Optimizing Renin-Angiotensin System Inhibitor Use in CKD

Introduction

Renin-angiotensin system inhibitors (RASi), and specifically angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARBs), decrease blood pressure (BP), reduce mortality in heart failure, decrease proteinuria, and slow the progressive loss of kidney function in patients with CKD (¹). Yet RASi continue to be underused for reasons that may stem from their known “functional” side effects: hyperkalemia secondary to inhibition of the effects of aldosterone in the distal nephron and an acute reversible decline in glomerular filtration rate (GFR) usually encountered at the initiation of therapy (²). We discuss our approach to optimizing RASi use in patients with CKD and high BP, guided by the recommendations and practice points from the Kidney Disease Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease (³).

Patient Presentation

A 59-year-old man with CKD and obesity was referred for management of high BP diagnosed 6 months ago. He felt well and had no other relevant comorbid conditions. Pertinent laboratory studies included serum creatinine of 2.1 mg/dl and estimated GFR of 33 ml/min per 1.73 m² with urine albumin-to-creatinine ratio (UACR) of 500 mg/g. On examination, the average of three BP readings taken after 5 minutes of rest was 160/90 mm Hg and heart rate was 75 beats per minute. He had mild lower extremity edema, and the rest of the examination was unremarkable. Current medications included amlodipine 10 mg daily and chlorthalidone 25 mg daily.

Deciding When to Initiate RASi

While a discussion regarding BP targets in CKD is beyond the scope of this article, our patient’s BP was clearly too high. The KDIGO BP guideline recommends initiating RASi in most patients with high BP and CKD, but the strength of the recommendations varies. For patients such as ours who have high BP and CKD without diabetes but with severely increased albuminuria (UACR >300 mg/g), the evidence supporting RASi initiation is strong (Grade 1B), while the evidence in patients without diabetes and only albuminuria (UACR 30–300 mg/g) is weaker (Grade 2C) (³). For patients with high BP and CKD with diabetes, the evidence for RASi initiation is strong for moderately and severely increased albuminuria (Grade 1B). The KDIGO BP guideline (³) harmonizes with guidelines from the American College of Cardiology/American Heart Association (⁴) and the European Society of Cardiology/European Society of Hypertension (⁵), and with the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (⁶).

There are certain CKD subgroups for whom the benefits of RASi are less certain. For patients with high BP, CKD, and no albuminuria regardless of diabetes status, there is no clear benefit of RASi in slowing CKD progression but some evidence of cardiovascular benefit, leading the KDIGO BP guideline to suggest the use of RASi as an ungraded practice point in that population. The benefits of RASi initiation in patients with estimated GFR <15 ml/min per 1.73 m² have never been tested in a randomized trial, and thus the statements above do not apply to that population, nor do they necessarily apply to patients receiving maintenance dialysis. Despite low quality of evidence, the use of ARBs in kidney transplant recipients was strongly recommended (Grade 1C) (³).

Incorporating RASi into Existing BP-Lowering Regimens

No specific combination of BP-lowering medications is superior to another in CKD. We tend to follow the algorithm for the intensive treatment group from the Systolic BP Intervention Trial (SPRINT), which specified using combination therapy with a RASi and a thiazide-type diuretic and/or a calcium channel blocker. Our patient had mild peripheral edema, which could be explained by underlying CKD, dietary sodium indiscretion, and by the use of amlodipine, a dihydropyridine calcium channel blocker. Calcium channel blockers preferentially dilate the precapillary vessels, which promotes the extravasation of fluid into the interstitial space, leading to dose-dependent edema. Adding a RASi in this scenario leads to dilation of the postcapillary vessels, reducing the transcapillary pressure gradient and reducing the edema. Our patient was using chlorthalidone, a thiazide-like diuretic, which is a logical choice to continue given the edema. Notably, chlorthalidone can induce a diuresis and lower BP even in patients with advanced CKD (⁷) and is our preferred diuretic choice.

