Blood pressure control in patients with chronic kidney disease.

Uncontrolled blood pressure (BP) in patients with chronic kidney disease (CKD) can lead to serious adverse outcomes. To prevent the occurrence of cardiovascular events (CVEs), and end-stage kidney disease, achieving an optimal BP level is important. Recently, there has been a paradigm shift in the management of BP largely as a result of the Systolic Blood Pressure Intervention Trial (SPRINT), which showed a reduction in CVEs by lowering systolic BP to 120 mmHg. A lower systolic blood pressure (SBP) target has been accepted by the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines. However, whether intensive control of SBP targeting < 120 mmHg is also effective in patients with CKD is controversial. Notably, this lower target SBP is associated with a higher risk of adverse kidney outcomes. Unfortunately, there have been no randomized controlled trials on this issue involving only patients with CKD, particularly those with advanced CKD. In this review, we discuss the optimal control of BP in patients with CKD in terms of reduction in death and CVEs as well as attenuation of CKD progression based on the evidence-based literature.

INTRODUCTION

Chronic kidney disease (CKD) and hypertension are closely connected and affect each other. Hypertensive kidney disease is the second most common cause of kidney failure with replacement therapy (KFRT), and deterioration of kidney function is accelerated by excessive high blood pressure (BP) [1-4]. Uncontrolled hypertension can cause adverse cardiovascular and cerebrovascular outcomes such as acute coronary syndrome, hemorrhagic and ischemic stroke, heart failure, and even death [5-10]. Therefore, in clinical practice, physicians typically prioritize BP control to preserve kidney function and reduce the rate of cardiovascular events (CVEs) and mortality in patients with CKD.

Therefore, the question for consideration is, “What is the optimal target BP that will achieve these goals in patients with CKD?” Unfortunately, this issue has not yet been resolved. In addition to reducing the rate of adverse CVEs and mortality in patients with and without CKD, other important goals of BP control are to prevent the development of CKD for non-CKD patients and to attenuate the deterioration of kidney function in patients with CKD. Epidemiologic studies have shown that, in patients without CKD, even a pre-hypertension level of systolic blood pressure (SBP; 130 to 140 mmHg) is associated with a higher risk of CKD development compared with an SBP of < 120 mmHg [11-14]. In addition, a meta-analysis of observational data showed a higher risk of CVEs in individuals with an SBP of 120 to 129 mmHg compared to those with an SBP of < 120 mmHg [15]. Notably, guidelines from various countries do not agree on BP control in patients with CKD [16-22]. Over the last two decades, < 140/90 mmHg has typically been the target BP in patients without albuminuria and < 130/80 mmHg in those with albuminuria [17,23]. This conventional concept has been challenged by the results of the Systolic Blood Pressure Intervention Trial (SPRINT) study, which demonstrated the benefit of intensive control of SBP < 120 mmHg compared with the conventional target of < 140 mmHg [24]. The SPRINT study results are included in the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines, which suggest a target SBP of < 120 mmHg in patients with CKD [25]. However, not all studies favor this lower target, given the negative results of intensive BP control [26-28]. In fact, some guidelines still recommend the conventional BP target for patients with CKD [29-31]. BP targets in patients with CKD are listed in Table 1 [18,19,22,25,32-35].

Table 1.

Guideline comparisons of goal BP and first-line treatment for CKD patients with hypertension

Guideline	BP target in CKD patients without proteinuria, mmHg	BP target in CKD patients with proteinuria, mmHg	Recommended first-line treatment
ISHIB [35]	< 130/< 80	< 130/< 80	Diuretic or CCB
NICE [19]	< 140/< 90	< 130/< 80	ACEi or ARB
JNC8 [18]	< 140/< 90	< 140/< 90	ACEi or ARB
ACC/AHA [32]	< 130/< 80	< 130/< 80	ACEi
ESC/ESH [34]	SBP 130–139	SBP 130–139	ACEi or ARB
ISH [33]	< 130/< 80	< 130/< 80	ACEi or ARB
Hypertension Canada [22]	SBP < 120	SBP < 120	ACEi or ARB
KDIGO [25]	SBP < 120	SBP < 120	ACEi or ARB

BP, blood pressure; CKD, chronic kidney disease; ISHIB, International Society on Hypertension in Blacks; CCB, calcium channel blocker; NICE, National Institute for Health and Clinical Excellence; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; JNC8, Eighth Joint National Committee; ACC/AHA, American College of Cardiology/American Heart Association; ESC/ESH, European Society of Cardiology and the European Society of Hypertension; SBP, systolic blood pressure; ISH, International Society of Hypertension; KDIGO, Kidney Disease: Improving Global Outcomes.

