Author details

Ana Kolakovic, Maja Zivkovic and Aleksandra Stankovic\*

\*Address all correspondence to: alexas@vin.bg.ac.rs

Department of Health and Environment, Laboratory for Radiobiology and Molecular Genetics, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia

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### **RAAS Blockade as First-Line Antihypertensive Therapy among People with CKD RAAS Blockade as First-Line Antihypertensive Therapy among People with CKD**

Panagiotis I. Georgianos, Elias V. Balaskas and Pantelis E. Zebekakis Panagiotis I. Georgianos, Elias V. Balaskas and Pantelis E. Zebekakis

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66180

### **Abstract**

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Hypertension among people with chronic kidney disease is highly prevalent and remains often poorly controlled. To adequately control blood pressure (BP), a combi‐ nation antihypertensive drug therapy is often required. The choice of the appropriate antihypertensive regimen should be individualized according to the patient clinical characteristics, the severity of chronic kidney disease (CKD), the levels at which BP should be targeted and the presence or absence of proteinuria. In proteinuric CKD, solid evidence from large‐scaled randomized trials suggest that agents blocking the renin‐ angiotensin‐aldosterone system (RAAS) should be the antihypertensive therapy of first choice, given their superiority over the other antihypertensive drug classes in reducing proteinuria and delaying nephropathy progression to end‐stage‐renal‐disease (ESRD). In contrast, inhibition of the RAAS is shown to have no additional benefits towards renoprotection in people with non‐proteinuric CKD. Combined RAAS blockade as an alternative approach to gain additive reduction in proteinuria and greater retardation of renal function decline is shown to be associated with increased risk of hypotension, serious hyperkalemia and acute kidney injury. In this chapter, we discuss the role of RAAS blockade as first‐line antihypertensive therapy among people with proteinuric and non‐proteinuric nephropathy, providing an overview of the evidence derived from large‐scaled renal outcome trials.

**Keywords:** hypertension, chronic kidney disease, proteinuria, RAAS blockade, randomized controlled trials

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

## **1. Introduction**

Hypertension in people with chronic kidney disease (CKD) is very common, often difficult to control and represents an independent predictor of kidney injury progression to end‐stage‐ renal‐disease (ESRD)requiringdialysis [1, 2].Apartfromachievinganadequate bloodpressure (BP) control as a tool to delay nephropathy progression, the choice of the appropriate antihy‐ pertensive regimen may be another factor determining the long‐term renal prognosis in people with CKD. In this regard, agents blocking the renin‐angiotensin‐aldosterone system (RAAS) are considered as the antihypertensive therapy of first choice in people with diabetic or nondiabetic proteinuric CKD on the basis of large‐scaled outcome trials showing that these agents are superior to the other antihypertensive drug classes in retarding kidney injury progression over time [3, 4]. In contrast, RAAS blockade in people with non‐proteinuric CKD is shown to confer no additional benefits toward renoprotection [4]. Furthermore, the promise thattheuseof combinedRAASblockademayoffer additive anti‐proteinuric andrenoprotective effects relative to monotherapy is shown to be counteracted by an excess risk of serious hyperkalemia and acute kidney injury [5, 6].

In this chapter, we discuss the use of RAAS blockade for renoprotection in people with proteinuric and non‐proteinuric CKD, summarizing the currently available evidence from large‐scaled outcome trials in nephrology. We conclude with clinical practice recommenda‐ tions for the choice of the appropriate antihypertensive regimen in people with CKD and provide directions for future research in this important area.