Studies have demonstrated clinical benefit of RASi for the desired cardiovascular and kidney benefits, including the more recent sodium-glucose cotransporter-2 inhibitor (SGLT2i) trials, especially when prescribing RASi at the maximally tolerated dose. In our patient, we would preferentially reduce the dose of the calcium channel blocker if needed to allow up-titration of the RASi. Once the patient is on the maximally tolerated RASi dose, we would consider adding on an SGLT2i, which might necessitate down-titration of chlorthalidone given the osmotic diuresis induced by SGLT2i.

Dietary sodium restriction reduces BP and potentiates the beneficial effects of RASi through effects on local tissue RAS expression in the kidney, vasculature, brain, and the immune system (⁸). We therefore counsel all patients on the importance of limiting sodium intake to <2 g per day and refer patients to a dietitian when available.

Monitoring for Adverse Events

Mechanistically, RASi block angiotensin II, leading to vasodilation of the efferent arterioles in the glomeruli, decreased intraglomerular pressure, and a decline in GFR (⁹,¹⁰). The common teaching is that a threshold of >30% rise in serum creatinine should prompt further evaluation for other conditions such as volume depletion, nonsteroidal anti-inflammatory medication use, or underlying bilateral renal artery stenosis. There is, however, no definitive evidence that supports the >30% rise in serum creatinine as the threshold for discontinuing or reducing the dose of RASi, and a recent observational study showed poorer outcomes when RASi was stopped after a decline in estimated GFR (⁹). Treatment decisions should therefore be individualized.

In addition, RASi interfere with the stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland, which can lead to reduced potassium excretion and hyperkalemia. The availability of novel oral potassium-binding agents has improved the safety and tolerability of RASi. We usually check the serum creatinine and potassium within 2–4 weeks of initiation or intensification of RASi to evaluate and manage these side effects (Figure 1) (⁶). Two large trials that enrolled patients with CKD with or without diabetes demonstrated that using any combination of ACEi, ARB, or direct renin inhibitors had higher rates of hyperkalemia and acute kidney injury without evidence of clinical benefit (¹⁰,¹¹), and is therefore not recommended.

Figure 1.: Monitoring of serum creatinine and potassium during ACEi or ARB treatment. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug. Reprinted and adapted from ref. ⁶, with permission.

Patient Follow-Up

We started the patient on lisinopril 10 mg daily. Four weeks later, serum creatinine was 2.5 mg/dl and serum potassium was 4.8 mg/dl. The dose of lisinopril was increased to 20 mg daily, and serum creatinine continued to range between 2.3 and 2.5 mg/dl. After another 4 weeks, patient’s systolic BP decreased to 110–120 mm Hg and UACR decreased to 300 mg/g. The lisinopril was then increased to the maximum dose of 40 mg daily, the serum creatinine and potassium remained stable, and UACR improved to 150 mg/g. We plan to discuss SGLT2i initiation at the next clinic visit.

Among patients with CKD and high BP, RASi have been shown to have beneficial effects on cardiovascular and kidney outcomes, yet they continue to be underused in this population. Clinicians should always consider whether to initiate RASi in appropriate candidates and adjust the medication regimens with a goal of maximizing RASi dosing to improve optimized outcomes.

Disclosures

T.I. Chang reports consultancy agreements with Bayer, Gilead, Novo Nordisk, and Tricida; receiving honoraria from the American Society of Nephrology; serving on the Kidney Disease Improving Global Outcomes Executive Committee and the National Kidney Foundation Medical Advisory Board; and was a member of the KDIGO BP in CKD guidelines writing committee. E.V. Lerma reports employment with Associates in Nephrology; consultancy agreements with Bayer and Vifor; ownership interest in Fresenius Joint Venture; receiving honoraria from Elsevier Publishing, McGraw-Hill Publishing, National Kidney Foundation, UpToDate, and Wolters Kluwer Publishing; serving as a scientific advisor or editorial board member of Journal of Clinical Lipidology, International Urology and Nephrology, Journal of Vascular Access, Prescribers Letter, Renal and Urology News, ASN Kidney News, Reviews in Endocrinology and Metabolic Disorders, and American Journal of Kidney Diseases Blog; serving as a Visual Abstract Editor for CJASN; speakers bureau for AstraZeneca, Bayer, Otsuka, and Vifor; and KDIGO Knowledge Translation Lead.

Funding

None.