In this article, we discuss the following three goals of optimal BP control in patients with CKD: (1) to prevent CVEs and all-cause death, (2) to prevent the development of incident CKD, and (3) to delay the progression of CKD. Finally, we briefly describe conventional and potential drug therapies for improving outcomes in patients with CKD.

BP MEASUREMENT

The KDIGO 2021 BP guidelines recommend use of standardized rather than routine office BP measurement [25], as suggested by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines [32]. Standardized office BP measurement refers to BP measurement following the recommended preparation procedure. A summary of standardized office BP measurement is provided in Table 2 [32]. In contrast, routine office BP measurement is performed without considering the recommended BP measurement procedure. Notably, BP readings using office BP measurement are typically higher than those using standardized BP measurement [36]. BP measurement procedures vary among clinical trials, a critical point that should be considered when interpreting study results. However, for the sake of convenience, routine office BP measurement is commonly used in the real world. Given the possible risk of overtreatment and hypotension events associated with office BP measurement, use of standardized BP measurement should be encouraged in clinical practice.

Table 2.

Summary of standardized office BP measurement

Preparing the patient	Caffeine, exercise, and smoking should be avoided for at least 30 minutes prior to measuring BP. Make sure the patient emptied their bladder before BP measurement. The patient should be seated in a chair with back support and feet placed on the floor, then relax for more than 5 minutes. The patient or the observer should not talk during the resting and measurement period. All clothing covering the cuff placing location should be removed.
Choosing the BP measurement for diagnosis and treatment of elevated BP	Measure BP from both arms on the first visit, and choose the arm with the higher BP for the following measurements.
BP measuring technique	Use validated BP measuring device, which should be regularly calibrated. Patient should have arm-support, with the cuff positioned on upper arm of patient. Use proper sized cuff, with the bladder 80% of the arm circumference.
Documentation of BP measurement	≥ 2 BP measurements with 1–2 minutes interval should be taken, and document the average of these BP measurements. Record both SBP, DBP, and the time of most recent BP medication intake prior to BP measurement.

BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure.

BP CONTROL FOR PREVENTION OF CARDIOVASCULAR DISEASE AND DEATH IN CKD

Given the lack of randomized controlled trials (RCTs) in patients with only CKD, this issue has been evaluated by analyses of secondary outcomes. As mentioned above, the SPRINT study demonstrated that intensive control of SBP to < 120 mmHg resulted in better cardiovascular outcomes compared to control to < 140 mmHg [24]. This finding has been adopted by the ACC/AHA 2017 guidelines [16] and the KDIGO 2021 guidelines [25]. Notably, the SPRINT study excluded patients with diabetes and a history of stroke. Most participants with CKD had CKD G3a; their mean estimated glomerular filtration rate (eGFR) was 48 mL/min/1.73 m2. Therefore, it is unclear whether intensive control using a lower BP target is beneficial in other risk groups, such as patients with diabetes or CKD G3b, G4, or G5. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial involving patients with type 2 diabetes, intensive control of SBP < 120 mmHg did not reduce the rate of a composite outcome of fatal and nonfatal major CVEs or death as compared with a standard target (< 140 mmHg), although intensive control decreased the rate of nonfatal stroke events [26]. Nevertheless, 2,646 participants with an eGFR of < 60 mL/min/1.73 m2 in the SPRINT study provided adequate statistical power to examine the effect of intensive BP control on cardiovascular outcomes in patients with early CKD. In this separate analysis of participants with CKD, the intensive SBP intervention group had a 19% lower risk of composite cardiovascular outcomes and a 28% lower risk of all-cause death compared to the standard BP control group [37]. In addition, in a meta-analysis of 123 trials including 613,815 participants with BP lowering intervention, each 10 mmHg reduction in SBP significantly decreased the risk of major CVEs and all-cause mortality [38]. Notably, a greater reduction in SBP resulted in a larger decrease in the relative risk of CVEs. That study also showed a significant risk reduction with a decrease in SBP in patients with CKD. However, a pooled analysis of four multicenter RCTs including 4,983 CKD patients with control of SBP to < 130 mmHg did not improve all-cause mortality and cardiovascular outcomes compared to standard control of SBP to < 140 mmHg [39]. In that study, the average BP achieved was 125.0 mmHg in the intensive group and 136.9 mmHg in the standard group. After excluding patients with an eGFR of ≥ 60 mL/min/1.73 m2 and intensive glucose control, the all-cause mortality rate was reduced in the intensive BP control group. Finally, in another meta-analysis of patients with CKD G3–G5, more intensive control (SBP 132 mmHg) resulted in a 14.0% lower risk of all-cause mortality compared with less intensive control (SBP 140 mmHg) [40]. Therefore, the evidence supports intensive BP control to reduce adverse CVE and all-cause mortality rates, even in patients with CKD. A summary of these RCTs is presented in Table 3 [24,26,27,37,41,42]. In contrast to RCTs, analyses of observational cohort studies have shown a U-shaped association between SBP and the risk of death in patients with CKD, suggesting a potential hazard for excessively low BP [43-46]. A low BP itself may reflect an unhealthy condition and underlying disease burden.

