding an MRA, spironolactone, to maximal ACE inhibition in patients with diabetic nephropathy . Patients were randomly assigned placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 weeks. Despite no differences in blood pressure, albuminuria decreased more in the low-dose spironolactone group than in the losartan group, when compared with placebo (34% vs 16.8%) . These benefits have been extended to a selective MRA, eplerenone, when used in combination with ACE inhibitor therapy [10•]. The safety of combining MRA therapy with ACE-inhibitor and/or ARB therapy has been confirmed in numerous studies [11, 12]. In conclusion, it appears that adding even low-dose MRA therapy to maximal ACE inhibition or ARB therapy is a safe and effective method for reducing proteinuria in patients with diabetic nephropathy.
Combination therapy can also protect against the “angiotensin II escape” and “aldosterone breakthrough” phenomena, which could attenuate the effect of RAAS blockade over time. Sato et al.  found that aldosterone breakthrough was observed in 40% of type 2 diabetic patients with early nephropathy during 40 weeks of trandolapril therapy. Trandolapril reduced albuminuria in patients without aldosterone breakthrough, whereas the antialbuminuric effect of trandolapril was abrogated in patients with aldosterone breakthrough. Furthermore, the addition of low-dose spironolactone to trandolapril significantly reduced albuminuria without a change in blood pressure for individuals with diabetic nephropathy and aldosterone breakthrough .
Direct renin inhibitors (DRI) target the rate-limiting step of the RAAS and appear beneficial in managing diabetic nephropathy. The AVOID trial evaluated the renoprotective effects of dual RAAS blockade in hypertensive individuals with diabetic nephropathy [14•]. The AVOID trial was powered for evaluating proteinuria reduction and was performed in individuals with proteinuric (>300 mg/d) CKD Stage 2 and 3. Adding a DRI, aliskiren, to losartan resulted in a 20% reduction in albuminuria (95% CI, 9%–30%; P < 0.001) with a reduction of 50% or more in 24.7% of the patients who received aliskiren, compared with 12.5% of those who received placebo (P < 0.001) [14•]. The reduction in proteinuria conferred by dual RAAS blockade with aliskiren and losartan occurred independently of blood pressure–lowering effects. From a safety perspective, dual RAAS blockade did not result in more adverse events, including hyperkalemia, than occurred in the monotherapy group. Another trial, ALTITUDE, will determine whether adding aliskiren to ACE inhibitor or ARB therapy can reduce cardiovascular and renal events in three groups of high-risk patients age 35 years or older who have type 2 diabetes: 1) those with a urinary albumin/creatinine ratio (UACR) greater than 200 mg/g; 2) those with microalbuminuria (UACR ≥ 20 mg/g but <200 mg/g) and an eGFR of at least 30 but less than 60 mL/min/1.73 m2; and 3) those within the same eGFR limits as the second group, with or without microalbuminuria, but also with a history of cardiovascular disease [15•]. This study should be helpful to evaluate not only the benefits of this novel form of dual RAAS blockade on renal and cardiovascular outcomes, but also the relationship to cardiovascular events of change in proteinuria and microalbuminuria.
Why is dual RAAS blockade so beneficial for renal outcomes in diabetic nephropathy? Park et al.  identified “non-ACE” pathways responsible for most angiotensin II production in the type 2 diabetic leptin receptor–deficient mouse kidney. Intrarenally formed angiotensin II from the substrate angiotensin I produces potent afferent arteriole vasoconstriction in the presence of ACE inhibition in the diabetic kidney. In the normal kidney, however, afferent arteriolar vasoconstriction secondary to intrarenally formed angiotensin II is blocked by ACE inhibition. Inhibition of these “non-ACE” enzymes abolished the afferent arteriole response to intrarenal conversion of angiotensin I to angiotensin II in the diabetic kidney but not in the control kidney . These studies provide a plausible explanation for the superior effects of combining an ACE inhibitor with an angiotensin type 1 receptor antagonist versus ACE inhibitor therapy alone in diabetic nephropathy.