### **2. RAAS blockade in patients with proteinuric CKD**

Accumulated evidence from large‐scaled randomized controlled trials (RCTs) support the notion that inhibition of the RAAS among people with overt diabetic nephropathy confers benefits towards slower progression of kidney injury to ESRD [4]. In the Collaborate Study Group trial, 409 patients with insulin‐dependent type 1 diabetes and overt nephropathy (proteinuria >500 mg/day and serum creatinine <2.5 mg/dl) were randomly assigned to receive therapy with the angiotensin‐converting enzyme (ACE) inhibitor captopril or placebo for a mean follow‐up of 3 years [7]. Compared with placebo, captopril treatment produced a 30% reduction in the level of proteinuria and decreased by 50% the risk of reaching the combined renal endpoint of all‐cause death and need for dialysis or renal transplantation [95% confidence interval (CI) 18–70%, *p* < 0.01] [7]. The renoprotective effect of RAAS blockade among people with type 2 diabetes and overt nephropathy is supported by two landmark RCTs, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) [8] and Irbesartan Diabetic Nephropathy Trial (IDNT) [9]. The RENAAL trial enrolled 1513 patients with overt diabetic nephropathy aiming to compare the effect of the angiotensin receptor blocker (ARB) losartan (50–100 mg daily) versus placebo, both administered on top of conventional antihypertensive drug therapy, on a composite renal endpoint of doubling of serum creatinine, ESRD or death [8]. Over a mean follow‐up of 3.4 years, losartan reduced by 25% the risk of doubling of serum creatinine (P = 0.006) and by 28% the risk of ESRD requiring dialysis relative to placebo (P = 0.002), but had no impact on mortality [8]. In the IDNT trial, 1715 hypertensive patients with overt diabetic nephropathy were randomized to receive irbesartan (300 mg daily), amlodipine (10 mg daily) or placebo for a mean follow‐up of 2.6 years. The level of proteinuria was reduced by 33% in the irbesartan group versus 6% in the amlodipine and 10% in the placebo groups [9]. Compared with placebo, ARB treatment decreased by 20% the occurrence of the combined renal endpoint of doubling of serum creatinine, ESRD or death [relative risk (RR): 0.80; 95% CI: 0.66–0.97]; ARB therapy was also superior to the calcium channel blocker (CCB) amlodipine in improving renal outcomes (RR: 0.77; 95% CI: 0.63–0.93 for the combined renal endpoint) [9].

**1. Introduction**

40 Renin-Angiotensin System - Past, Present and Future

hyperkalemia and acute kidney injury [5, 6].

provide directions for future research in this important area.

**2. RAAS blockade in patients with proteinuric CKD**

Hypertension in people with chronic kidney disease (CKD) is very common, often difficult to control and represents an independent predictor of kidney injury progression to end‐stage‐ renal‐disease (ESRD)requiringdialysis [1, 2].Apartfromachievinganadequate bloodpressure (BP) control as a tool to delay nephropathy progression, the choice of the appropriate antihy‐ pertensive regimen may be another factor determining the long‐term renal prognosis in people with CKD. In this regard, agents blocking the renin‐angiotensin‐aldosterone system (RAAS) are considered as the antihypertensive therapy of first choice in people with diabetic or nondiabetic proteinuric CKD on the basis of large‐scaled outcome trials showing that these agents are superior to the other antihypertensive drug classes in retarding kidney injury progression over time [3, 4]. In contrast, RAAS blockade in people with non‐proteinuric CKD is shown to confer no additional benefits toward renoprotection [4]. Furthermore, the promise thattheuseof combinedRAASblockademayoffer additive anti‐proteinuric andrenoprotective effects relative to monotherapy is shown to be counteracted by an excess risk of serious

In this chapter, we discuss the use of RAAS blockade for renoprotection in people with proteinuric and non‐proteinuric CKD, summarizing the currently available evidence from large‐scaled outcome trials in nephrology. We conclude with clinical practice recommenda‐ tions for the choice of the appropriate antihypertensive regimen in people with CKD and