Table 3.

Summary of the major clinical trials with BP intervention for cardiovascular outcomes and mortality

Trial	Number		BP target (achieved), mmHg		Diabetes	CKD	Main outcomes	Key findings (risk reduction vs. standard group)
	Active	Standard	Active	Standard
HOT [42]	DBP (achieved), mmHg				1,503 (8)	1,367 (7)[a]	Composite nonfatal MI, nonfatal stroke, or CVD death	NR (↓51 vs. ≤ 90 mmHg among diabetic patients)
	≤ 80 (81.1) (n = 6,262)
	≤ 85 (83.2) (n = 6,264)
	≤ 90 (85.2) (n = 6,264)
UKPDS [41]	758	390	< 150/85 (144/82)	< 160/90 (154/87)	1,148 (100)	198 (17)[b]	All-cause mortality	NR
							MI	NR
							Stroke	↓44%
							PVD	NR
							Microvascular disease[c]	↓37%
ACCORD [26]	2,362	2,371	SBP < 120 (119.3)	SBP < 140 (133.5)	4,733 (100)	403 (9)	Composite nonfatal MI, nonfatal stroke, or death from CVD	NR
SPRINT [24]	4,678	4,683	SBP < 120 (121.4)	SBP < 140 (136.2)	None	2,646 (28)	Composite MI, ACS, stroke, HF, or CVD death	↓25%
HOPE-3 [27]	6,356	6,349	SBP < 130 (128)	SBP < 140 (134)	731 (8)	348 (3)	Composite cardiovascular death, nonfatal MI, or nonfatal stroke	NR
SPRINT post hoc analysis in CKD [37]	1,330	1,316	SBP < 120 (123.3)	SBP < 140 (136.9)	None	2,646 (100)	Composite MI, ACS, stroke, HF, or CVD death	NR
							Composite MI, ACS, stroke, HF, CVD death, or all-cause death	NR
							All-cause death	↓28%

Values are presented as number (%).

BP, blood pressure; CVD, cardiovascular disease; HOT, Hypertension Optimal Treatment; DBP, diastolic blood pressure; MI, myocardial infarction; NR, no reduction in relative risk; UKPDS, UK Prospective Diabetes Study Group; PVD, peripheral vascular disease; ACCORD, Action to Control Cardiovascular Risk in Diabetes; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; ACS, acute coronary syndrome; HF, heart failure; HOPE-3, Heart Outcomes Prevention Evaluation-3.

Definition of CKD: serum creatinine > 115 μmol/L.

Definition of CKD: albuminuria ≥ 50 mg/L.

Retinopathy requiring photocoagulation, vitreous hemorrhage, and fatal or nonfatal renal failure.