ONTARGET, a trial using the ARB telmisartan alone and in combination with the ACE inhibitor ramipril, has sparked both efficacy and safety concerns within the nephrology community regarding the use of dual RAAS blockade to achieve more desirable renal outcomes [17•]. Two important considerations are required in interpreting these results: the context of the cohort studied (nonproteinuric CKD patients at low risk of progression) and the inadequate power of the study to assess renal outcomes. The cardiac and renal protection afforded from dual RAAS blockade in select populations, particularly proteinuric CKD, is supported by literature. Moreover, the response to dual RAAS blockade involving different combinations of ACE inhibitors, ARBs, MRAs, and DRIs may not be uniform among all patient populations. That being said, the use of dual RAAS blockade should be avoided in managing nonproteinuric CKD until more conclusive data become available. ALTITUDE and VA NEPHRON-D are two ongoing trials examining the long-term renal effects of dual RAAS blockade in patients with diabetic kidney disease [15•, 18•].
There is powerful evidence supporting the use of RAAS-blocking agents in the management of nondiabetic proteinuric CKD. In the REIN study, nondiabetic patients with proteinuric kidney disease (average serum creatinine of 2.4 mg/dL and 24-h urine protein excretion >3 g/d) who were randomly assigned to ramipril experienced a 55% decrease from baseline in median urine protein excretion, significant decreases in the rate of GFR decline, and lower risk of doubling serum creatinine or progression to ESRD . In this trial, the only baseline variable that correlated significantly with decline in GFR and progression of disease to ESRD was urinary protein excretion. Thus, patients with baseline urinary protein excretion less than 2.5 g/d had a lower rate of GFR decline over 3 years of follow-up, whereas in those with proteinuria in the nephrotic range (>4.3 g/d), GFR declined by 10 mL/min/1.73 m2 per year and the kidney failure rate exceeded 50% at 3 years . The risk of kidney disease progression still decreased significantly with RAAS inhibition, even after adjusting for blood pressure reduction. The REIN study showed that despite similar blood pressure control in the two treatment groups, patients with proteinuria of 3 g/d or more who received the ACE inhibitor had a significantly lower rate of GFR decline and a lower risk of ESRD or doubling of serum creatinine levels than did patients receiving conventional antihypertensive therapy.
The benefits of RAAS blockade in this population apply to all spectrums and severities of disease. In further analyses of the REIN trial, the benefits with ramipril appear to extend to those with less severe proteinuria and are observed in patients with varying degrees of renal insufficiency . Additional follow-up at 60 months found that some patients on continued ramipril therapy even had increased GFR compared with baseline values. Ramipril therapy decreased the rate of decline in GFR by 20%, 22%, and 35%, respectively, among patients with initial GFRs within the lowest (11–33 mL/min/1.73 m2), middle (33–51 mL/min/1.73 m2), and highest tertiles (51–101 mL/min/1.73 m2); the incidence of ESRD decreased by 33%, 37%, and 100% . Benefits with ramipril also appear to be independent of the initial severity of renal failure but are maximal when begun early in the course of the disease .
In the Angiotensin-Converting-Enzyme Inhibition In Progressive Renal Insufficiency study, almost 600 patients were enrolled, who had various types of underlying CKD, including glomerulopathies, polycystic disease, nephrosclerosis, and interstitial nephritis . The trial patients were randomly assigned to benazepril or placebo, in addition to their preexisting blood pressure regimens. The mean serum creatinine was 2.1 mg/dL and mean protein excretion was 1.8 g/d. At 3 years, 31 patients in the benazepril group and 57 in the placebo group had reached the primary end point (P < 0.001). In the benazepril group, the reduction in the risk of reaching the end point was 53% overall (95% CI, 27–70%), 71% (95% CI, 21–90%) among the patients with mild renal insufficiency, and 46% (95% CI, 12–67%) among those with moderate renal insufficiency. The reduction in risk was greatest among patients with baseline urinary protein excretion greater than 1 g/d . The beneficial effects of benazepril appeared to be attributable to mechanisms other than blood pressure reduction alone.