Accumulated evidence from large‐scaled randomized controlled trials (RCTs) support the notion that inhibition of the RAAS among people with overt diabetic nephropathy confers benefits towards slower progression of kidney injury to ESRD [4]. In the Collaborate Study Group trial, 409 patients with insulin‐dependent type 1 diabetes and overt nephropathy (proteinuria >500 mg/day and serum creatinine <2.5 mg/dl) were randomly assigned to receive therapy with the angiotensin‐converting enzyme (ACE) inhibitor captopril or placebo for a mean follow‐up of 3 years [7]. Compared with placebo, captopril treatment produced a 30% reduction in the level of proteinuria and decreased by 50% the risk of reaching the combined renal endpoint of all‐cause death and need for dialysis or renal transplantation [95% confidence interval (CI) 18–70%, *p* < 0.01] [7]. The renoprotective effect of RAAS blockade among people with type 2 diabetes and overt nephropathy is supported by two landmark RCTs, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) [8] and Irbesartan Diabetic Nephropathy Trial (IDNT) [9]. The RENAAL trial enrolled 1513 patients with overt diabetic nephropathy aiming to compare the effect of the angiotensin receptor blocker (ARB) losartan (50–100 mg daily) versus placebo, both administered on top of conventional antihypertensive drug therapy, on a composite renal endpoint of doubling of serum creatinine, ESRD or death [8]. Over a mean follow‐up of 3.4 years, losartan reduced by The renoprotective properties of ACE inhibitors and/or ARBs among patients with diabetic nephropathy are also supported by carefully conducted meta‐analyses of RCTs. An earlier meta‐analysis by Strippoli et al. [10] showed that compared with placebo, ACE inhibitor use was associated with a trend towards greater reduction in the risk of doubling of serum creatinine (RR: 0.60; 95% CI: 0.34–1.05) and incident ESRD (RR: 0.64; 95% CI: 0.40–1.03). ACE inhibitor use was associated with 55% reduced risk of progression from micro‐ to macro‐ albuminuria (RR: 0.45; 95% CI: 0.28–0.71) and 3.42‐fold higher rate of regression from micro‐ to normoalbuminuria among patients with diabetic CKD (RR: 3.42; 95% CI: 1.95–5.99) [10]. Similarly to ACE inhibitors, the combined analysis of RCTs comparing the effect of ARBs versus placebo on nephropathy progression associated the use of ARBs with reduced risk of doubling of serum creatinine (RR: 0.78; 95% CI: 0.67–0.91) and ESRD incidence (RR: 0.79; 95% CI: 0.67–0.93) [10]. The favorable effect of RAAS blockade on nephropathy progression was confirmed in an updated meta‐analysis of 24 RCTs showing that compared with placebo, ACE inhibitors reduced by 30% the risk of incident ESRD (RR: 0.70; 95% CI: 0.46–1.05) and by 29% the risk of doubling of serum creatinine (RR: 0.71; 95% CI: 0.56–0.91); ARB use was associated with 22% lower risk of ESRD incidence (RR: 0.78; 95% CI: 0.67–0.91) and 21% lower risk of doubling of serum creatinine (RR: 0.79; 95% CI: 0.68–0.91) [11].

In accordance with the renoprotective action of RAAS blockade among people with diabetic kidney disease, a growing body of evidence supports the notion that ACE inhibitors and ARBs are similarly effective in delaying kidney injury progression in patients with other types of proteinuric nephropathy. In the REIN‐2 study (Ramipril‐Efficacy‐In‐Nephropathy‐2), 352 nondiabetic patients with CKD and proteinuria of at least 1 g/day were randomized to receive double‐blind therapy with ramipril (5 mg daily) or placebo in addition to conventional antihypertensive therapy targeted at achieving a diastolic BP goal of <90 mmHg [12]. The rate of estimated glomerular filtration rate (eGFR) decline, which was the primary trial endpoint, was significantly slower over time in ramipril‐treated patients than in placebo‐treated patients (0.53 vs. 0.83 ml/min/1.73 m2 , P = 0.03). The proportional reduction in the level of proteinuria among ramipril‐treated patients was inversely associated with the rate of eGFR decline and was an independent predictor of the risk of doubling of serum creatinine and incident ESRD during follow‐up [12]. In the African American Study of Kidney Disease (AASK), 1094 African‐ American patients with hypertensive CKD (mean baseline eGFR: 45.6 ml/min/1.73 m2 ; mean urinary protein excretion 0.6 g/day) were randomized to achieve goal mean arterial pressure 102–107 mmHg or ≤92 mmHg and to initial BP‐lowering treatment with metoprolol (2.5–10 mg daily), ramipril (2.5–10 mg daily) or amlodipine (5–10 mg daily) in a 3 × 2 factorial design [13]. Compared with metoprolol and amlodipine groups, administration of the ACE inhibitor ramipril was associated with 22 and 38% reduction in the risk of reaching the composite renal outcome of decrease from baseline in eGFR by 50% or greater, incident ESRD, or death, respectively [13]. In a subsequent analysis of 224 patients with advanced stage nondiabetic CKD (baseline serum creatinine range: 3.1–5.0 mg/dl and mean proteinuria 1.6 g/day), Hou et al. [14] compared the effect of benazepril (20 mg daily) versus placebo on top of conventional antihypertensive therapy on a composite renal endpoint of doubling of serum creatinine, ESRD or death. Over a mean follow‐up of 3.4 years, the risk of reaching the above combined endpoint was by 43% lower in the ACE inhibitor group than in the placebo group. Additional benefits of the ACE inhibitor therapy were an associated 52% reduction in the level of proteinuria along with a 23% slower rate of eGFR decline [14]. Additional support to the renoprotective action of ACE inhibitors is provided by an earlier meta‐analysis of 11 RCTs conducted by Jafar et al. [15]. In this analysis, after adjustment for patient and trial characteristics at baseline and changes in BP and proteinuria levels during follow‐up, the use of an ACE inhibitor‐based antihypertensive regimen was associated with 31% greater reduction in the risk of developing ESRD (RR: 0.69; 95% CI: 0.51–0.94) and 30% decrease in the risk of doubling of serum creatinine or ESRD (RR: 0.70; 95% CI: 0.55–0.88) in comparison with antihypertensive regimens non‐ including ACE inhibitors [15].