BP CONTROL FOR THE PREVENTION OF CKD

No RCT has examined the effect of intensive BP control on the development of incident CKD. Studies on this issue are mostly post hoc analyses of RCTs comparing the effect of intensive versus standard BP control in patients with high cardiovascular risk. Among these, the ACCORD trial showed that intensive control of SBP < 120 mmHg increased the risk of incident CKD [26]. In line with this study, a similar SBP intervention in the SPRINT study resulted in a higher frequency of adverse kidney outcomes among patients without diabetes [24]. Therefore, intensive BP control is not beneficial for preserving kidney function. However, intensive BP control is effective in reducing albuminuria. Despite the increased risk of CKD, the ACCORD trial showed a significant reduction in macroalbuminuria by intensive BP control. In a similarly designed RCT involving patients with type 2 diabetes, active BP control significantly reduced the risk of microalbuminuria and macroalbuminuria [47,48]. A reduction in albuminuria by intensive BP control was also found in a meta-analysis of 19 RCTs including both diabetic and non-diabetic patients [49]. For the prevention of CKD, these studies indicate that intensive BP control carries both a risk and a benefit: a decline in eGFR and reduction in albuminuria. To mitigate concerns on the increase in the risk of adverse kidney outcomes by intensive BP control, the SPRINT and ACCORD investigators showed that various kidney injury markers were not elevated in the intensive BP control group, suggesting that the increased serum creatinine level was associated with hemodynamic alterations [50,51]. Despite the debate on its validity as a surrogate marker of renal function, albuminuria is widely accepted as an appropriate target or surrogate marker for kidney disease progression [52]. The United States Food and Drug Administration recently agreed to use early change in albuminuria as a surrogate marker for kidney disease progression in phase 3 trials dealing with diseases involving moderate to severe albuminuria, and intervention trials in which decreasing albuminuria is presumed to be the primary mechanism of action [53]. The key findings of major RCTs are shown in Table 4.

Table 4.

Summary of the major clinical trials with BP intervention for adverse kidney outcome

Trial	Number		BP target (achieved), mmHg		Main outcomes		Key findings
	Active	Standard	Active	Standard
MDRD [59]	432	408	MAP < 92, SBP/DBP < 125/75 (93.3, 126/77)	MAP < 107, SBP < 140 (98.4, 134/81)	GFR decline		↓29%[a]
					KFRT or death		NR
ABCD [65]	237	243	SBP/DBP < 130/80 (128/75)	SBP/DBP < 140/90 (137/81)	CCl		NR
					Albuminuria	Normoalbuminuria to microalbuminuria	↓
						Microalbuminuria to overt albuminuria	↓
REENAL post hoc [66]	Post hoc analysis categorized SBP into < 130 (n = 169), 130–139 (n = 209), 140–159 (n = 610), 160–179 (n = 373), and ≥ 180 mmHg (n = 152)				Composite 2XSCr, KFRT, or death		HR (95% CI) vs. SBP < 130 mmHg: 1.08 (0.83–1.40), 1.49 (1.18–1.90), 2.74 (2.12–3.54), and 3.51 (2.50–4.93)
REIN-2 [28]	167	168	SBP/DBP < 130/80 (130/80)	SBP/DBP < 135/90 (134/82)	KFRT		NR
IDNT post hoc [67]	Post hoc analysis categorized SBP into < 145 (n = 391), 145–158 (n = 411), 159–170 (n = 383), and > 170 mmHg (n = 405)				Composite 2XSCr or KFRT		RR vs. SBP > 170 mmHg: 0.55, 0.92, 0.66, and 0.70
ADVANCE [47]	5,569	5,571	SBP 145–135[b]	SBP 145–140[b]	Composite macroalbuminuria, 2XSCr, KFRT, renal-cause death, or microalbuminuria		↓21%
					Composite macroalbuminuria, 2XSCr, KFRT, renal-cause death		↓18%[c]
					Microalbuminuria		↓21%
ACCORD [26]	2,362	2,371	SBP < 120 (119.3)	SBP < 140 (133.5)	Serum creatinine elevation[d]		NR
					Decreased eGFR < 30 mL/min/1.73 m2		NR
AASK [58]	540	554	SBP/DBP < 130/80 (130/78)	SBP/DBP < 140/90 (141/86)	Composite 2XSCr, KFRT, or death		↓27%[e]
SPRINT [24]	4,678	4,683	SBP < 120 (123.3)	SBP < 140 (136.2)	Participants with baseline CKD	Composite ≥ 50% reduction eGFR to < 60 mL/min/1.73 m2, longterm dialysis, or KT	NR
					Participants without baseline CKD	≥ 30% eGFR reduction to <60 mL/min/1.73 m2	NR