In the AASK trial, a total of 1094 African American patients with hypertensive renal disease (mean serum creatinine level of 2.2 mg/dL, and mean proteinuria of about 500–600 mg/d) were randomly assigned to ramipril, amlodipine, or metoprolol . The investigators also examined two levels of blood pressure in each treatment group (140/90 vs 125/75 mm Hg). The primary outcome measure was rate of change in GFR (GFR slope); the secondary outcome was a clinical composite of reduction in GFR by 50% or more from baseline, ESRD, or death. The ramipril group manifested risk reduction in the clinical composite outcome of 22% compared with the metoprolol group (95% CI, 1–38%; P = 0.04) and 38% compared with the amlodipine group (95% CI, 14–56%; P = 0.04) . Additionally, therapy with ramipril resulted in the lowest change in geometric mean of proteinuria from baseline. A post hoc analysis of the AASK trial showed that baseline proteinuria was the key factor that predicted renal outcome benefits of the lower blood pressure goal, because the lower target of 125/75 mm Hg preserved renal function in the subset of patients with proteinuria greater than 1000 mg/d .
Does the use of RAAS blockade in nondiabetic renal disease confer renoprotection at more advanced stages of disease? Hou et al.  performed a randomized, double-blind study to determine the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency. In this study, 104 patients with serum creatinine levels of 1.5–3.0 mg/dL (group 1) received 20 mg of benazepril per day, whereas 224 patients with serum creatinine levels of 3.1–5.0 mg/dL (group 2) were randomly assigned to receive 20 mg of benazepril per day (112 patients) or placebo (112 patients) and then were observed for a mean of 3.4 years . The mean protein excretion ranged from 1.6 to 1.7 g/d in the various groups. Compared with placebo, benazepril therapy was associated with a 43% reduction in the risk of the primary end point (composite of doubling of serum creatinine, ESRD, or death) in group 2 (P = 0.005). This benefit did not appear to be attributable to blood pressure control. Benazepril therapy was associated with a 52% reduction in the level of proteinuria and a 23% reduction in the rate of decline in renal function . The overall incidence of major adverse events in the subgroups of group 2 was similar.
Similarly, a meta-analysis of patients with nondiabetic CKD and proteinuria ranging from 0.1 g/d to 3.1 g/d showed that regimens including an ACE inhibitor were associated with a decrease in urinary protein excretion (0.46 g/d [95% CI, 0.33–0.59 g/d]) . More importantly, after adjusting for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, the relative risk for ESRD in the ACE inhibitor group was 0.69 (95% CI, 0.51–0.94) and 0.70 (95% CI, 0.55–0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or ESRD. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P = 0.03 for the ESRD group and P = 0.001 for the combined-outcome group), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d . It is apparent that RAAS blockade can dramatically alter the downward slope of GFR decline in nondiabetic, proteinuric renal disease.
Nonproteinuric Chronic Kidney Disease
There is a dearth of large-scale, randomized, controlled trials examining the impact of RAAS blockade on renal end points in individuals with nonproteinuric CKD. The benefits of RAAS blockade in nonproteinuric CKD can be extrapolated from trials that do not evaluate the impact of RAAS blockade alone. The renal outcomes study in the recent ACCOMPLISH trial was a double-blind, randomized trial that examined the effects of the drug combinations (ACE inhibitor/calcium channel blocker versus ACE inhibitor/hydrochlorothiazide) on CKD outcomes in a large population of patients who were at risk for cardiovascular events [25•]. The frequency of the composite end point of progression of CKD, defined as doubling serum creatinine or ESRD, was analyzed. More than half of the patients in each treatment group had diabetic nephropathy, but only 5.1% (585 patients) of the total population had albuminuria more than 33.9 mg/mmol [25•]. In the intention-to-treat population, there were fewer combined cardiovascular deaths and CKD events in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. The combined end point of progression of CKD and all-cause mortality was also lower in the benazepril plus amlodipine group (346 events, 6%) than in the benazepril plus hydrochlorothiazide group (465 events, 8.1%; HR, 0.73; 95% CI, 0.64–0.84; P < 0.011) [25•]. Differences in blood pressure control throughout the study could not account for these findings. In conclusion, patients with hypertension, CKD, and minimal or no albuminuria who were treated with the combination of benazepril and amlodipine had lower rates of cardiovascular events and slower progression of CKD than did patients treated with the combination of benazepril and hydrochlorothiazide.
It is important to note that because clinical proteinuria is such an important predictive factor for renal disease progression, clinical trials to evaluate RAAS intervention with lesser degrees of proteinuria or albuminuria will require many more patients and a much longer period of follow-up. The expense of such studies makes them impractical to perform. Therefore, nephrologists will be forced to make judgments regarding the value of RAAS blockade in slowing nonproteinuric CKD from trials that do not specifically aim to substantiate this practice.