Post hoc analyses of the aforementioned RCTs provided evidence that the higher the level of proteinuria at baseline the higher was the risk of nephropathy progression to ESRD [16–18]. Most importantly, achievement of an early regression of proteinuria under RAAS blockade (i.e., in the first 6 months after drug initiation) was shown to be associated with reduced long‐ term risk of doubling of serum creatinine, ESRD incidence or death [16–18]. The notion that drug‐induced reduction in proteinuria culminates in subsequent improvement in renal outcomes is further supported by a recent meta‐regression analysis of 21 RCTs involving a total of 78,342 patients and 4843 incident ESRD events [19]. The placebo‐adjusted treatment effect on proteinuria significantly correlated with the treatment effect on ESRD incidence, since each 30% of drug‐induced reduction in the level of proteinuria was associated with a 23.7% reduced risk of subsequent kidney injury progression to ESRD (95% CI: 11.4–34.2%, P = 0.001) [19]. Taken together, the above data support the notion that regression of proteinuria is a major target of therapy in order to delay nephropathy progression in patients with both diabetic and nondiabetic proteinuric CKD.

### **3. RAAS blockade in patients with non-proteinuric nephropathy**

Unlike the well‐documented benefits of RAAS inhibition among patients with proteinuric CKD, either diabetic or nondiabetic, it remains largely uncertain whether ACE inhibitors and/ or ARBs carry with them a similarly beneficial effect in slowing nephropathy progression among patients with non‐proteinuric CKD. This issue is of major clinical relevance, given the fact that high albuminuria or overt proteinuria is present only in a small proportion of the overall CKD population, whereas the vast majority of people with CKD have normoalbumi‐ nuria or microalbuminuria [20–22]. For example, the prevalence of CKD among individuals with age >70 years is estimated to be around 40%, but proteinuria is present in approximately 5% of elderly CKD patients. The prevalence of CKD in the general hypertensive population is estimated to be around 15% (ranging up to 30% in those aged >65 years), but again <5% of hypertensives with CKD exhibit macroalbuminuria [20–22]. Regardless of its high clinical significance, there are no data from properly designed RCTs to evaluate the effect of RAAS blockade on "hard" renal outcomes in patients with non‐proteinuric nephropathy. The currently available evidence on this issue is derived mainly from secondary analyses of major cardiovascular outcome trials.