BP, blood pressure; MDRD, Modification of Diet in Renal Disease; MAP, mean arterial pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, glomerular filtration rate; KFRT, kidney failure with replacement therapy; NR, no reduction in relative risk; ABCD, Appropriate Blood Control in Diabetes; CCl, creatinine clearance; REENAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; 2XSCr, doubling of serum creatinine; HR, hazard ratio; REIN-2, Blood Pressure Control for Renoprotection in Patients with Non-diabetic Chronic Renal Disease; IDNT, Irbesartan Diabetic Nephropathy Trial; RR, relative risk; ADVANCE, Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation; ACCORD, Action to Control Cardiovascular Risk in Diabetes; eGFR, estimated glomerular filtration rate; AASK, African-American Study of Kidney Disease and Hypertension; SPRINT, Systolic Blood Pressure Intervention Trial; CKD, chronic kidney disease; KT, kidney transplantation.

In subgroup patients with GFR 22–55 mL/min/1.73 m2.

Change in SBP from baseline to follow-up; There was no pre-specified BP target in ADVANCE trial.

Relative reduction: p value 0.055.

Men > 1.5 mg/dL, women > 1.3 mg/dL.

In patients with baseline urinary protein-to-creatinine ratio > 0.22.

In contrast to previous RCTs involving patients with an increased risk of CVD and a baseline SBP of ≥ 130 mmHg, observational studies provide comprehensive information on individuals at low risk of CKD and few comorbidities, even those without pre-existing hypertension. Interestingly, there was a graded relation ship between SBP and the risk of incident CKD, and the risk was lower for an SBP of < 120 mmHg [11-13,54,55]. We observed similar findings in two large representative Korean adult cohorts using meticulous analytical approaches [56,57]. These findings raised the question of whether reducing SBP to < 120 mmHg in individuals with hypertension and at high risk of CVD is equivalent to an intrinsically normal BP in healthy adults. In summary, intensive BP control for the prevention of incident CKD has not yet been justified. If kidney injury associated with intensive BP control is minimal and reversible, a lower BP target can be implemented in clinical practice with a permissive decline in eGFR given the proven benefit on prevention of adverse CVEs.

BP CONTROL FOR DELAYING THE PROGRESSION OF CKD

CKD progression is generally faster in patients with than in those without diabetes. In non-diabetic patients with CKD, three clinical trials have evaluated the effect of intensive BP control on CKD progression: the Modification of Diet in Renal Disease (MDRD) study; the AASK trial; and the Blood Pressure Control for Renoprotection in Patients with Non-diabetic Chronic Renal Disease (REIN-2) trial [28,58,59]. The African-American Study of Kidney Disease and Hypertension (AASK) and REIN-2 trials excluded patients with diabetes. Only 5% of participants in the MDRD study were patients with diabetes. The target BPs in the intensive control arm were < 125/75 mmHg (mean arterial pressure < 92 mmHg) for the MDRD study and < 130/80 mmHg for the AASK and the REIN-2 trials. The MDRD study, published in 1994, showed that the beneficial effect of a lower BP target was particularly evident in patients with daily urinary protein excretion > 1.0 g [59]. Long-term follow-up of the MDRD study with observation extended to 10 years also showed that CKD outcomes and the all-cause mortality rate were decreased by intensive BP control [60]. However, the AASK and REIN-2 trials failed to delay the progression of CKD or the development of KFRT in patients with intensive BP control. Notably, in the AASK trial, a subgroup of patients with CKD and a protein-to-creatinine ratio of ≥ 0.22 g/g in the intensive BP control group had a significant reduction in the risk of KFRT or death. These findings suggest that intensive BP control is more effective in non-diabetic patients with CKD and significant proteinuria. A systemic review and meta-analysis supports the ability of intensive control of BP < 130/80 mmHg to attenuate CKD progression in non-diabetic patients with CKD and significant proteinuria [61,62].