Autosomal Dominant Polycystic Kidney Disease
A meta-analysis of eight randomized trials of progression of ADPKD provides evidence for this hypothesis . At a mean follow-up of 2.3 years, urinary protein excretion significantly decreased in the ACE inhibitor group compared with the control group (−0.33 g/d vs +0.19 g/d) . This benefit was greater in those with higher levels of baseline urine protein excretion. There was also a nonsignificant trend for a decreased incidence of progression of renal dysfunction with ACE inhibitor therapy (29% vs 41%, P = 0.17) . A study that was not included in the previous meta-analysis found that effective blood pressure control with an ACE inhibitor appeared to delay the onset of renal failure . In this prospective study, 24 patients with ADPKD, hypertension, and creatinine clearance greater than 50 mL/min/1.73 m2 were randomly assigned to either amlodipine or enalapril. At 5 years, there was a similar degree of blood pressure control and preservation of renal function, with a mean yearly decline in creatinine clearance of approximately 3.4 mL/min per 1.73 m2. These findings compare favorably with the rate of progression in patients with ADPKD and uncontrolled hypertension (yearly declines of 5.3–5.8 mL/min/1.73 m2 in the MDRD study) . In addition, enalapril, but not amlodipine, had a consistent antiproteinuric effect, but the ability to lower proteinuria did not correlate with the preservation of kidney function in these patients.
ARBs appear to confer the same renal benefits in ADPKD as ACE inhibitors. A randomized trial of 49 hypertensive patients with ADPKD compared amlodipine versus candesartan . Blood pressure was equally well controlled in both groups. Serum creatinine was higher in the amlodipine group than in the candesartan group at 24 and 36 months (P < 0.05). The decrease in creatinine clearance at 36 months was larger in the amlodipine group than in the candesartan group (−20.9 ± 13.1 vs −4.8 ± 13.8 mL/min; P < 0.01). Urinary albumin excretion was significantly lower in the candesartan group than in the amlodipine group at 12, 24, and 36 months .
HALT PKD, a large randomized clinical trial that is currently under way, will determine the impact of intensive blockade of the RAAS and the level of blood pressure control on progressive renal disease in individuals with early and more advanced stages of ADPKD [29•]. In Study A, participants with a GFR greater than 60 mL/min/1.73 m2 will be randomized to one of four conditions in a 2-by-2 design: combination ACE inhibitor and ARB therapy at two levels of blood pressure control, standard (systolic 120–130 and diastolic 70–80 mm Hg) versus low (systolic 95–110 and diastolic 60–75 mm Hg), or ACE inhibitor monotherapy at the same two levels of blood pressure control. The primary outcome of Study A is the percentage change in total kidney volume, as measured by MRI. Study B will assess the effects of intensive blockade of the RAAS through combination ACE inhibitor and ARB therapy compared with ACE inhibitor monotherapy, with both groups treated to standard levels of blood pressure control; the composite end point is the time to 50% reduction in baseline estimated GFR, ESRD, or death. HALT PKD will help determine the efficacy of aggressive RAAS blockade in preventing or slowing the decline of renal function in ADPKD.
The value of RAAS blockade in IgA nephropathy includes (but is not limited to) blood pressure control, proteinuria reduction, slowing of renal disease progression, and the possibility of inducing remission. Proteinuria reduction is particularly important in the treatment of IgA nephropathy because proteinuria in IgA nephropathy has a strong, adverse prognostic effect. Observational studies by Reich et al.  revealed that proteinuria during follow-up was the most important predictor of the rate of GFR decline in patients with IgA nephropathy. Among the 171 patients with less than 1 g/d of sustained proteinuria, the rate of decline was 90% slower than the mean rate . The rate of decline increased with the amount of proteinuria: those with sustained proteinuria greater than 3 g/d (n = 121) lost renal function 25-fold faster than those with less than 1 g/d. Patients who presented with at least 3 g/d of proteinuria and achieved a partial remission (<1 g/d) had a course similar to that of patients with proteinuria no higher than 1 g/d throughout, and they fared far better than patients who never achieved remission . These results underscore the relationship between proteinuria and prognosis in IgA nephropathy.