102–107 mmHg or ≤92 mmHg and to initial BP‐lowering treatment with metoprolol (2.5–10 mg daily), ramipril (2.5–10 mg daily) or amlodipine (5–10 mg daily) in a 3 × 2 factorial design [13]. Compared with metoprolol and amlodipine groups, administration of the ACE inhibitor ramipril was associated with 22 and 38% reduction in the risk of reaching the composite renal outcome of decrease from baseline in eGFR by 50% or greater, incident ESRD, or death, respectively [13]. In a subsequent analysis of 224 patients with advanced stage nondiabetic CKD (baseline serum creatinine range: 3.1–5.0 mg/dl and mean proteinuria 1.6 g/day), Hou et al. [14] compared the effect of benazepril (20 mg daily) versus placebo on top of conventional antihypertensive therapy on a composite renal endpoint of doubling of serum creatinine, ESRD or death. Over a mean follow‐up of 3.4 years, the risk of reaching the above combined endpoint was by 43% lower in the ACE inhibitor group than in the placebo group. Additional benefits of the ACE inhibitor therapy were an associated 52% reduction in the level of proteinuria along with a 23% slower rate of eGFR decline [14]. Additional support to the renoprotective action of ACE inhibitors is provided by an earlier meta‐analysis of 11 RCTs conducted by Jafar et al. [15]. In this analysis, after adjustment for patient and trial characteristics at baseline and changes in BP and proteinuria levels during follow‐up, the use of an ACE inhibitor‐based antihypertensive regimen was associated with 31% greater reduction in the risk of developing ESRD (RR: 0.69; 95% CI: 0.51–0.94) and 30% decrease in the risk of doubling of serum creatinine or ESRD (RR: 0.70; 95% CI: 0.55–0.88) in comparison with antihypertensive regimens non‐

Post hoc analyses of the aforementioned RCTs provided evidence that the higher the level of proteinuria at baseline the higher was the risk of nephropathy progression to ESRD [16–18]. Most importantly, achievement of an early regression of proteinuria under RAAS blockade (i.e., in the first 6 months after drug initiation) was shown to be associated with reduced long‐ term risk of doubling of serum creatinine, ESRD incidence or death [16–18]. The notion that drug‐induced reduction in proteinuria culminates in subsequent improvement in renal outcomes is further supported by a recent meta‐regression analysis of 21 RCTs involving a total of 78,342 patients and 4843 incident ESRD events [19]. The placebo‐adjusted treatment effect on proteinuria significantly correlated with the treatment effect on ESRD incidence, since each 30% of drug‐induced reduction in the level of proteinuria was associated with a 23.7% reduced risk of subsequent kidney injury progression to ESRD (95% CI: 11.4–34.2%, P = 0.001) [19]. Taken together, the above data support the notion that regression of proteinuria is a major target of therapy in order to delay nephropathy progression in patients with both diabetic and

**3. RAAS blockade in patients with non-proteinuric nephropathy**

Unlike the well‐documented benefits of RAAS inhibition among patients with proteinuric CKD, either diabetic or nondiabetic, it remains largely uncertain whether ACE inhibitors and/ or ARBs carry with them a similarly beneficial effect in slowing nephropathy progression among patients with non‐proteinuric CKD. This issue is of major clinical relevance, given the

including ACE inhibitors [15].

42 Renin-Angiotensin System - Past, Present and Future

nondiabetic proteinuric CKD.

The first trial to evaluate the issue of renoprotection with RAAS blockade in patients with non‐ proteinuric CKD was the appropriate blood pressure control in diabetes (ABCD) [23]. This trial enrolled 470 patients with hypertension and type 2 diabetes, of whom only 18% had overt nephropathy (i.e., macro‐albuminuria and/or impaired renal function). Study participants were randomly assigned to nisoldipine or enalapril and intensive or moderate BP control in a 2 × 2 factorial design. The rate of change in creatinine clearance over a 5.3‐year‐long follow‐up was no different between the enalapril and nisoldipine groups [23]. However, the most definite renal endpoint of incident ESRD requiring dialysis was not evaluated in the ABCD study; accordingly, this study cannot provide direct evidence on whether the enalapril‐induced reduction in the level of proteinuria would be translated into a slower kidney injury progres‐ sion in a population predominantly without overt diabetic nephropathy.