The clinical benefits of intensive BP control are unclear in patients with type 2 diabetes. The BP goals in most early studies were > 140 mmHg, which was considered suboptimal [41,42,63,64]. The Appropriate Blood Control in Diabetes (ABCD) study evaluated the effect of a lower BP target of < 130/80 mmHg on the preservation of kidney function in patients with type 2 diabetes compared with a standard control of < 140/90 mmHg but failed to demonstrate a benefit of intensive BP control [65]. However, two post hoc analyses of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and the Irbesartan Diabetic Nephropathy Trial (IDNT) showed that a lower BP level was associated with improved kidney outcomes [66,67]. In contrast to the less-intensive BP targets in the studies above, the intervention in the ACCORD trial lowered SBP to < 120 mmHg [26]. However, as discussed above, a lower target BP increased the frequency of adverse kidney events such as an elevated serum creatinine level or a decline in eGFR of < 30 mL/min/1.73 m2. It should be noted that the ACCORD study excluded patients with a serum creatinine level of > 1.5 mg/dL; therefore, the participants were unlikely to be representative of patients with CKD and diabetes. We have summarized the results of major RCTs on this topic in Table 4 [24,26,28,47,58,59,65-67].

DRUG TREATMENT

Besides achieving the optimal BP, choosing medications with renoprotective effects is important. A detailed description of this issue is beyond the scope of this review. Here, we briefly describe conventional drugs and introduce several with potential for prevention of CKD progression.

Renin-angiotensin system blockers (RASBs), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), are a cornerstone therapy in patients with CKD. In a groundbreaking study by Lewis et al. [68], captopril was first used to protect against a decline in kidney function in patients with insulin-dependent type 1 diabetes and CKD studies with RASBs have consistently demonstrated the renoprotective effects of these drugs, including a reduction in proteinuria and attenuation of eGFR decline. These beneficial effects were evident in patients with and without diabetes. In the AASK trial, patients randomly assigned to ramipril showed a slower decline in eGFR compared to those on other treatments [69]. In patients with type 2 diabetes and CKD, the RENAAL and IDNT studies confirmed the superior protective effects of ARBs against the progression of CKD [70,71]. RASBs have been tested in patients with early CKD, even those without microalbuminuria. In the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT), ACEi prevented the onset of microalbuminuria in patients with type 2 diabetes and normal urinary albumin excretion [72]. All guidelines recommend the use of RASBs as first-line therapy based on high-quality evidence [18,19,22,25,32-34].

RASBs cannot stop the progression of CKD and no other drugs are used widely in clinical practice. Recently, many studies with new anti-diabetic drugs, such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA), have consecutively demonstrated outstanding renoprotective effects [73,74]. The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the KDIGO accepted the results of these studies and recommend SGLT2i and GLP1RA as firstline therapies for patients with diabetic kidney disease [75,76]. Interestingly, these drugs have also been reported to reduce adverse CVEs and death [77-79]. Moreover, in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risk of the composite outcome of kidney failure or death from renal or cardiovascular causes even in non-diabetic patients with CKD [80]. In addition, these drugs can reduce BP by 5 mmHg [79,81,82].

Atrasentan is a highly selective endothelin receptor A receptor (ETAR) antagonist, the short-term use of which reportedly reduces albuminuria in patients with diabetic nephropathy [83]. The Study of Diabetic Nephropathy with Atrasentan (SONAR) tested the long-term effect of atrasentan in 2,648 patients with type 2 diabetes and overt albuminuria [84]. Atrasentan resulted in a significant reduction in the composite adverse kidney outcome of doubling serum creatinine or KFRT. A recent phase 2 study of sparsentan, a dual ETAR antagonist and ARB, also showed a significant reduction in proteinuria in patients with primary focal segmental glomerulosclerosis [85]. ETAR antagonists are reported to decrease BP [85,86]. The effects of ETAR antagonists are under investigation in other primary glomerular diseases (NCT03762850, NCT03493685, NCT04573478).