A randomized, controlled trial examined the impact on renal survival of enalapril versus non-RAAS-blocking antihypertensive therapies in individuals with IgA nephropathy, proteinuria (>0.5 g/d, mean 1.9 g/d), and a serum creatinine concentration <1.5 mg/dL at baseline . At follow-up of about 6 years, renal survival (defined as <50% increase in serum creatinine) was significantly more likely in the enalapril group (92% vs 55%). Enalapril was associated with a significant decrease in proteinuria, which correlated with renal survival . These benefits were observed despite no significant difference between the two groups in blood pressure control.
In the double-blind, placebo-controlled HKVIN study, 109 Chinese patients with IgA nephropathy and protein excretion greater than 1 g/d (mean about 2 g/d) were randomly assigned to receive valsartan or placebo, with other non-ACE or non-ARB antihypertensive therapies to achieve blood pressure lower than 140/90 mm Hg . Patients in the valsartan group had lower baseline proteinuria and achieved blood pressure. In adjusted analyses, valsartan was associated with significant improvement in proteinuria (33% reduction vs placebo) and a slower yearly rate of decline in GFR (4.6 vs 6.9 mL/min) .
In the IgACE trial, 65 young patients (range 9–35 years) with IgA nephropathy and moderate proteinuria (between 1 and 3.5 g/d per 1.73 m2) were randomly assigned to benazepril or placebo . At a median follow-up of 38 months, the primary end point (>30% decrease in renal function) was reached by fewer patients in the treatment arm. However, this study was underpowered to address this outcome. Nevertheless, active therapy resulted in a significantly lower incidence of the secondary composite end point (>30% decrease in creatinine clearance or worsening of proteinuria until the nephrotic range was reached) and a higher incidence of partial remission (41% vs 9%) or complete remission (13% vs 0%) . Blood pressure probably did not influence the study results, as blood pressures were higher in the placebo group only during the last 2 years of the study.
The addition of an ARB to an ACE inhibitor in patients with IgA nephropathy appears to produce a more potent antiproteinuric effect. Russo et al.  examined the antiproteinuric effect of combining ACE inhibitor therapy with ARB therapy in normotensive patients with IgA nephropathy. In this study, when enalapril and losartan were co-administered, proteinuria decreased by a greater extent compared with either agent alone. Moreover, an additional reduction in proteinuria was observed when combined-therapy doses were doubled . The reduction in proteinuria appeared to occur independently of blood pressure reduction. In conclusion, this study shows that combination therapy with enalapril and losartan has an additive, dose-dependent, antiproteinuric effect.
In summary, there are no prospective randomized controlled trials to show a benefit of RAAS blockade on hard renal end points in patients with IgA nephropathy, but its beneficial effects on blood pressure, proteinuria, and slope of change of GFR are indicative of potential benefit.
The use of ACE inhibitor or ARB therapy is associated with longer patient and graft survival after renal transplantation. A retrospective cohort study was conducted in 2031 patients who received renal transplants from 1990 to 2003 and survived at least 3 months . Patient and graft survival was compared between patients treated with ACE inhibitors and/or ARBs versus patients without such treatment. The 10-year survival rates were 74% for the group treated with ACE inhibitors and/or ARBs but only 53% in the group without such treatment (P < 0.001). The hazard ratio (HR) for mortality with ACE inhibitor or ARB use was 0.57 (95% CI, 0.40–0.81) compared with nonuse . The 10-year actual graft survival rate was 59% in ACE inhibitor/ARB patients but only 41% in nonusers (P = 0.002). The HR of actual graft failure for ACE inhibitor/ARB recipients was 0.55 (95% CI, 0.43–0.70) compared with nonusers, and the HR of functional graft survival was 0.56 (95% CI, 0.40–0.78). Ten-year unadjusted functional graft survival rates were 76% among ACE inhibitor/ARB recipients and 71% in the others (P = 0.57). In conclusion, more frequent use of these medications may reduce the high incidence of death and renal allograft failure in renal transplant recipients. However, not all retrospective studies of RAAS blocker use in transplant recipients demonstrate similar benefits on renal and cardiovascular outcomes.