The absence of additive renal benefits under RAAS blockade among patients with non‐ proteinuric CKD is further supported by a secondary analysis of the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [24]. This trial enrolled 33,000 hypertensive patients with an age of 55 years or higher and at least one additional risk factor for ischemic heart disease. The exclusion criteria included a serum creatinine >2 mg/dl and therapy with an ACE inhibitor for underlying CKD prior to the study enrolment. Although actual measurements of the level of albuminuria were not included in the protocol procedures, it is reasonable to hypothesize that participants in the ALLHAT trial were mainly hypertensives without high albuminuria. Incidence of ESRD or >50% reduction in eGFR during follow‐up, which was the primary composite renal endpoint of this secondary analysis, was no different between amlodipine‐treated and chlorothalidone‐treated participants (RR: 1.12; 95% CI: 0.89– 1.40) [24]. Similarly, the ACE inhibitor lisinopril was not superior to chlorothalidone in reducing the incidence of ESRD or >50% reduction in eGFR (RR: 1.11; 95% CI: 0.89–1.38). When the analysis was stratified according to the level of eGFR at baseline, lisinopril therapy was not associated with a reduced incidence of ESRD relative to chlorthalidone in the subgroups of patients with baseline eGFR of 60–89 ml/min/1.73 m2 (RR: 1.34; 95% CI: 0.87–2.06) as well as in those with baseline eGFR <60 ml/min/1.73 m2 (RR: 0.98; 95% CI: 0.73–1.31) [24]. In addition, at 4 years of follow‐up, eGFR was 3–6 ml/min/1.73 m2 higher in amlodipine‐treated than in chlorothalidone‐treated participants, depending on baseline eGFR stratum. The results of the ALLHAT come in sharp contrast to the clear renoprotective effect of RAAS blockade seen in trials involving patients with overt diabetic nephropathy (i.e., the aforementioned IDNT). This discrepancy is possibly explained by the different characteristics of patients included in the ALLHAT trial. It is reasonable to hypothesize that the absence of renoprotection with lisinopril therapy and the better retardation of eGFR over time in amlodipine‐treated participants was possibly due to the fact that patients enrolled in the ALLHAT were more likely to suffer from ischemic rather than proteinuric nephropathy.

Additional support to for the notion that RAAS blockade is not associated with greater renoprotection in comparison to other antihypertensive drug classes among patients with non‐ proteinuric CKD was provided by the renal outcomes of Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH trial)[25]. ACCOMPLISH randomized 11,506 hypertensive patients at high cardiovascularrisk to receive combination therapy with benazepril plus amlodipine or benazepril plus hydro‐ chlorothiazide. The clear benefit of the benazepril/amlodipine combination in reducing cardiovascular morbidity and mortality led to the premature termination of the ACCOM‐ PLISH trial. Similarly to the cardiovascular benefit, the analysis of the renal outcomes showed the benazepril/amlodipine combination was associated with a slower annual rate of eGFR decline in comparison with the benazepril/hydrochlorothiazide combination (−0.88 vs. −4.22 mL/min/1.73 m2 per year), despite the fact that proteinuria was less effectively reduced in patients receiving the ACE inhibitor/CCB combination [25]. Most importantly, compared with the benazepril/hydrochlorothiazide combination, the ACE inhibitor/CCB combination reduced by 48% the incidence of composite renal endpoint of doubling of serum creatinine or ESRD requiring dialysis [hazard ratio (HR): 0.48; 95% CI: 0.41–0.65] and by 27% the risk of doubling serum creatinine, need for dialysis or death (HR: 0.73; 95% CI: 0.64–0.84) [25]. The superiority of the ACE inhibitor/CCB combination in delaying the kidney injury progression despite its less pronounced anti‐proteinuric effect could be once again explained by the characteristics of the patients participating in the ACCOMPLISH trial. ACCOMPLISH participants were predominantly older than 65 years, had preserved renal function at baseline (mean baseline eGFR of 79 mL/min/1.73 m2 ) and macro‐albuminuria was present in only 5% of study participants. Accordingly, it seems reasonable that patients with such clinical characteristics are less likely to benefit from a therapeutic strategy targeting on proteinuria remission; in contrast, these patients are prone to acute kidney injury due to dehydration and hypotension.