Finally, mineralocorticoid receptor antagonists (MRAs) have renoprotective and cardioprotective effects [87-89]. It also reduces BP in individuals with resistant hypertension [90,91]. Spironolactone, a first-generation nonselective MRA, was initially reported to provide renoprotective effects by reducing proteinuria and preserving eGFR in non-diabetic patients with CKD [87]. Recently, finerenone, a new-generation selective MRA, has emerged as a potential therapy. In the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study, finerenone reduced the risk of CKD progression and the development of CVEs in patients with CKD and type 2 diabetes [92]. These drugs are promising and expected to improve kidney survival and major clinical outcomes in combination with RASBs. Table 5 lists clinical trials of drug treatments [68,70-72,74,77,78,80,84,85,87,92,93].

Table 5.

Summary of major intervention trials with RAS blockers and new potential drugs for kidney outcomes

Trial		Number	Main inclusion criteria	Intervention	Control	Main outcome	Key findings	BP by intervention, mmHg
								Baseline	Follow-up
RAS blockers
	Lewis et al. [68]	409	Diabetic nephropathy	Catopril	Placebo	2XSCr	↓48% risk	SBP 135	SBP 128–134
	IDNT [70]	1,715	Type 2 diabetic nephropathy	Irbesartan	Placebo	Composite 2XSCr, KFRT, or all-cause death	↓20% risk	160/87	140/77
				Irbesartan	Amlodipine		↓23% risk	159/87	141/77
	RENAAL [71]	1,513	Type 2 diabetic nephropathy	Losartan	Placebo	Composite 2XSCr, KFRT or death	↓16% risk	152/82	140/74
	BENEDICT [72]	904	DM without microalbuminuria	Trandolapril + verapamil	Placebo	% Microalbuminuria	5.7% vs. 10%	151/88	139/80
				Trandolapril	Placebo		6.0% vs. 11.9%	151/88	139/81
Mineralocorticoid receptor antagonists
	Bianchi et al. [87]	165	CKD treated with RASi	Spironolactone + RASi	RASi	Proteinuria reduction	↓54.2%	133/79	127/76
						eGFR decline (mL/min/1.73 m2)	–6.2 vs. –9.0
	FIDELIO- CKD [92]	5,734	CKD, T2DM	Finerenone + RASi	RASi	Kidney failurea, eGFR decrease ≥ 40%, or renal death	↓18% risk	SBP 138
Endothelin receptor antagonists
	DUET [85]	109	FSGS, eGFR > 30 mL/min/1.73 m2, UPCR ≥ 1.0 g/g	Sparsentan	Irbesartan	Proteinuria reduction	↓26%	132/84	120/75
						FSGS PR	↓19% risk
	SONAR [84]	2,648	CKD, T2DM, albuminuria	Atrasentan	Placebo	2XSCr or KFRT	↓35% risk	136/75	139/-
SGLT2 inhibitors
	EMPA-REG post hoc [78]	7,020	T2DM, eGFR ≥ 30 mL/min/1.73 m2	Empagliflozin	Placebo	Macroalbuminuria, 2XCr, RRT, or renal death	↓39% risk	Patients with eGFR < 60 mL/min/1.73 m2: 136/75	-
						2XCr with eGFR ≤ 45 mL/min/1.73 m2	↓44% risk	Patients with eGFR ≥ 60 mL/min/1.73 m2: 135/77
	CANVAS [77]	10,142	T2DM, high CVD riskb	Canagliflozin	Placebo	Composite CVD death, nonfatal MI, nonfatal stroke	↓14% risk	136/78	131/73
						40% eGFR reduction, RRT, or renal death	↓40% risk
	DECLARE–TIMI 58 [93]	17,160	T2DM with CVDc or multiple CVD risk factorsd	Dapagliflozin	Placebo	40% eGFR reduction, KFRT, or renal/CVD death	↓ 24% risk	Patients with eGFR < 60 mL/min/1.73m2:	-
						40% eGFR reduction, KFRT, or renal death	↓ 47% risk	Patients with 60 ≤ eGFR < 90 mL/min/1.73 m2: 135/78
								Patients with eGFR ≥ 90 mL/min/1.73 m2: 135/79
	CREDENCE [74]	4,401	T2DM with albuminuric CKD	Canagliflozin	Placebo	Composite KFRT, 2XSCr, or renal/CVD death	↓30% risk	140/78	136/76
	DAPA-CKD [80]	4,300	G2–4 CKD, albuminuria	Dapagliflozin	Placebo	Composite eGFR decline ≥ 50%, KFRT, renal/CVD death	↓39% risk	137/77	-