Chronic allograft injury is characterized by a progressive decline in kidney function and is recognized as the principal cause of late graft loss. Some of the pathogenic factors involved in chronic allograft injury, such as hypertension, atherosclerosis, and calcineurin inhibitor nephrotoxicity, are associated with RAS activation. Accordingly, inhibition of the RAAS has been shown to slow down the progression of chronic allograft injury. Amuchastegui et al.  demonstrated that losartan is clearly better than a calcium channel blocker in protecting against chronic allograft injury. Similarly, a retrospective cohort study of the effects of long-term ACE inhibitor and ARB administration to a group of renal transplant recipients demonstrates that RAAS blockade can slow the rate of progression of established chronic renal allograft dysfunction and is also associated with excellent long-term graft function and survival .
Transforming growth factor β1 (TGF-β1) plays an integral role in the pathogenesis of chronic allograft injury, and the production of TGF-β1 is modulated through the intrarenal RAAS. RAAS blockade decreases the synthesis and secretion of renal TGF-β1 in patients with chronic allograft injury and can decrease the rate of histopathologic progression in chronic allograft nephropathy [38, 39]. In a recent double-blind, placebo-controlled and crossover study, losartan exerted a beneficial effect against tubular injury and graft fibrosis and thus may have a role in preventing chronic allograft injury . In this study, losartan reduced urinary excretion of the proteins TGF-β1 (associated with tubular damage) and amino-terminal propeptide of type III procollagen (associated with graft fibrosis) .
RAAS blockade in renal transplant patients may have additional benefits by reducing proteinuria and inducing regression of LVH. Proteinuria is an important predictor of poor long-term graft and patient survival in the renal transplant population, and LVH is an independent risk factor for heart failure and death in renal transplant recipients. A prolonged course of ACE inhibitor therapy can induce regression of LVH in renal transplant recipients by mechanisms independent of blood pressure control . Hiremath et al.  found that in renal transplant recipients, RAAS blockade is associated with an average reduction in proteinuria of 470 mg/d. Theoretically, RAAS blockade may reduce the relative risk of cardiovascular events among renal transplant recipients by reducing proteinuria and LVH.
The use of ACE inhibitors and ARBs in renal transplant patients is safe and efficacious. In a 2-year, prospective, randomized, double-blind study comparing the effects of quinapril and atenolol on blood pressure and allograft function in 70 patients with posttransplant hypertension, the use of quinapril was not associated with a change in creatinine clearance. Additionally, retrospective subgroup analysis of subjects with decreased kidney function (defined as serum creatinine >1.4 mg/dL) showed significant improvement in this number in the ACE inhibitor group (from 1.9 to 1.6 mg/dL; P < 0.01), which was not seen in the atenolol group (1.7–2.0 mg/dL; P = NS). A prospective, randomized, double-blind, placebo-controlled, multicenter study demonstrated that the use of valsartan significantly reduced blood pressure without adversely affecting serum creatinine in renal transplant recipients .
In conclusion, RAAS blockade in the renal transplant population is a safe and effective strategy for improving blood pressure, reducing proteinuria and LVH, and suppressing some of the proinflammatory and profibrotic cytokines that may promote interstitial fibrosis and tubular atrophy in the renal allograft. Although we lack data from a prospective randomized controlled trial with these drugs versus placebo, the prevailing evidence suggests that the use of RAAS blockade may provide important benefits for the patient and the renal allograft.
Renal disease progression is only partially dependent on the nature and activity of the underlying disease. Secondary factors that contribute to renal disease progression can be mitigated by the implementation of RAAS blocking agents, which therefore represents a powerful strategy to halt renal disease progression. The heterogeneity of renal disease progression factors hinders the evidence-based substantiation of the benefit of applying RAAS blockade to all specific forms of CKD. Although strong, evidence-based support for this generalized approach to renal disease may not always be available, nephrologists should make a conscious effort to assess the value of RAAS blockade in all forms of CKD, with an understanding that the benefit of RAAS blockade may extend beyond its renoprotective effects. Regardless of the disease etiology, the use of RAAS-blocking strategies should be the cornerstone of all therapies designed to slow renal disease progression.
Dr. Weir has received consulting fees from Amgen, Novartis, NicOx, and Daiichi Sankyo. No other potential conflicts of interest relevant to this article were reported.