RAS, renin-angiotensin system; BP, blood pressure; 2XSCr, doubling of serum creatinine; SBP, systolic blood pressure; IDNT, Irbesartan Diabetic Nephropathy Trial; KFRT, kidney failure with replacement therapy; RENAAL, Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; DM, diabetes mellitus; CKD, chronic kidney disease; RASi, renin-angiotensin system inhibitor; eGFR, estimated glomerular filtration rate; FIDELIO-CKD, Finerenone in Reducing Kidney Failure and Disease Progression in Chronic Kidney Disease; T2DM, type 2 diabetes mellitus; DUET, Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS); FSGS, focal segmental glomerulosclerosis; UPCR, urine protein-to-creatinine ratio; PR, partial remission; SONAR, Study of Diabetic Nephropathy with Atrasentan; SGLT2, sodium-glucose co-transporter 2; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; RRT, renal replacement therapy; CANVAS, Canagliflozin Cardiovascular Assessment Study; CVD, cardiovascular disease; MI, myocardial infarction; DECLARE–TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease.

KFRT or an eGFR less than 15 mL/min/1.73 m2.

Age ≥ 30 years with symptomatic atherosclerotic CVD history or age ≥ 50 years with ≥ 2 risk factors for CVD: diabetes duration ≥ 10 years, SBP ≥ 140 mmHg while antihypertensive agents, current smoking, microalbuminuria or macroalbuminuria, or high-density lipoprotein cholesterol level < 1 mmol/L (38.7 mg/dL).

Age ≥ 40 years and either ischemic heart disease, cerebrovascular disease, or peripheral arterial disease.

Age ≥ 55 years (men) or ≥ 60 years (women) plus at least one of dyslipidemia, hypertension, or current tobacco use.

CONCLUSIONS

In patients with CKD, the scope of ‘optimal BP control’ should encompass improved cardiovascular outcomes, reduced mortality, and delayed CKD progression. However, despite much research, the optimal BP reduction to achieve these goals has not been determined. Table 6 presents a summary of BP control based on the KDIGO 2021 guidelines. These recommendations and suggestions are helpful in clinical practice, and the guidelines support intensive BP control targeting an SBP of < 120 mmHg because the cardiovascular benefits of SBP intervention outweigh the risk of kidney injury associated with the lower BP target. However, many uncertainties remain to be resolved in future trials. We anticipate that a greater number of well-designed RCTs will assess the effects of intensive BP control by various interventions in diverse groups of patients with CKD with and without diabetes, a high cardiovascular risk, or proteinuria, and with early versus late CKD.

Table 6.

Key BP control recommendations and suggestions by the KDIGO 2021 guideline

BP management in patients with non-dialysis CKD, with, or without diabetes.
Recommendation 1	We recommend adults with high BP and CKD be treated with a target SBP < 120 mmHg, when tolerated, using standardized office BP measurement (2B).
Recommendation 2	We recommend starting RASi (ACEi or ARB) for people with high BP, CKD, and severely increased albuminuria (G1–G4, A3) without diabetes (1B).
Recommendation 3	We recommend starting RASi (ACEi or ARB) for people with high BP, CKD, and moderately increased albuminuria (G1–G4, A2) without diabetes (2C).
Recommendation 4	We recommend starting RASi (ACEi or ARB) for people with high BP, CKD, and moderately-to-severely increased albuminuria (G1–G4, A2, and A3) with diabetes (1B).
Recommendation 5	We recommend avoiding any combination of ACEi, ARB, and direct renin inhibitor (DRI) therapy in patients with CKD, with or without diabetes (1B).

1B, strong recommendation based on moderate quality evidence; 2C, weak recommendation based on low quality evidence; A1, ACR < 30 mg/g (< 3 mg/mmol); A2, ACR 30–300 mg/g (3–30 mg/mmol); A3, ACR > 300 mg/g (> 30 mg/mmol).

BP, blood pressure; KDIGO, Kidney Disease: Improving Global Outcomes; CKD, chronic kidney disease; SBP, systolic blood pressure; RASi, renin-angiotensin system inhibitor; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.